Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[O:12][C:11]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[F:20])=[N:10][C:9]=1[CH:21]([NH:26][CH2:27][C@H:28]1[C@@H:32]([F:33])[CH2:31][N:30]([C:34]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:35])[CH2:29]1)[C:22]([CH3:25])([CH3:24])[CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[C:53]([O:56][C@@H:57]([CH3:61])[C:58](Cl)=[O:59])(=[O:55])[CH3:54]>ClCCl>[C:53]([O:56][C@@H:57]([CH3:61])[C:58]([N:26]([CH2:27][C@H:28]1[C@@H:32]([F:33])[CH2:31][N:30]([C:34]([O:36][CH2:37][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)=[O:35])[CH2:29]1)[C@@H:21]([C:9]1[N:10]=[C:11]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[F:20])[O:12][C:8]=1[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:22]([CH3:25])([CH3:24])[CH3:23])=[O:59])(=[O:55])[CH3:54]
Reactant: CC(C)(C)C(NC[C@@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1F)c1nc(-c2cc(F)ccc2F)oc1Cc1ccccc1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)O[C@@H](C)C(=O)N(C[C@@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1F)[C@@H](c1nc(-c2cc(F)ccc2F)oc1Cc1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 17 %

Procedure:
To a solution of (±)-(3R,4R)-benzyl 3-((1-(5-benzyl-2-(2,5-difluorophenyl)oxazol-4-yl)-2,2-dimethylpropylamino)methyl)-4-fluoropyrrolidine-1-carboxylate (37 mg, 0.063 mmol) in dichloromethane (0.63 mL, 0.1 M solution) at room temperature was added N,N-diisopropylethylamine (55 μL, 0.313 mmol). (S)-1-Chloro-1-oxopropan-2-yl acetate (15.8 μL, 0.125 mmol) was then added dropwise over 2 min. The resulting solution was stirred at room temperature for 2 h. The reaction mixture was quenched with saturated NaHCO3 solution and extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Two diastereomers were separated on preparative TLC (2% MeOH in dichloromethane). The polar diastereomer, (3R,4R)-benzyl 3-(((S)-2-acetoxy-N-((R)-1-(5-benzyl-2-(2,5-difluorophenyl)oxazol-4-yl)-2,2-dimethylpropyl)propanamido)methyl)-4-fluoropyrrolidine-1-carboxylate, was obtained in 17% yield (7.5 mg). LC/MS (uplc): MH+ 706.4, 1.34 min. The nonpolar diastereomer, (3R,4R)-benzyl 3-(((S)-2-acetoxy-N—((S)-1-(5-benzyl-2-(2,5-difluorophenyl)oxazol-4-yl)-2,2-dimethylpropyl)propanamido)methyl)-4-fluoropyrrolidine-1-carboxylate, was obtained in 16% yield (7.0 mg). LC/MS (uplc): MH+ 706.4, 1.35 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[F:15][C:16]([F:32])([F:31])[C:17]1[O:21][N:20]=[C:19]([C:22]2[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=2)[C:25](O)=[O:26])[N:18]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][N:12]([C:25]([C:24]3[CH:28]=[CH:29][CH:30]=[C:22]([C:19]4[N:18]=[C:17]([C:16]([F:31])([F:15])[F:32])[O:21][N:20]=4)[CH:23]=3)=[O:26])[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(N2CCNCC2)c1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Product: COc1cccc(N2CCN(C(=O)c3cccc(-c4noc(C(F)(F)F)n4)c3)CC2)c1
Yield: 49 %

Procedure:
This compound was synthesized from 1-(3-methoxyphenyl)piperazine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described for example 37 step 3 (110 mg, yield 49%). 1H NMR (400 MHz, CDCl3) δ 8.22-8.20 (m, 2H), 7.67-7.60 (m, 2H), 7.23-7.19 (m, 1H), 6.57-6.54 (m, 1H), 6.49-6.48 (m, 2H), 3.98 (m, 2H), 3.80 (s, 3H), 3.61 (m, 2H), 3.30-3.16 (m, 4H). MS (ESI) m/z: Calculated for C21H18F3N4O3: 432.14. found: 433.2 (M+H)+
Reaction SMILES: [O:1]([CH2:19][CH:20]([CH3:35])[CH2:21][CH2:22][CH2:23][C:24]([CH:27]1[O:31][C:30]([CH2:33][Br:34])([OH:32])[CH2:29][CH2:28]1)([OH:26])[CH3:25])[Si:2]([C:15]([CH3:18])([CH3:17])[CH3:16])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:36](OCC(C)CCCC(C1OC(CBr)(OC)CC1)(O)C)C1C=CC=CC=1>>[O:1]([CH2:19][CH:20]([CH3:35])[CH2:21][CH2:22][CH2:23][C:24]([CH:27]1[O:31][C:30]([CH2:33][Br:34])([O:32][CH3:36])[CH2:29][CH2:28]1)([OH:26])[CH3:25])[Si:2]([C:15]([CH3:18])([CH3:16])[CH3:17])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COC1(CBr)CCC(C(C)(O)CCCC(C)COCc2ccccc2)O1
Reactant: CC(CCCC(C)(O)C1CCC(O)(CBr)O1)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Product: COC1(CBr)CCC(C(C)(O)CCCC(C)CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)O1

Procedure:
7-t-Butyldiphenylsiloxy-2-[2-bromomethyl-2-methoxy-tetrahydrofuran-5-yl]-6-methyl-heptan-2-ol is prepared as a mixture of cis:trans isomers by employing 7-t-butyldiphenylsiloxy-2-[2-bromomethyl-2-hydroxy-tetrahydrofuran-5-yl]-6-methyl-heptan-2-ol (1.33 g) in place of 7-benzyloxy-2-(2-bromomethyl-2-hydroxy-tetrahydrofuran-5-yl)-6-methyl-heptan-2-ol in the process for the preparation of 7-benzyloxy-2-[2-bromomethyl-2-methoxy-tetrahydrofuran-5-yl]-6-methyl-heptan-2-ol. The mixture of cis and trans isomers is separated by chromatography on silica gel (ethyl acetate:hexane gradient) to give the cis isomer as a yellow oil (0.324 g) and then the trans isomer as a yellow oil (0.151 g):
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([OH:11])[C:9]#[CH:10]>[Cu]I.C(NCC)C>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:10]#[C:9][CH2:8][OH:11]
Reactant: Brc1ccccn1
Reactant: C#CCO
Agent: [Cu]I
Solvent: CCNCC
Product: OCC#Cc1ccccn1
Yield: 77 %

Procedure:
The mixture that consists of 16.6 ml (173 mmol) of 2-bromopyridine, 21.6 ml of propargyl alcohol, 2.5 g of palladium-bis-triphenylphosphine-dichloride and 173 mg of copper(I) iodide is mixed with 510 ml of diethylamine and heated for 1.5 hours to 80° C. After filtration and removal of the solvent, the residue is purified by chromatography on fine silica gel with a gradient system that consists of n-hexane and ethyl acetate. 17.8 g (134 mmol, 77%) of the title compound is isolated as a colorless oil.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4][C@H:3]1[F:15].[O-]S([O-])(=O)=O.[Na+].[Na+].[O:23]=[C:24]1[NH:29][C:28]2[CH:30]=[C:31]([CH:34]=O)[CH:32]=[CH:33][C:27]=2[S:26][CH2:25]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)CCl.CCO>[F:15][C@H:3]1[CH:2]([NH:1][CH2:34][C:31]2[CH:32]=[CH:33][C:27]3[S:26][CH2:25][C:24](=[O:23])[NH:29][C:28]=3[CH:30]=2)[CH2:7][CH2:6][NH:5][CH2:4]1
Reactant: O=Cc1ccc2c(c1)NC(=O)CS2
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)[C@H](F)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCO
Product: O=C1CSc2ccc(CNC3CCNC[C@H]3F)cc2N1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of cis-4-amino-1-tert-butoxycarbonyl-3-fluoropiperidine (5a) (340 mg, 1.60 mmole) in ClCH2CH2Cl (8 mL) and EtOH (0.8 mL) was treated with anhydrous Na2SO4 (450 mg) and 3-oxo-3,4-dihydro-2-benzo[1,4]thiazine-6-carboxaldehyde (1n) (330 mg, 1.80 mmole). The resulting solution was stirred at room temperature for 6 hr, then sodium triacetoxy borohydride (500 mg, 2.40 mmole) was added. The resulting slurry was stirred at room temperature for a further 10 hr, then was quenched by the addition of water (2 mL) and the volatiles were removed in vacuo. The residue was partitioned between EtOAc (2×50 mL) and brine (20 mL). The organic phases were combined, dried (MgSO4), and concentrated in vacuo. The residue was passed through a column of silica gel (100% ethyl acetate), the eluant was concentrated in vacuo and the residue was disolved in 10 mL of CH2Cl2 and treated with 1.25 mL of 4N HCl in dioxane for 2 h. The volitiles were removed in vacuo and the residue was dissolved in 10 mL of CH3OH. MP-carbonate resin (1.08 g) was added and stirred at rt for 1 h. The reaction was filtered to remove the resin and concentration under reduced pressure gave the desired compound as a white solid:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:6]([NH2:8])[CH:7]=1.[CH3:16][O:17][C:18]1[CH:19]=[CH:20][C:21]([O:26][CH2:27][CH2:28][O:29][S:30]([C:33]2[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=2)(=[O:32])=[O:31])=[C:22]([CH:25]=1)[CH:23]=O.[Na]>ClC(Cl)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:6]([NH:8][CH2:23][C:22]2[CH:25]=[C:18]([O:17][CH3:16])[CH:19]=[CH:20][C:21]=2[O:26][CH2:27][CH2:28][O:29][S:30]([C:33]2[CH:34]=[CH:35][C:36]([CH3:37])=[CH:38][CH:39]=2)(=[O:32])=[O:31])[CH:7]=1
Reactant: COc1ccc(OCCOS(=O)(=O)c2ccc(C)cc2)c(C=O)c1
Reactant: Nc1cc(F)ccc1Oc1ccccc1
Agent: [Na]
Solvent: CC(Cl)Cl
Solvent: O
Product: COc1ccc(OCCOS(=O)(=O)c2ccc(C)cc2)c(CNc2cc(F)ccc2Oc2ccccc2)c1
Yield: 71 %

Procedure:
To stirred solution of 9.1 g (45 mmol) 1b, 15.8 g (45 mmol) 5a and one drop of glacial acid in 60 ml dichloroethane (pH=5) were added 14.8 g (70 mmol) sodium tris-acetoxy hydro borane. The reaction mixture was stirred over night and diluted with 5 ml water. The pH value was adjusted with aqueous sodium hydroxyd solution to pH=8-9. The mixture was extracted three times with dichloromethane. The combined organic phases were washed with water and brine and were dried with magnesium sulfate. The desired crude product 5b was obtained in 71% yield (17.2 g, 32.0 mmol) as yellow oil. The crude product 5b was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12](N(OC)C)=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:18]1([Mg]Br)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: Br[Mg]c1ccccc1
Reactant: COc1ccc(CC(=O)N(C)OC)cc1OC
Solvent: C1CCOC1
Product: COc1ccc(CC(=O)c2ccccc2)cc1OC
Reaction time: 2 h
Yield: 60.4 %

Procedure:
Under N2, to a mixture of 2-(3,4-dimethoxyphenyl)-N-methoxy-N-methylacetamide (200 mg, 0.84 mmol) in anhydrous THF was added phenylmagnesium bromide (2.1 mL, 2.1 mmol) at −78° C., and the mixture was stirred for 2 hours. When TLC indicated that the start material was consumed, the reaction mixture was diluted with EtOAc, washed with water and brine, concentrated, and purified by column chromatography (PE:EtOAc=20:1) to give Intermediate 7 (130 mg, yield 61%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:19][CH2:20][CH3:21])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].C(=O)([O-])[O-].[Na+].[Na+].[N+:28]([O-])([N+]([O-])=O)=[O:29]>O1CCCC1.C(Cl)Cl>[Cl:1][CH2:2][CH2:3][N:4]([N:28]=[O:29])[C:5]([N:7]([CH2:19][CH2:20][CH3:21])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: O=[N+]([O-])[N+](=O)[O-]
Reactant: CCCN(C(=O)NCCCl)C1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCCN(C(=O)N(CCCl)N=O)C1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Yield: 77.9 %

Procedure:
3.3 g of 1-(2-chloroethyl)-3-n-propyl-3-D-galactopyranosylurea are dissolved in a mixture of 60 ml of tetrahydrofuran and 60 ml of methylene chloride, and 15 g of sodium carbonate anhydrate are added thereto. 5 g of nitrogen tetroxide gas are introduced into the mixture for 10 minutes under ice-cooling. The mixture is treated in the same manner as described in Example 2. 2.8 g of 1-(2-chloroethyl)-1-nitroso-3-n-propyl-3-D-galactopyranosylurea are thereby obtained as pale yellow caramel. [α]D23 +18.0°(C=1.0, methanol)
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[CH2:3][N:4]([CH3:9])[C:5](=[O:8])[CH2:6][OH:7].[OH-].[K+].Cl[C:15]1[S:16][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:18][N:19]=1>C(#N)C>[F:1][C:2]([F:10])([F:11])[CH2:3][N:4]([CH3:9])[C:5](=[O:8])[CH2:6][O:7][C:15]1[S:16][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:18][N:19]=1
Reactant: Clc1nnc(-c2ccccc2)s1
Reactant: CN(CC(F)(F)F)C(=O)CO
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: CN(CC(F)(F)F)C(=O)COc1nnc(-c2ccccc2)s1
Reaction time: 15 h
Yield: 59.4 %

Procedure:
12 g (0.07 mol) of N-(2,2,2-trifluoroethyl)-N-methyl-hydroxyacetic acid amide and 4.5 g of potassium hydroxide powder were dispersed in 100 ml of acetonitrile at 0° C., and a solution of 12 g of 2-chloro-5-phenyl-1,3,4-thiadiazole in 50 ml of acetonitrile was added at 10° C. The mixture was stirred at 30° to 40° C. for 15 hours and concentrated, the concentrate was diluted with water and the mixture was filtered. The crystalline product was recrystallized from isopropanol. 12 g (63% of theory) of N-(2,2,2-trifluoroethyl)-N-methyl-5-phenyl-1,3,4-thiadiazol-2-yl-oxyacetic acid amide of melting point 123° C. were obtained.
Reaction SMILES: [C:1]([C:3](=[C:7](SC)[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)[C:4]([NH2:6])=[O:5])#[N:2].Cl.[NH:18]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[NH2:19].[OH-].[Na+].CO>C(Cl)Cl>[NH2:2][C:1]1[N:18]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:19]=[C:7]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: CSC(=C(C#N)C(N)=O)c1ccc(C)cc1
Reactant: CCOC(=O)CNN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)Cn1nc(-c2ccc(C)cc2)c(C(N)=O)c1N
Yield: 27.5 %

Procedure:
The title compound was prepared from 2-cyano-3-methylthio-3-(4-tolyl)acrylamide (425 mg, 1.83 mmol), ethyl hydrazinoacetate hydrochloride (311 mg, 2.01 mmol) and sodium hydroxide (80 mg, 2.01 mmol) following the procedure used for the compound of Example 12. The crude product was subjected to column chromatography (SiO2, 10% methanol in CH2Cl2) and was recrystallised from ethyl acetate to give the title compound as white crystals (152 mg) m.p. 179°. δH (CDCl3) 7.43 (2H, d, J 8.1 Hz), 7.26 (2H, d, J 8.1 Hz), 5.56 (2H, br s), 5.22 (2H, br s), 4.77 (2H, s), 4.27 (2H, q, J 7.2 Hz), 2.40 (3H, s) and 1.32 (3H, t, J 7.2 Hz).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:17][CH2:18][C:19]#[N:20])[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Sn]([N:34]=[N+:35]=[N-:36])(CCCC)CCCC)CCC>C1COCC1>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:17][CH2:18][C:19]1[NH:36][N:35]=[N:34][N:20]=1)[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: COC(=O)[C@H](CCC#N)NC(=O)OCc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)[C@H](CCc1nnn[nH]1)NC(=O)OCc1ccccc1

Procedure:
A mixture of methyl (2S)-2-benzyloxycarbonylamino-4-cyanobutyrate (10 g), tri-n-butyltin azide [prepared according to the method in Rec. Trav. Chim. Pavs-Bas, 1963, 81, 286; 12 g] and THF (60 ml) was stirred and heated to reflux for 40 hours. The mixture was evaporated. The resultant brown oil was triturated in diethyl ether which had been saturated with hydrogen chloride gas. The precipitate was isolated and washed with diethyl ether. There was thus obtained methyl (2S)-2-benzyloxycarbonyl-amino-4-(tetrazol-5-yl)butyrate (2.23 g, 32%);
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].CN(C)C=O.[C:21]([C:23]([C:29]#[N:30])=[C:24](C#N)[C:25]#[N:26])#[N:22]>O>[CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([C:24]([C:25]#[N:26])=[C:23]([C:29]#[N:30])[C:21]#[N:22])=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2]
Reactant: CCn1c2ccccc2c2ccccc21
Reactant: N#CC(C#N)=C(C#N)C#N
Solvent: CN(C)C=O
Solvent: O
Product: CCn1c2ccccc2c2cc(C(C#N)=C(C#N)C#N)ccc21
Temperature: 100 °C

Procedure:
About 1 gram (5.24 × 10-3 3 moles) N-ethyl carbazole and 20 milliliters of dimethylformamide are placed in a 50 milliliter one neck flask equipped with a magnetic stirring bar and a nitrogen inlet tube. The flask is purged of air with nitrogen, the contents of the flask agitated and about 0.67 grams (5.24 × 10-3 moles) of tetracyanoethylene introduced into the flask. Upon the admixture of these materials the contents of the flask turns deep blue. This mixture is heated to 100° C for 20 hours, the contents of the flask poured into 60 milliliters of water at room temperature and the redish brown crystals thereby precipitated isolated from the solution by filtration and washed with ethanol. Yield: 1.13 grams brick red crystals m. p. 239°-241° C. Analysis: calculated, carbon 77, hydrogen 4.08, nitrogen 18.92; actual, carbon 77.24, hydrogen 4.07, nitrogen 18.78.
Reaction SMILES: N1C=CC=CC=1.[F:7]N1N=C(F)C=C(F)N1.[NH2:16][C:17]1([C:22]2[N:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:23]=2[C:24](O)=[O:25])[CH2:21][CH2:20][CH2:19][CH2:18]1>ClCCl>[NH2:16][C:17]1([C:22]2[N:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:23]=2[C:24]([F:7])=[O:25])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: FC1=CC(F)=NN(F)N1
Reactant: NC1(c2nc(Cl)ccc2C(=O)O)CCCC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: NC1(c2nc(Cl)ccc2C(=O)F)CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.3 %

Procedure:
0.34 ml (4.15 mmol) of pyridine and 0.53 ml (6.23 mmol) of 2,4,6-trifluorotriazine are added to a suspension of 1.0 g (4.15 mmol) of 2-(aminocyclopentyl)-6-chloronicotinic acid in 12 ml of dichloromethane. The mixture is stirred for 2 hours at ambient temperature and then diluted with dichloromethane. The organic phase is washed twice with an ice-cold solution of NaHCO3aq and then dried over Na2SO4, filtered, and concentrated under reduced pressure. 1 g of product is obtained in the form of a brown oil, which is used immediately in the next step. Quantitative crude yield.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[Br:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1.[N:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:22]>ClCCl>[Br:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]([N:21]([OH:22])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:18])=[CH:15][CH:14]=1
Reactant: O=Nc1ccccc1
Reactant: O=Cc1ccc(Br)cc1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(c1ccc(Br)cc1)N(O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
DBU (3.8 mg, 0.025 mmol) was added under argon to a solution of 4-bromobenzaldehyde (185 mg, 1 mmol), nitrosobenzene (107 mg, 1 mmol) and catalyst (1.82 mg, 0.005 mmol) in dichloromethane (5 mL). The reaction mixture was stirred at room temperature for 10 min. The solvent was removed under vacuum, and the residue was purified by flash silica gel column chromatography using hexane and ethyl acetate as the eluents.
Reaction SMILES: C[O:2][C:3](=[O:25])[C@@H:4]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([C:13](=[O:15])[NH2:14])=[CH:8][C:7]=1[CH3:16].[Li+].[OH-]>C1COCC1>[C:21]([O:20][C:18]([NH:17][C@@H:4]([CH2:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([C:13](=[O:15])[NH2:14])=[CH:8][C:7]=1[CH3:16])[C:3]([OH:25])=[O:2])=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: COC(=O)[C@H](Cc1c(C)cc(C(N)=O)cc1C)NC(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(C(N)=O)cc(C)c1C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Temperature: 0 °C

Procedure:
Into an ice-cooled solution of methyl ester from Step C (2.99 g, 8.54 mmol) in THF (50 mL) was added an aqueous LiOH solution (1N, 50 mL) and stirred at 0° C. Upon consumption of the starting materials, the organic solvents were removed and the aqueous phase was neutralized with cooled 1N HCl at 0° C., and extracted with EtOAc, and dried over Na2SO4 overnight. Filtration and evaporation to dryness led to the title acid (S)-2-tert-butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethylphenyl)propionic acid (2.51 g, 87%); 1H NMR (300 MHz, DMSO-d6): δ 1.30 (9H, s), 2.32 (6H, s), 2.95 (1H, dd, J=8.8, 13.9 Hz), 3.10 (1H, dd, J=6.2, 14.0 Hz), 4.02-4.12 (1H, m), 7.18-7.23 (2H, m), 7.48 (2H, s), 7.80 (1H, s); MS (ES+) (relative intensity): 236.9 (6) (M−Boc)+.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[S:10][CH:9]=[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=3)[C:6]=2[N:7]=1.[O:20]1[CH2:25][CH2:24][N:23]([C:26]2[N:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=2)[CH2:22][CH2:21]1>>[O:20]1[CH2:25][CH2:24][N:23]([C:26]2[N:31]=[CH:30][C:29]([NH:32][C:2]3[N:3]=[CH:4][C:5]4[S:10][CH:9]=[C:8]([C:11]5[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=5)[C:6]=4[N:7]=3)=[CH:28][CH:27]=2)[CH2:22][CH2:21]1
Reactant: O=[N+]([O-])c1cccc(-c2csc3cnc(Cl)nc23)c1
Reactant: Nc1ccc(N2CCOCC2)nc1
Product: O=[N+]([O-])c1cccc(-c2csc3cnc(Nc4ccc(N5CCOCC5)nc4)nc23)c1
Yield: 80.6 %

Procedure:
N-(6-Morpholinopyridin-3-yl)-7-(3-nitrophenyl)thieno[3,2-d]pyrimidin-2-amine (480 mg, 78% yield) was prepared in the same manner as Step 10 of Example 1 using 2-chloro-7-(3-nitrophenyl)thieno[3,2-d]pyrimidine (400 mg, 1.37 mmol) and 6-morpholinopyridin-3-amine (369 mg, 2.06 mmol).
Reaction SMILES: [CH:1]([C:3]1[O:11][C:10]2[CH:9]=[CH:8][N:7]=[C:6]([NH:12][C:13](=[O:20])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:5]=2[CH:4]=1)=O.[NH2:21]/[C:22](/[CH3:26])=[CH:23]\[C:24]#[N:25]>C(O)(=O)C>[C:24]([C:23]1[CH:1]([C:3]2[O:11][C:10]3[CH:9]=[CH:8][N:7]=[C:6]([NH:12][C:13](=[O:20])[C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:5]=3[CH:4]=2)[C:5]([C:6]#[N:7])=[C:4]([CH3:3])[NH:21][C:22]=1[CH3:26])#[N:25]
Reactant: C/C(N)=C/C#N
Reactant: O=Cc1cc2c(NC(=O)c3ccccc3)nccc2o1
Solvent: CC(=O)O
Product: CC1=C(C#N)C(c2cc3c(NC(=O)c4ccccc4)nccc3o2)C(C#N)=C(C)N1
Temperature: 110 °C
Reaction time: 0.75 h
Yield: 87.5 %

Procedure:
A mixture of 69 mg (0.260 mmol) N-(2-formylfuro[3,2-c]pyridin-4-yl)benzamide (Example 3A) and 43 mg (0.52 mmol) (2Z)-3-aminobut-2-enenitrile in acetic acid (4.5 ml) was stirred for 45 min at 110° C. Upon cooling, the reaction mixture was concentrated under reduced pressure, and the residue was treated with ethyl acetate and saturated aq. sodium carbonate solution. The organic layer was separated, washed with brine and water, dried over sodium sulfate, and concentrated under reduced pressure to afford the title compound (45 mg, 43% of th.) as a pale yellow solid.
Reaction SMILES: [N+]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:5]=1[C:6]#[N:7])([O-])=O.[CH3:15][C:16]1([CH3:32])[O:31][C@H:19]2[O:20][CH:21]([CH2:29][OH:30])[C@@H:22]3[O:26][C:25]([CH3:28])([CH3:27])[O:24][C@@H:23]3[C@@H:18]2[O:17]1>>[N+:12]([C:8]1[CH:9]=[CH:10][CH:11]=[C:4]([O:30][CH2:29][CH:21]2[O:20][C@@H:19]3[O:31][C:16]([CH3:32])([CH3:15])[O:17][C@H:18]3[C@H:23]3[O:24][C:25]([CH3:28])([CH3:27])[O:26][C@@H:22]23)[C:5]=1[C:6]#[N:7])([O-:14])=[O:13]
Reactant: CC1(C)O[C@H]2OC(CO)[C@@H]3OC(C)(C)O[C@@H]3[C@@H]2O1
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Product: CC1(C)O[C@H]2OC(COc3cccc([N+](=O)[O-])c3C#N)[C@@H]3OC(C)(C)O[C@@H]3[C@@H]2O1
Yield: 59 %

Procedure:
Prepared as in Example 111c from 2,6 dinitrobenzonitrile and ((3aR,5aS,8as,8bS)-2,2,7,7-tetramethyltetrahydro-3aH-bis[1,3]dioxolo[4,5-b:4′,5′-d]pyran-5-yl)methanol in 59% yield as white sticky material. MS 408 (MH+), 424 (MH2O+).
Reaction SMILES: C(OC([NH:11][CH:12]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](=[CH:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:13]1)=O)C1C=CC=CC=1>C(O)C.[Pd]>[NH2:11][CH:12]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:13]1
Reactant: CCOC(=O)C=C1CC(NC(=O)OCc2ccccc2)Cc2ccccc21
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CC1CC(N)Cc2ccccc21
Yield: 85.4 %

Procedure:
To a solution of 3-benzyloxycarbonylamino-1-carboethoxymethylene-1,2,3,4-tetrahydronaphthalene (2.7:1 stereoisomeric mixture, 55 mg) in ethanol (2 mL) stirring at room temperature was added 10% palladium on carbon (6 mg). The reaction mixture was hydrogenated (balloon) for 3 d. At the conclusion of this period, the reaction mixture was filtered through Celite® and evaporated under vacuum to obtain the title compound (30 mg) as a cis-trans mixture which was inseparable by HPLC.