Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[NH4+].[Cl:3][C:4]1[CH:19]=[CH:18][C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N+:15]([O-])=O)=[CH:6][CH:5]=1>C(O)C.O.[Fe]>[Cl:3][C:4]1[CH:19]=[CH:18][C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[NH2:15])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1cnccc1Oc1ccc(Cl)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1cnccc1Oc1ccc(Cl)cc1
Yield: 74.6 %

Procedure:
To a refluxing mixture of iron powder (1.91 g, 34.43 mmol) and ammonium chloride (230 mg, 4.30 mmol) in ethanol (45 μL) and water (8 mL) was added 4-(4-chlorophenoxy)-3-nitropyridine (AMR01116, 1.57 g, 6.26 mmol) and the resulting mixture was stirred at reflux for 1 h. After removal of the solvent, the residue was diluted in aqueous sodium hydrogen carbonate (40 mL) and extracted with DCM (3×20 mL). The organic layer was dried (MgSO4), filtered and evaporated. Flashmaster chromatography of the crude product using DCM/MeOH 9:1 as eluent gave 4-(4-chlorophenoxy)-pyridin-3-ylamin (1.03 g, 75%) as a white solid, mp 104-106° C.
Reaction SMILES: [N:1]1([C:7]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[C:17](=[O:33])[C:16]=1[C:34]#[N:35]>C1(C)C=CC=CC=1>[F:32][C:29]1[CH:28]=[CH:27][C:26]([CH2:25][N:18]2[C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:15]([N:4]3[CH2:5][CH2:6][N:1]([C:7]([C:9]4[S:10][CH:11]=[CH:12][CH:13]=4)=[O:8])[CH2:2][CH2:3]3)=[C:16]([C:34]#[N:35])[C:17]2=[O:33])=[CH:31][CH:30]=1
Reactant: N#Cc1c(Cl)c2ccccc2n(Cc2ccc(F)cc2)c1=O
Reactant: O=C(c1cccs1)N1CCNCC1
Solvent: Cc1ccccc1
Product: N#Cc1c(N2CCN(C(=O)c3cccs3)CC2)c2ccccc2n(Cc2ccc(F)cc2)c1=O
Temperature: 120 °C
Yield: 96.8 %

Procedure:
Piperazine-1-yl-thiophen-2-yl-methanone (234 mg, 1.19 mmol) was added to a solution of Compound 8 (170 mg, 0.54 mmol) in toluene (40 mL) and heated overnight at 120° C. The solvent was removed under vacuum. The residue was suspended in water, sonicated, and filtered to yield 247 mg (97%) of white solids. M.P. 258° C. 1H NMR (DMSO-d6): δ 3.69 (m, 4H), 3.94 (m, 4H), 5.47 (s, 2H), 7.16 (m, 3H), 7.28 (m, 3H), 7.43 (d, J=8.5 Hz, 1H), 7.50 (d, J=3.3 Hz, 1H), 7.64 (t, J=7.25, 2H), 7.81 (d, J=4.8 Hz, 1H) 7.95 (d, J=7.5 Hz, 1H). EIMS m/z 473 (M+1), 495 (M+23). Anal. (C26H21FN4O2S) C, H, N.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][CH2:22][CH2:23][N:24]([CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[C:42]([C:46]([F:49])([F:48])[F:47])[C:41]=3[Cl:50])[CH2:25][CH:26]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>CO.CCOCC>[ClH:50].[Cl:50][C:41]1[C:42]([C:46]([F:47])([F:48])[F:49])=[CH:43][CH:44]=[CH:45][C:40]=1[CH2:39][N:24]([CH2:25][CH:26]([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:23][CH2:22][CH2:21][O:20][C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[N:15]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(OCCCN(Cc3cccc(C(F)(F)F)c3Cl)CC(c3ccccc3)c3ccccc3)n2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: FC(F)(F)c1cccc(CN(CCCOc2cccc(N3CCNCC3)n2)CC(c2ccccc2)c2ccccc2)c1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirring solution of [4-{6-(3-[(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-amino]-propoxy}-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (40 mg, 0.05 mmol) in methanol (0.8 ml) was added 1 N HCl in Et2O. The reaction mixture was stirred at RT for 4 h and concentrated under vacuum to provide the title compound as an off-white solid, 31 mg (91%). MS (ESI) 609.2 (M+).
Reaction SMILES: [C:1](/[C:3](=[C:7](\OCC)/[CH3:8])/[C:4](=[S:6])[NH2:5])#[N:2].[NH3:12]>CO>[NH2:12]/[C:7](/[CH3:8])=[C:3](\[C:1]#[N:2])/[C:4](=[S:6])[NH2:5]
Reactant: CCO/C(C)=C(\C#N)C(N)=S
Reactant: N
Solvent: CO
Product: C/C(N)=C(/C#N)C(N)=S
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
(2E)-2-Cyano-3-ethoxybut-2-enethioamide (method 2) (150 g, 0.88 mol) was dissolved in 7M solution of ammonia in methanol (2.9 L) and stirred at r.t. overnight. The reaction mixture was concentrated and the residue was crystallized from hot water (1. L) to provide (2E)-3-amino-2-cyanobut-2-enethioamide (111.6 g, 89%) as brown crystals. 1H NMR (300 MHz, DMSO-d6) δ 2.22 (s, 3H), 7.73 (bs, 1H), 8.53 (bs, 1H), 9.01 (bs, 1H), 11.60 (bs, 1H).
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5]1.Cl.[C:15](=O)([O:18]C)[O:16][CH3:17]>>[C:15]([CH:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:12][CH2:13][C:4]1=[O:3])([O:16][CH3:17])=[O:18]
Reactant: COC(=O)OC
Reactant: O=C1CCc2ccccc2C1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: COC(=O)C1C(=O)CCc2ccccc21
Temperature: 25 °C

Procedure:
To a suspension of sodium hydride (60% oil dispersion, 4.8 g gross) in dimethyl carbonate (150 mL) stirring at room temperature under argon, was added 2-oxo-1,2,3,4-tetrahydronaphthalene (14.6 g). The resulting mixture was then refluxed for 30 min before cooling to 0° C. Once at the prescribed temperature and while maintaining inert atmosphere, 2.0 M aqueous hydrochloric acid solution (200 mL) was added slowly. Upon completion of the addition, the reaction mixture was extracted with ethyl acetate (three times). The combined extracts were dried over anhydrous magnesium sulfate and evaporated under vacuum to yield a residue. The residue was purified by silica gel chromatography eluting with 15% ethyl acetate in hexane to obtain the title compound (16.9 g).
Reaction SMILES: [C:1]([OH:10])(=O)[C@@H:2]([C@H:4]([C:6](O)=[O:7])[OH:5])[OH:3].C([NH2:19])CCCCCCC>O>[C:1]1(=[O:10])[NH:19][C:6](=[O:7])[CH:4]([OH:5])[CH:2]1[OH:3]
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Reactant: CCCCCCCCN
Solvent: O
Product: O=C1NC(=O)C(O)C1O
Temperature: 120 °C
Reaction time: 12 h

Procedure:
0.1 mol (15.0 g) of L(+)-tartaric acid is dissolved in 5 ml of hot water and 0.1 mol (12.9) g) of n-octylamine is added dropwise (at about 100° C.). A homogeneous solution is obtained by heating to about 120° C., with considerable formation of foam. The reaction mixture is then allowed to stand for about 12 hours and is then heated at about 140° C. for 8 hours; the water formed in the condensation reaction is volatized. After cooling, the liquid solidifies; the product, composed of about 28 g of a brown, viscous mass, is recrystallized 3 times from ethanol and is washed with diethyl ether. The pure product melts at 140° C. to 143° C. and has an [α]20°C.D of +117° C. in ethanol.
Reaction SMILES: CN(C1C=CC=CN=1)C.Cl.CN(CCCN=C=NCC)C.[CH2:22]([N:24]1[CH:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:27](=[O:35])[N:26]([C:36]([CH3:41])([CH3:40])[C:37]([OH:39])=O)[CH2:25]1)[CH3:23].[Cl:42][C:43]1[C:49]([Cl:50])=[CH:48][CH:47]=[CH:46][C:44]=1[NH2:45]>ClCCl.O>[Cl:42][C:43]1[C:49]([Cl:50])=[CH:48][CH:47]=[CH:46][C:44]=1[NH:45][C:37](=[O:39])[C:36]([N:26]1[C:27](=[O:35])[CH:28]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:24]([CH2:22][CH3:23])[CH2:25]1)([CH3:41])[CH3:40]
Reactant: Nc1cccc(Cl)c1Cl
Reactant: CCN1CN(C(C)(C)C(=O)O)C(=O)C1c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CCN1CN(C(C)(C)C(=O)Nc2cccc(Cl)c2Cl)C(=O)C1c1ccccc1
Reaction time: 0.25 h
Yield: 21.9 %

Procedure:
Dimethylaminopyridine (50 mg) and dimethylaminopropylethylcarbodiimide hydrochloride (0.5 g) were added to a solution of 2-(1-ethyl-5-phenylimidazolidin-4-on-3-yl)isobutyric acid (0.6 g) prepared according to Example 8 in dichloromethane (15 mL) at 0° C. After stirring for 15 minutes at 0° C. to room temperature, 2,3-dichioroaniline (0.4 g) was added and the mixture was stirred overnight at room temperature. The reaction solution was poured into water whose pH was 2, and the mixture was extracted with chloroform. The organic layer was washed with water and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the resulting crude product was purified by thin-layer chromatography (silica gel, ethyl acetate/n-hexane=2/3) to give 0.2 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[O:12][N:11]=[C:10]2[C:15]2[C:19]([CH2:20][CH2:21][O:22]C)=[N:18][O:17][N:16]=2)[CH:5]=[CH:6][C:7]=1[F:8].B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[O:12][N:11]=[C:10]2[C:15]2[C:19]([CH2:20][CH2:21][OH:22])=[N:18][O:17][N:16]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COCCc1nonc1-c1noc(=O)n1-c1ccc(F)c(Cl)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=c1onc(-c2nonc2CCO)n1-c1ccc(F)c(Cl)c1
Temperature: 25 °C

Procedure:
To a solution of 4-(3-chloro-4-fluorophenyl)-3-[4-(2-methoxyethyl)-1,2,5-oxadiazol-3-yl]-1,2,4-oxadiazol-5(4H)-one (2.55 g, 0.00748 mol) in DCM (24 mL) was added 1.0 M of boron tribromide in DCM (22.4 mL) under an atmosphere of nitrogen at −78° C. The reaction solution was allowed to warm to rt over 2.5 h. The reaction was quenched with saturated NaHCO3 at 0° C. and diluted with ethyl acetate. The aqueous layer was extracted with ethyl acetate once, the combined organic solutions were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (60% ethyl acetate/hexane) to give the desired product as an off white solid (2.3 g, 96%). MF═C12H8ClFN4O4; LCMS calculated for C12H9ClFN4O4(M+H)+: m/z=327.0.
Reaction SMILES: [Mg].[CH3:2][O:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[C:7]([C:13]([OH:15])=[O:14])[NH:8]2.Cl.N.[CH3:18]O>>[CH3:18][O:14][C:13]([CH:7]1[CH2:6][C:5]2[C:9](=[CH:10][CH:11]=[CH:12][C:4]=2[O:3][CH3:2])[NH:8]1)=[O:15]
Reactant: COc1cccc2[nH]c(C(=O)O)cc12
Reactant: CO
Agent: Cl
Agent: N
Agent: [Mg]
Product: COC(=O)C1Cc2c(cccc2OC)N1
Temperature: 110 °C
Reaction time: 3 h
Yield: 64 %

Procedure:
119 mg (4.90 mmol) of magnesium turnings are added to a solution of 500 mg (2.44 mmol) of 4-methoxy-1H-indole-2-carboxylic acid in 10 ml of methanol. The mixture is stirred for 3 hours in a bath at 110° C. and then for 1 hour at room temperature. 20 ml of hydrochloric acid are added at 0° C. and the mixture is stirred for one hour. 3 N ammonia solution is then added to pH 10 and the mixture is extracted with 3 times 50 ml of ethyl acetate. The organic phases are dried over magnesium sulfate, filtered and concentrated under reduced pressure. The evaporation residue is purified by chromatography on a silica column using a dichloromethane/ethyl acetate mixture (98/5, then 95/5; v/v) as the eluent to give the expected product in the form of a brown oil with a yield of 64%.
Reaction SMILES: C1(C2CCC(=O)CC2)C=CC=CC=1.N1CCC([N:20]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[NH:22][C:21]2=[O:29])CC1.CC1C=CC(S(O)(=O)=O)=CC=1.CC1C=CC=CC=1>O>[N:20]1[C:21](=[O:29])[N:22]=[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=12
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C1CCC(c2ccccc2)CC1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1N=c2ccccc2=N1

Procedure:
A mixture of 7 parts of 4-phenylcyclohexanone, 8.8 parts of 1-(4-piperidinyl)-2H-benzimidazol-2-one, 0.3 parts of 4-methylbenzenesulfonic acid and 225 parts of methylbenzene is stirred and refluxed for 40 hours with water-separator. The reaction mixture is cooled and the solvent is removed in vacuo, yielding 15 parts of 1-[4-phenyl-1-cyclohexenyl)-4-piperidinyl]-2H-benzimidazol-2-one as a residue.
Reaction SMILES: C([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[CH2:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:9]1)C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].Cl[C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34]>C(Cl)(Cl)Cl>[CH2:36]([O:35][C:33]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[CH2:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:9]1)=[O:34])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCc1cccc2c1CN(Cc1ccccc1)C2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)NCc1cccc2c1CN(C(=O)OCc1ccccc1)C2
Yield: 91.1 %

Procedure:
3.38 g of 2-benzyl-4-(tertbutyloxycarbonylaminomethyl)isoindoline was dissolved in 10 ml of chloroform and 1.27 g of sodium carbonate was added to it. To this solution was added dropwise 2.04 g of benzyl chloroformate under ice-cooling and stirring, and the mixture was stirred for 2 hours at room temperature. Insoluble materials were removed by filtration and the filtrate was concentrated. Recrystallization from ether gave 3.48 g of 2-benzyloxycarbonyl-4-(tertbutyloxycarbonylaminomethyl)isoindoline.
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:15])[NH:8][C:9]1([C:12](=[NH:14])[NH2:13])[CH2:11][CH2:10]1)([CH3:5])([CH3:4])[CH3:3].CN([C:19]([CH:21]=[CH2:22])=O)C.CNC>CCO>[C:2]([O:6][C:7](=[O:15])[NH:8][C:9]1([C:12]2[N:13]=[CH:22][CH:21]=[CH:19][N:14]=2)[CH2:11][CH2:10]1)([CH3:5])([CH3:3])[CH3:4]
Reactant: C=CC(=O)N(C)C
Reactant: CC(C)(C)OC(=O)NC1(C(=N)N)CC1
Agent: CNC
Agent: Cl
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1(c2ncccn2)CC1
Temperature: 70 °C

Procedure:
To a solution of (1-Carbamimidoyl-cyclopropyl)-carbamic acid tert-butyl ester hydrochloride (3.62 g, 15.4 mmol) in anhydrous EtOH (62 mL) was added dimethylaminoacrolein (3.6 mL, 36. mmol) and dimethylamine (2 M in THF, 10. mL, 20. mmol). The reaction was heated at 70° C. for 18 h. The EtOH was removed in vacuo and the residue was dissolved in EtOAc (150 mL) and washed with water (3×100 ml). The organic phase was dried with Na2SO4 and concentrated to give a red oil. The product was crystallized from the oil using warm hexanes (30 mL) and the light orange solids were collected by filtration. The filtrate was re-processed in the same manner two additional times. In total 2.23 g of the title compound was isolated as a light orange powder, m/z 236.40 [M+1]+
Reaction SMILES: S(Cl)(Cl)=O.[F:5][C:6]1[CH:24]=[CH:23][C:9]([C:10]([NH:12][C:13]2[C:14](=[C:18]([Cl:22])[CH:19]=[CH:20][CH:21]=2)[C:15]([OH:17])=[O:16])=O)=[CH:8][CH:7]=1>ClCCCl>[F:5][C:6]1[CH:24]=[CH:23][C:9]([C:10]2[O:16][C:15](=[O:17])[C:14]3[C:18]([Cl:22])=[CH:19][CH:20]=[CH:21][C:13]=3[N:12]=2)=[CH:8][CH:7]=1
Reactant: O=C(Nc1cccc(Cl)c1C(=O)O)c1ccc(F)cc1
Solvent: ClCCCl
Solvent: O=S(Cl)Cl
Product: O=c1oc(-c2ccc(F)cc2)nc2cccc(Cl)c12
Reaction time: 1 h
Yield: 82.7 %

Procedure:
15.5 parts of thionyl chloride are added to a suspension of 29 parts of N-(4'-fluorobenzoyl)-6-chloroanthranilic acid in 250 parts of 1,2-dichloroethane at room temperature, and the mixture is then stirred for one hour under reflux. Thereafter, it is evaporated down and the residue is taken up in methylene chloride; this solution is extracted once with water, and then with twice 100 parts by volume of 0.5 N sodium hydroxide solution. Thereafter, it is dried, chromatographed on neutral alumina and evaporated down, 22.5 parts of 2-(4'-fluorophenyl)-5-chloro-4H-3,1-benzoxazin-4-one, of melting point 159°-162° C., being isolated; yield: 82.7%.
Reaction SMILES: I[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@@H:10]([CH2:21][CH:22]([CH3:24])[CH3:23])[CH2:9]2)[CH:5]=[N:4][CH:3]=1.[F:25][C:26]1[C:31]([C:32](N(OC)C)=[O:33])=[CH:30][CH:29]=[CH:28][N:27]=1>C1COCC1>[F:25][C:26]1[N:27]=[CH:28][CH:29]=[CH:30][C:31]=1[C:32]([C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@@H:10]([CH2:21][CH:22]([CH3:24])[CH3:23])[CH2:9]2)[CH:5]=[N:4][CH:3]=1)=[O:33]
Reactant: CON(C)C(=O)c1cccnc1F
Reactant: CC(C)C[C@H]1CN(c2cncc(I)n2)CCN1C(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: CC(C)C[C@H]1CN(c2cncc(C(=O)c3cccnc3F)n2)CCN1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 61.3 %

Procedure:
A solution of (S)-tert-butyl 4-(6-iodopyrazin-2-yl)-2-isobutylpiperazine-1-carboxylate (1.05 g, 2.353 mmol) in THF (15 mL) was cooled to −78° C. and nBuli 2.5M in hexanes (988.4 μL of 2.5 M, 2.471 mmol) was added slowly. The solution was stirred for 10 mins after which a solution of 2-fluoro-N-methoxy-N-methyl-pyridine-3-carboxamide (455.1 mg, 2.471 mmol) in THF (5 mL) was added and the solution stirred for 1 hr at −78° C. The reaction was quenched with Sat NH4Cl and extracted into EtOAc (3×30 ml). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated to give an orange oil. Columned on silica gel eluting with 1:1 EtOAc/hexanes to give (S)-tert-butyl 4-(6-(2-fluoronicotinoyl)pyrazin-2-yl)-2-isobutylpiperazine-1-carboxylate as a yellow oil (0.64 g, 61%).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9]O)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[I-:13].[Cs+].B(F)(F)F.CCOCC>C(#N)C>[C:1]([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][I:13])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(CO)cc1
Reactant: [I-]
Agent: FB(F)F
Agent: [Cs+]
Solvent: CCOCC
Solvent: CC#N
Product: CC(=O)Oc1ccc(CI)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of 4-acetoxybenzyl alcohol (0.332 g, 2 mmol), and cesium iodide (0.571 g, 2.2 mmol) in anhyd. acetonitrile (10 mL) under nitrogen, boron trifluoride etherate (0.28 mL, 2.2 mmol) in acetonitrile (5 mL) was introduced. After stirring overnight, the reaction mixture was poured into ice-cold water (20 mL) and the solid separated was filtered, washed with water and later with hexanes. The product was dried under high vacuum. Yield, 0.39 g, 71%; TLC, hexanes:EtOAC (4:1). 1H NMR (CDCl3): δ 2.3 (s, 3H), 4.35 (s, 2H), 7.05 (d, 2H), 7.5 (d, 2H).
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].CN(C)C=O.[CH2:15]([Sn](CCCC)(CCCC)CCCC)[CH:16]=[CH2:17]>C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:17]([C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4])[CH:16]=[CH2:15]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: Nc1ccc(F)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCc1cc(F)ccc1N
Temperature: 80 °C
Reaction time: 17 h

Procedure:
A round-bottom flask was fitted with a condenser, stirbar and septa and flushed with nitrogen. 2-bromo-4-fluoro aniline (9.70 g, 40.9 mmol), N,N-dimethylformamide (100 mL), allyltributyltin (15.0 mL, 48.9 mmol) and Pd(PPh3)4 (1.50 g, 1.30 mmol) were added, giving a mixture that was warmed to 80° C. After 17 hours, the reaction was cooled to room temperature, diluted with ethyl acetate (300 mL) and washed with 1:1 H2O:saturated aqueous NaCl solution (2×150 mL). The aqueous washes were combined and extracted with ethyl acetate (50 mL). The organic extracts were then combined, dried over MgSO4, filtered and concentrated in vacuo to give an oil that was purified via flash chromatography on silica gel (0% to 35% ethyl acetate/hexanes linear gradient) to give the desired product.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:23])[CH3:22])[C:12]([CH:24]=[O:25])=[C:11]([I:26])[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].I[C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=1>>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:19])([CH3:20])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:22])[CH3:23])[C:12]([C@@H:24]([OH:25])[C:28]3[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=3)=[C:11]([I:26])[C:10]1=2)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC(C)c1nc2c(c(I)c1C=O)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2
Reactant: N#Cc1ccc(I)cc1
Product: CC(C)c1nc2c(c(I)c1[C@@H](O)c1ccc(C#N)cc1)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2

Procedure:
Obtained by starting from (S)-5-(tert-butyldimethylsilyloxy)-4-iodo-2-isopropyl-7,7-dimethyl-5,6,7,8-tetrahydroquinoline-3-carbaldehyde and 4-iodobenzonitrile.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16]([C:18]3[C:19]4[N:20]=[CH:21][CH:22]=[N:23][C:24]=4[C:25]([C:28]4[C:33](Cl)=[C:32](OC)[CH:31]=[C:30](OC)[C:29]=4Cl)=[CH:26][CH:27]=3)=[O:17])=[N:13][CH:14]=2)[CH2:4][CH2:3]1.CN(C(ON1N=N[C:50]2[CH:51]=CC=[CH:54][C:49]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCN(C2C=CC(NC(C3C4N=CC=NC=4C(C4C5C(=CC=CC=5)C=CC=4)=CC=3)=O)=CC=2)CC1>C(Cl)Cl.CO>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16]([C:18]3[C:19]4[N:20]=[CH:21][CH:22]=[N:23][C:24]=4[C:25]([C:28]4[C:33]5[C:32](=[CH:54][CH:49]=[CH:50][CH:51]=5)[CH:31]=[CH:30][CH:29]=4)=[CH:26][CH:27]=3)=[O:17])=[N:13][CH:14]=2)[CH2:6][CH2:7]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3ccc(CN4CCN(C)CC4)cn3)c3nccnc23)c1Cl
Agent: CN1CCN(c2ccc(NC(=O)c3ccc(-c4cccc5ccccc45)c4nccnc34)cc2)CC1
Agent: F[B-](F)(F)F
Solvent: CO
Solvent: ClCCl
Product: CN1CCN(Cc2ccc(NC(=O)c3ccc(-c4cccc5ccccc45)c4nccnc34)nc2)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but stirring the reaction mixture for 72 h at rt and using 3 equiv of 5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-ylamine hydrochloride (Example 31), TBTU (2.4 equiv) and 8-naphthalen-1-yl-quinoxaline-5-carboxylic acid (Example 46). Title compound: ESI-MS: 489.1 [M+H]+; tR=3.73 min (System 1); TLC: Rf=0.08 (DCM/MeOH, 9:1).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([S:12][CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[C:6]=2[N:7]=1.[NH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[CH:13]1([S:12][C:8]2[C:6]3[N:7]=[C:2]([N:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)[N:3]=[C:4]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[C:5]=3[N:11]=[CH:10][N:9]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: C1CNCCN1
Reactant: Clc1nc(N2CCOCC2)c2ncnc(SC3CCCCC3)c2n1
Product: c1nc(SC2CCCCC2)c2nc(N3CCNCC3)nc(N3CCOCC3)c2n1

Procedure:
This compound was prepared analogous to Example 1 from 2-chloro-8-cyclohexylthio-4-morpholino-pyrimido-[5,4-d]-pyrimidine (m.p.: 179°-181° C.) and piperazine.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[N:5]([C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[N:16]=[C:15](Cl)[C:14]=1[N+:24]([O-:26])=[O:25])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2].[OH-].[NH3:29]>O1CCCC1>[CH2:1]([O:3][C:4](=[O:27])[N:5]([C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[N:16]=[C:15]([NH2:29])[C:14]=1[N+:24]([O-:26])=[O:25])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2]
Reactant: N
Reactant: CCOC(=O)N(Cc1ccccc1)c1cc(C(F)(F)F)nc(Cl)c1[N+](=O)[O-]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCOC(=O)N(Cc1ccccc1)c1cc(C(F)(F)F)nc(N)c1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Ethyl-[2-chloro-3-nitro-6-(trifluoromethyl)-pyridin-4-yl]-benzylcarbamate (63 gm 160 mmol) was dissolved in tetrahydrofuran (300 mL) and to this was added concentrated ammonia hydroxide solution (0.88 specific gravity, 100 mL) to give two phases. This was transferred to a pressure vessel, sealed and heated to 80° C. with stirring for 2 hours. The tetrahydrofuran was evaporated and the residue was partitioned between saturated brine and diethyl ether. The organic extracts were dried over sodium sulphate, filtered and evaporated to give a thick yellow slurry (65 gm) of ethyl-[2-amino-3-nitro-6-(trifluoromethyl)-pyridin-4-yl]-benzylcarbamate.