Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]=1.Cl[C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][C:26]=1[N+:33]([O-:35])=[O:34].C(N(CC)CC)C.CO>C(O)C.C(Cl)Cl>[C:29]([C:28]1[CH:31]=[CH:32][C:25]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3[C:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]=2)=[C:26]([N+:33]([O-:35])=[O:34])[CH:27]=1)#[N:30]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2c[nH]c3ccc(N)cc23)CC1
Reactant: N#Cc1ccc(Cl)c([N+](=O)[O-])c1
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC=C(c2c[nH]c3ccc(Nc4ccc(C#N)cc4[N+](=O)[O-])cc23)CC1
Yield: 40 %

Procedure:
5-Amino-3-(N-t-butoxycarbonyl-1,2,5,6-tetrahydropyrid-4-yl)-1H-indole and 4-chloro-3-nitrobenzonitrile were used. Triethylamine was used as base, absolute ethanol was used as solvent, and the reaction was heated at reflux for 2 hours. Column chromatography using 1% methanol in methylene chloride afforded the title compound (40%) as a red foam: mp, decomposes 85° C.; Rf =0.35 in 1% methanol in methylene chloride; HRMS calculated for C25H25N5O4 459.1909, found 459.1853.
Reaction SMILES: Br[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Br:8])[N:3]=1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][NH2:18])=[CH:13][CH:12]=1.CN1CCOCC1.O>CN1CCCC1=O>[Br:8][C:4]1[N:3]=[C:2]([NH:18][CH2:17][C:14]2[CH:15]=[CH:16][C:11]([O:10][CH3:9])=[CH:12][CH:13]=2)[CH:7]=[N:6][CH:5]=1
Reactant: Brc1cncc(Br)n1
Reactant: COc1ccc(CN)cc1
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CN1CCOCC1
Product: COc1ccc(CNc2cncc(Br)n2)cc1
Temperature: 100 °C
Yield: 76.2 %

Procedure:
A mixture of 2,6-dibromopyrazine (3.431 mmol; 816.1 mg), (4-methoxyphenyl)methanamine (3.431 mmol; 470.6 mg; 0.4452 mL), and N-Methylmorpholine (8.577 mmol; 876 mg; 0.952 mL) in 1-methyl-2-pyrrolidinone (10 mL) in a sealed pressure vial was heated at 100° C. overnight. The mixture was poured into water, and extracted with EtOAc. The organic layer was concentrated. The residue was purified on silica eluted with 0 to 100% EtOAc in DCM to afford 6-bromo-N-[(4-methoxyphenyl)methyl]pyrazin-2-amine (768.8 mg, 29%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]1([PH:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1>[C:2]1([P:14](=[O:21])([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[PH](c1ccccc1)c1ccccc1
Reactant: Brc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=P(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
A 20 mL of reactor equipped with magnetic stir bar was charged with 93 mg (0.10 mmol) of {[(t-Bu)2P(OH)]2PdCl}2, 0.314 g (2.0 mmol) of bromobenzene, 0.404 g (2.0 mmol) of di-phenylphosphine oxide and 0.276 g (2.0 mmol) of K2CO3 in 5.0 mL of 1,4-dioxane. The resulting mixture was refluxed for 8 h to afford tri-phenylphosphine oxide. 31P NMR (CDCl3, 121 MHz): δ30.3 ppm.
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][C:11]=2[N+:13]([O-:15])=[O:14])[NH:6][CH:5]=1.[CH3:16]I>CN(C=O)C>[I:3][C:4]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][C:11]=2[N+:13]([O-:15])=[O:14])[N:6]([CH3:16])[CH:5]=1
Reactant: CI
Reactant: O=[N+]([O-])c1ccnc2[nH]cc(I)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cc(I)c2c([N+](=O)[O-])ccnc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 145.3 %

Procedure:
To a stirred suspension of sodium hydride (0.872 g, 21.80 mmol) in DMF (80 mL) was added 3-iodo-4-nitro-1H-pyrrolo[2,3-b]pyridine (D16) (4.2 g, 14.53 mmol) predissolved in DMF (20 mL) dropwise over 30 mins at 0° C. The reaction mixture was then left stirring at 0° C. for 15 mins. After which, methyl iodide (1.090 mL, 17.44 mmol) was added and the resulting reaction mixture was stirred at 0° C. for ca. 1 hour. The reaction mixture was quenched with ammonium chloride solution (ca. 150 mL). The aqueous phase was extracted with ethyl acetate (3×80 mL). The combined organic phases were dried and concentrated. Another batch of 3-iodo-4-nitro-1H-pyrrolo[2,3-b]pyridine (D16) (4.2 g, 14.53 mmol) was treated in the same way. The residue from both reactions were combined and purified by chromatography on silica, eluting with a gradient of 0-50% ethyl acetate in cyclohexane to give the title compound (6.4 g). The impure fractions were re-purified by chromatography on silica, eluting with a gradient of 0-30% ethyl acetate in cyclohexane to give another batch of the title compound (1.32 g). LCMS (A): m/z (M+H)+ 304, C8H6IN3O2 requires 303 (acidic).
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]([C@@H:18]([CH2:34][CH:35]([CH3:37])[CH3:36])[C:19]([NH:21][N:22]1[C:26](=[O:27])[C:25]2([CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[NH:24][C:23]1=[O:33])=[O:20])[CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:38]([O:45][C:46]([NH:48][CH2:49][C:50](O)=[O:51])=[O:47])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[CH2:38]([O:45][C:46]([NH:48][CH2:49][C:50]([N:30]1[CH2:31][CH2:32][C:25]2([NH:24][C:23](=[O:33])[N:22]([NH:21][C:19](=[O:20])[C@@H:18]([C@@H:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:34][CH:35]([CH3:37])[CH3:36])[C:26]2=[O:27])[CH2:28][CH2:29]1)=[O:51])=[O:47])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: CC(C)C[C@@H](C(=O)NN1C(=O)NC2(CCNCC2)C1=O)[C@H](CCCc1ccccc1)C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)C[C@@H](C(=O)NN1C(=O)NC2(CCN(C(=O)CNC(=O)OCc3ccccc3)CC2)C1=O)[C@H](CCCc1ccccc1)C(=O)OC(C)(C)C

Procedure:
A mixture of 0.257 g of 2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenylbutyl]-4-methyl-N-[2,4-dioxo-1,3,8-triazaspiro[4.5]decan-3-yl]valeramide and 0.209 g of N-(benzyloxycarbonyl)glycine in 5 ml of dry dimethylformamide was stirred and cooled to ice temperature. The mixture was treated with 0.225 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and was then stirred at room temperature for 2 days. The solvent was evaporated and the residue partitioned between water and ethyl acetate. The ethyl acetate layer was washed successively with water, 5% aqueous sodium bicarbonate solution, saturated sodium chloride solution and dried over anhydrous magnesium sulphate. The solvent was evaporated and the residue triturated with ether and there was obtained 0.261 g of N-[8-{N-(benzyloxycarbonyl)aminoacetyl]-2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenylbutyl]-4-methyl-N-[2,4-dioxo-1,3,8-triazaspiro[4.5]decan-3-yl]valeramide in the form of a white solid.
Reaction SMILES: Br[C:2]1[C:3]([CH3:10])=[N:4][CH:5]=[C:6]([CH3:9])[C:7]=1[NH2:8].[C:11]([O:15][CH2:16][CH3:17])(=[O:14])[CH:12]=[CH2:13].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCN(CC)CC>CN(C=O)C.O.C(O[Pd]OC(=O)C)(=O)C>[NH2:8][C:7]1[C:6]([CH3:9])=[CH:5][N:4]=[C:3]([CH3:10])[C:2]=1/[CH:13]=[CH:12]/[C:11]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: C=CC(=O)OCC
Reactant: Cc1cnc(C)c(Br)c1N
Agent: CC(=O)O[Pd]OC(C)=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C/c1c(C)ncc(C)c1N
Temperature: 150 °C
Yield: 90.8 %

Procedure:
A mixture of 3-bromo-2,5-dimethylpyridin-4-amine (5.0 g, 25 mmol), ethyl acrylate (5.0 g, 50 mmol), diacetoxypalladium (1.12 g, 5.0 mmol), PPh3 (3.28 g, 12.5 mmol), and NEt3 (7.6 g, 75 mmol) in DMF (50 mL) was heated in a microwave reactor at 150° C. for 2 h. The reaction mixture was cooled, diluted with water (100 mL), and extracted with DCM (250 mL×3). The combined organic layers were washed with saturated sodium chloride solution (100 mL×3), dried with sodium sulfate, concentrated, and purified by column chromatography to give 5.0 g of the product as a yellow solid. MS (ESI): m/z 221.2 [M+H]+.
Reaction SMILES: [CH:1]([C:4]1([C:10]([OH:12])=O)[CH2:8][CH2:7][C:6](=[O:9])[CH2:5]1)([CH3:3])[CH3:2].S(Cl)([Cl:15])=O>C1C=CC=CC=1>[CH:1]([C:4]1([C:10]([Cl:15])=[O:12])[CH2:8][CH2:7][C:6](=[O:9])[CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)C1(C(=O)O)CCC(=O)C1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CC(C)C1(C(=O)Cl)CCC(=O)C1
Temperature: 45 °C
Reaction time: 3 h
Yield: 30 %

Procedure:
A solution of 1-isopropyl-3-oxocyclopentylcarboxylic acid (20.1 g, 118.9 mmol) in benzene (150 mL) was slowly treated with thionyl chloride (23.5 mL, 322.1 mmol) and the resulting solution was stirred at 45° C. for 3 hours. The solvent and the volatile components were evaporated under reduced pressure (100 torr) and the residue was distilled to obtain 6.727 g (30%) of the desired product, B.P.: 110-114° C. at 5 torr. 1H NMR (500 MHz, CDCl3): 2.82 (dd, J=18.36, 1.76 Hz, 1H), 2.50 (m, 1H), 2.35 (m, 2H), 2.20 to 190 (bm, 3H), 1.03 (bd, J=8.2 Hz, 6H).
Reaction SMILES: C1(CN2CCC[C@H](CNC(C[C@H:19]3[CH2:23][CH2:22][CH2:21][N:20]3[C:24]([C@@H:26]3[CH2:30][C@@H:29]([O:31]S(C)(=O)=O)[CH2:28][N:27]3[C:36](=[O:57])[CH2:37][C:38]([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[O:25])=O)C2)CCCCC1.[CH3:58][N:59]([CH3:62])[CH:60]=O>C([O-])(=O)C.C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[C:29]([O:31][C@@H:29]1[CH2:28][N:27]([C:36](=[O:57])[CH2:37][C:38]([C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C@H:26]([C:24]([N:20]2[CH2:21][CH2:22][CH2:23][C@@H:19]2[C:24]([NH:20][CH2:19][C@H:23]2[CH2:22][CH2:21][CH2:60][N:59]([CH2:62][CH:39]3[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]3)[CH2:58]2)=[O:25])=[O:25])[CH2:30]1)(=[O:31])[CH3:28]
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](C(=O)N2CCC[C@@H]2CC(=O)NC[C@H]2CCCN(CC3CCCCC3)C2)N(C(=O)CC(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Reactant: CN(C)C=O
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCOC(C)=O
Product: CC(=O)O[C@H]1C[C@@H](C(=O)N2CCC[C@@H]2C(=O)NC[C@H]2CCCN(CC3CCCCC3)C2)N(C(=O)CC(c2ccccc2)(c2ccccc2)c2ccccc2)C1

Procedure:
A solution of 40 mg of (2R)-N-{((3R)-1-cyclohexylmethyl-3-piperidyl)methyl}-1-{(2S,4R)-4-(methylsulfonyloxy)-1-(3,3,3-triphenylpropanoyl)pyrrolidin-2-yl}carbonylpyrrolidine-2-carboxyamide and 30 mg of tetrabutylammonium acetate in 1 ml of N,N-dimethylformamide was stirred at 85° C. for 15 hours under heating. The reaction liquid was diluted with ethyl acetate, successively washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified with a preparative thin-layer chromatography (Kieselgel™ 60F254, Art. 5744 (Merck), chloroform/methanol/28% aqueous ammonia=100/8/1), to provide 14 mg of the title compound as a colorless oily substance.
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-])[CH3:3].[K+].[CH2:7]([N:14]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:15]1[C:20]([N+:21]([O-:23])=[O:22])=[C:19]([NH2:24])[CH:18]=[C:17]([Br:25])[N:16]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1COCC1>[CH2:26]([N:14]([CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:15]1[C:20]([N+:21]([O-:23])=[O:22])=[C:19]([NH:24][CH2:1][C:2]2[CH:5]=[N:21][C:20]([CH3:15])=[CH:19][CH:3]=2)[CH:18]=[C:17]([Br:25])[N:16]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)(C)[O-]
Reactant: Nc1cc(Br)nc(N(Cc2ccccc2)Cc2ccccc2)c1[N+](=O)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1ccc(CNc2cc(Br)nc(N(Cc3ccccc3)Cc3ccccc3)c2[N+](=O)[O-])cn1
Reaction time: 0.08 h

Procedure:
Potassium tert-butoxide (448 mg) was added portion-wise to a cooled solution (−18° C.—salt/ice bath) of N2,N2-dibenzyl-6-bromo-3-nitro-pyridine-2,4-diamine (1500 mg, 3.63 mmol) in THF (40 ml) under nitrogen. The solution changed from yellow to deep red/orange on addition of base. The solution was left to stir in the cooling bath for 5 minutes.
Reaction SMILES: [CH:1]([CH:4]1[N:9]([C:10]2[N:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[C:13]([C:20](OCC)=[O:21])=[CH:12][N:11]=2)[CH2:8][CH2:7][N:6]2[C:25]3[CH:31]=[C:30]([S:32]([CH3:35])(=[O:34])=[O:33])[CH:29]=[CH:28][C:26]=3[N:27]=[C:5]12)([CH3:3])[CH3:2].CC(C[AlH]CC(C)C)C.[NH4+].[Cl-]>C1(C)C=CC=CC=1>[CH:1]([CH:4]1[N:9]([C:10]2[N:15]=[C:14]([C:16]([F:18])([F:19])[F:17])[C:13]([CH2:20][OH:21])=[CH:12][N:11]=2)[CH2:8][CH2:7][N:6]2[C:25]3[CH:31]=[C:30]([S:32]([CH3:35])(=[O:33])=[O:34])[CH:29]=[CH:28][C:26]=3[N:27]=[C:5]12)([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cnc(N2CCn3c(nc4ccc(S(C)(=O)=O)cc43)C2C(C)C)nc1C(F)(F)F
Agent: CC(C)C[AlH]CC(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: CC(C)C1c2nc3ccc(S(C)(=O)=O)cc3n2CCN1c1ncc(CO)c(C(F)(F)F)n1
Temperature: -78 °C
Reaction time: 2 h
Yield: 61.8 %

Procedure:
To a solution of ethyl 2-(1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidine-5-carboxylate (10 mg, 0.02 mmol, prepared according to example 3) in anhydrous toluene (0.5 mL) was added DIBAL-H (0.2 mL, 0.20 mmol, 1M in THF) dropwise at −78° C. under N2. The mixture was stirred at −78° C. for 2 h. Sat. NH4Cl (5 mL) at −78° C. was added to the mixture, which was then extracted with EtOAc (3×5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, concentrated and then purified by basic preparative HPLC to afford a racemic mixture of (2-(1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidin-5-yl)methanol (5.80 mg, 63% yield) as a white solid. LC-MS m/z 470.1 [M+H]+. 1H NMR (CDCl3 400 MHz): δ 8.68 (s, 1H), 8.01 (s, 1H), 7.93-7.81 (m, 2H), 6.11 (d, J=8.0 Hz, 1H), 5.38 (dd, J=5.2 Hz, J=14.4 Hz, 1H), 4.74 (s, 2H), 4.38-4.30 (m, 1H), 4.25-4.15 (m, 1H), 3.86-3.76 (m, 1H), 3.10 (s, 3H), 2.56-2.47 (m, 1H), 1.32 (d, J=6.8 Hz, 3H), 1.08 (d, J=6.8 Hz, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:24][CH2:23][C:14]2([C:18](=[O:19])[N:17]([O:20][CH3:21])[C:16](=O)[CH2:15]2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:34])=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]([N:11]1[CH2:24][CH2:23][C:14]2([C:18](=[O:19])[N:17]([O:20][CH3:21])[C:16](=[S:34])[CH2:15]2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CON1C(=O)CC2(CCN(C(=O)OCc3ccccc3)CC2)C1=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CON1C(=O)C2(CCN(C(=O)OCc3ccccc3)CC2)CC1=S
Yield: 102.4 %

Procedure:
To a solution of 8-benzyloxycarbonyl-2-methoxy-2,8-diazaspiro[4,5]decane-1,3-dione (2.9 g) in toluene (30 ml) was added a Lawesson reagent ([2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphethane-2,4-disulfide]) (2.38 g), and the mixture was heated for 3 hours under reflux. The solvent was then evaporated off under reduced pressure, and the residual oil was dissolved in ethyl acetate (50 ml), which was washed with water and then dried over anhydrous magnesium sulfate. The solvent was evaporated off, and the residual oil was subjected to a silica gel column chromatography [eluent; methanol:dichloromethane=1.50 (V/V)]. The earlier eluate fraction and the later eluate fraction were separated. The solvent for the later eluate fraction was evaporated off and the residual solid was recrystallized from ethyl ether to obtain 2.1 g of a pale yellow solid, m.p. 89° to 90° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].CN1CCCC1=O.[CH:22]([NH2:26])([CH2:24][CH3:25])[CH3:23]>O>[CH:22]([NH:26][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13])([CH2:24][CH3:25])[CH3:23]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Reactant: CCC(C)N
Solvent: CN1CCCC1=O
Solvent: O
Product: CCC(C)Nc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 88.1 %

Procedure:
To a mixture of 1.05 g of 4-fluoro-3-nitro-benzo trifluoride and 10 ml of N-methylpyrrolidone was added 1.10 g of sec-butylamine under ice cool, and the mixture was heated up to room temperature and stirred for 1.5 hours. Into the reaction mixture was poured water, and the deposited solid was collected by filtration. This solid was washed with water, then, dried under reduced pressure to obtain 1.16 g of N-sec-butyl-2-nitro-4-trifluoromethylaniline.
Reaction SMILES: C([O:3][C:4](=[O:22])[CH2:5][NH:6][C:7]1[C:12]([NH:13][C:14]([C:16]2[S:17][C:18]([CH3:21])=[CH:19][CH:20]=2)=O)=[CH:11][CH:10]=[CH:9][N:8]=1)C.O.[OH-].[K+]>C(O)CO>[CH3:21][C:18]1[S:17][C:16]([C:14]2[N:6]([CH2:5][C:4]([OH:3])=[O:22])[C:7]3=[N:8][CH:9]=[CH:10][CH:11]=[C:12]3[N:13]=2)=[CH:20][CH:19]=1
Reactant: CCOC(=O)CNc1ncccc1NC(=O)c1ccc(C)s1
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: Cc1ccc(-c2nc3cccnc3n2CC(=O)O)s1
Yield: 65.3 %

Procedure:
A suspension of N-[3-[(5-methyl-2-thienylcarbonyl)amino]-2-pyridinyl]glycine ethyl ester (93.8 g, 0.293 mole) was refluxed in ethylene glycol (500 ml) for 45 minutes. The solution was cooled and water 9200 ml) and solid potassium hydroxide pellets (23.25 g, 0.41 mole) were added. The resulting solution was refluxed for one hour and then filtered hot into ice water (2 liters) and acidified with 3N hydrochloric acid to give a solid which was collected by filtration and dried to give 52.3 g of crude title compound (65% yield). A 2.0 g portion was dissolved in hot methanol, treated with charcoal, filtered while hot, and cooled to room temperature. Addition of water caused a precipitate to form which was collected by filtration and dried under high vacuum at room temperature overnight to gibe 0.68 g of title compound, mp>250° C.
Reaction SMILES: [Br:1][C:2]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[N:15][C:14]([C:17]3[N:18]=[N:19][NH:20][N:21]=3)=[CH:13][N:12]=2)[CH2:7][CH2:6]1.C(N(CC)CC)C.Br[CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37]>C1COCC1>[Br:1][C:2]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:12]=[CH:13][C:14]([C:17]3[N:18]=[N:19][N:20]([CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[N:21]=3)=[N:15][CH:16]=2)[CH2:7][CH2:6]1
Reactant: Fc1ccc(Br)c(OC2CCN(c3cnc(-c4nn[nH]n4)cn3)CC2)c1
Reactant: CC(C)(C)OC(=O)CBr
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Cn1nnc(-c2cnc(N3CCC(Oc4cc(F)ccc4Br)CC3)cn2)n1
Reaction time: 1 h

Procedure:
To a mixture of 2-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]-5-(2H-tetrazol-5-yl)pyrazine from Step 6 (5.00 g, 11.9 mmol) and triethylamine (3.32 mL, 23.8 mmol) in THF (50 mL) at 60° C. was added tert-butyl bromoacetate (3.48 g, 17.9 mmol). After a period of 1 h at 60° C., the reaction mixture was partitioned between ethyl acetate and saturated ammonium chloride. The organic phase was separated, dried over sodium sulfate, filtered and evaporated. To the solid was added 50 mL of acetone followed by slow addition of 100 mL of hexane. The resulting solid was filtered to provide tert-butyl (5-{5-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]pyrazin-2-yl}-2H-tetrazol-2-yl)acetate.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:13]2[CH:14]=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)=[N:4][C:5](Br)=[CH:6][C:7]=1[C:8]([O:10][CH3:11])=[O:9].[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.[F-].[Cs+]>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>[NH2:1][C:2]1[C:3]([C:13]2[CH:14]=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)=[N:4][C:5]([C:26]2[CH:27]=[CH:28][C:23]([O:22][CH3:21])=[CH:24][CH:25]=2)=[CH:6][C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COc1ccc(B(O)O)cc1
Reactant: COC(=O)c1cc(Br)nc(-c2ccc(OC)nc2)c1N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Product: COC(=O)c1cc(-c2ccc(OC)cc2)nc(-c2ccc(OC)nc2)c1N
Temperature: 80 °C
Yield: 67.6 %

Procedure:
A mixture of methyl 3-amino-6-bromo-6′-methoxy-2,3′-bipyridine-4-carboxylate (165 mg, 0.49 mmol), 4-methoxyphenylboronic acid (89 mg, 0.59 mmol), cesium fluoride (178 mg, 1.17 mmol) and tetrakis(triphenylphosphine)palladium(0) (28 mg, 0.024 mmol) in a vial was flushed with nitrogen. Dimethoxyethane (2.4 mL) was added and the reaction was heated at 80° C. overnight. It was partitioned between ethyl acetate and a saturated aqueous solution of sodium bicarbonate. The organic phase was separated, washed with brine, and dried with sodium sulfate. The solvent removed and the major product was isolated by silica gel radial chromatography (step gradient with hexane containing 5 to 20% ethyl acetate). This gave methyl 3-amino-6′-methoxy-6-(4-methoxyphenyl)-2,3′-bipyridine-4-carboxylate (121 mg, 68% yield) as a yellow solid. MS (ESI) m/z 366.1 (M+H). 1H NMR (CDCl3) δ ppm 8.57 (1H, d, J=2.44 Hz), 8.05 (1H, s), 7.96 (1H, dd, J=8.55, 2.44 Hz), 7.88-7.93 (2H, m), 6.92-6.97 (2H, m), 6.88 (1H, d, J=8.55 Hz), 5.88 (2H, s), 4.00 (3H, s), 3.96 (3H, s), 3.84 (3H, s).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=O)[CH3:11])[N:5]=1)(=O)[CH3:2].[CH2:13]([C:16]1[CH:22]=[C:21]([CH:23]([CH3:25])[CH3:24])[C:19]([NH2:20])=[C:18]([CH:26]([CH3:28])[CH3:27])[CH:17]=1)[CH:14]=[CH2:15].C(O)=O>CO>[CH2:13]([C:16]1[CH:17]=[C:18]([CH:26]([CH3:28])[CH3:27])[C:19]([N:20]=[C:1]([C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=[N:20][C:19]3[C:21]([CH:23]([CH3:24])[CH3:25])=[CH:22][C:16]([CH2:13][CH:14]=[CH2:15])=[CH:17][C:18]=3[CH:26]([CH3:28])[CH3:27])[CH3:11])[N:5]=2)[CH3:2])=[C:21]([CH:23]([CH3:24])[CH3:25])[CH:22]=1)[CH:14]=[CH2:15]
Reactant: C=CCc1cc(C(C)C)c(N)c(C(C)C)c1
Reactant: CC(=O)c1cccc(C(C)=O)n1
Solvent: CO
Solvent: O=CO
Product: C=CCc1cc(C(C)C)c(N=C(C)c2cccc(C(C)=Nc3c(C(C)C)cc(CC=C)cc3C(C)C)n2)c(C(C)C)c1

Procedure:
A solution containing 2,6-diacetylpyridine (0.30 g, 1.84 mmol), 4-allyl-2,6-diisopropylaniline (0.80 g, 3.68 mmol), and formic acid (2 ml) in 30 ml dry methanol was refluxed under argon for 14 hours. Yellow solid was collected by filtration and washed with cold methanol (3×5 ml). Recrystallization from CH2Cl2:hexane (1:4) yielded 0.70 g (68%) of yellow, 2,6-bis[1-(4-allyl-2,6-diisopropylphenylimino)ethyl]pyridine crystals. IR (KBr): v(C═N) 1639 cm−1. 1H-NMR (CDCl3): 8.47(d, 2H, Py-Hm), 7.92(t, 1H, Py-Hp), 6.98(s, 4H, Ph-Hm), 6.04(m, 2H, CH═C), 5.12(m, 4H, C═CH2), 3.40(d, 4H, CH2—C═C), 2.75(m, 4H, CH(Me)2), 2.27(s, 6H, CH3), 1.15(d, 24H, C(CH3)2); 13C-NMR(CDCl3): 167.04(C═N), 155.15(Py-C), 144.57(Ph-C), 138.12(Ph-C), 136.79(Py-C), 135.69(Ph-C), 134.75(—CH═), 123.16(Py-C), 122.12(Ph-C), 115.34(═CH2), 40.25(—CH2—), 28.31(C(Me)2), 23.24(CH3), 22.92(CH3), 17.14(CH3). C39H51N3 (561.86 g·mol-1): Anal. Calcd: C, 83.37; H, 9.15; N, 7.48. Found: C, 83.03; H, 9.13; N, 7.55.