Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@:11]([NH:15][C:16](=[O:19])[CH2:17]Cl)(C)[CH2:12][OH:13])[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[CH3:20]C([O-])(C)C.[K+].O>C(O)(C)(C)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:11]2[NH:15][C:16](=[O:19])[CH2:17][O:13][C@@H:12]2[CH3:20])[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: C[C@@](CO)(NC(=O)CCl)c1cc(Br)cc([N+](=O)[O-])c1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: C[C@H]1OCC(=O)NC1c1cc(Br)cc([N+](=O)[O-])c1
Temperature: 100 °C

Procedure:
N—[(R)-1-(3-Bromo-5-nitro-phenyl)-2-hydroxy-1-methyl-ethyl]-2-chloro-acetamide (4.45 g, 10.76 mmol) and KOtBu (2.414 g, 21.52 g) were suspended in 55 ml tert-butanol under N2 and heated 100° C. for 30 min. After completion water was added to the reaction and tert-butanol was removed under reduced pressure. The product was extracted with ethyl acetate from the remaining aqueous phase. The organic phases were washed with water and brine, combined and dried over Na2SO4. Volatiles were removed under reduced pressure. The crude product was purified by automated column chromatography (cyclohexane/ethyl acetate) yielding the title compound as tan solid. 1H-NMR (360 MHz, DMSO-d6): 8.88 (1H, NH), 8.35 (s, 1H), 8.28 (s, 1H), 8.14 (s, 1H), 4.16 (m, 1H), 4.06 (s, 2H), 3.74 (m, 1H), 1.50 (s, 3H); MS: 316 [(M+H)+].
Reaction SMILES: Cl.[NH2:2][C:3]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)=[C:4]([CH3:7])[C:5]#[N:6].C(N)(=[S:17])C>>[NH2:2][C:3]([C:8]1[CH:9]=[CH:10][C:11]([Cl:14])=[CH:12][CH:13]=1)=[C:4]([CH3:7])[C:5]([NH2:6])=[S:17]
Reactant: CC(N)=S
Reactant: CC(C#N)=C(N)c1ccc(Cl)cc1
Agent: Cl
Product: CC(C(N)=S)=C(N)c1ccc(Cl)cc1
Reaction time: 2 h
Yield: 82.3 %

Procedure:
Add hydrogen chloride (4 M in 1,4-dioxane, 858 mL, 16.0 equiv; 3.43 mol) to an E-/Z-mixture of 3-amino-3-(4-chlorophenyl)-2-methylacrylonitrile (41.3 g, 1.00 equiv, 214.4 mmol) and thioacetamide (32.71 g, 2 equiv, 2.00 equiv; 428.8 mmol) in a 2 L round bottom flask RBF (fitted with rubber septum, nitrogen blanket, stir bar and cooling bath). Maintain a solution temperature below 30° C. with an ice bath until the addition is complete. Remove the ice bath, stir for 2 h, and slowly add the mixture to 1.5 L of 30% aqueous NH4OH in an ice bath with stirring. Extract the mixture 2 times with ethyl acetate. Wash the organic phase 2 times with brine, dry (K2CO3), filter, and concentrated to dryness. Crystallize the mixture from hexane and chloroform (10/90). Triturate the resulting solid from ethanol and water (10/90) to afford 3-amino-3-(4-chlorophenyl)-2-methyl-thioacrylamide (as an uncharacterized E-/Z-mixture). Yield: 82.3%. 1H NMR (CD3OD) δ 9.95 (s, 2H), 8.74 (s, 1H), 8.29 (d, J=6.0 Hz, 2H), 8.25 (s, 1H), 8.11 (d, J=6.0 Hz, 2H), 4.099 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[C:3]=1[CH3:19].[CH3:20][C:21]1([CH3:40])[CH2:26][N:25]([C:27]2[CH:28]=[C:29]([NH2:39])[C:30]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[N:31][CH:32]=2)[CH2:24][CH2:23][O:22]1.Cl.O1CCOCC1.CN1C(=O)CCC1>>[CH3:20][C:21]1([CH3:40])[O:22][CH2:23][CH2:24][N:25]([C:27]2[CH:28]=[C:29]([NH:39][C:2]3[C:11]4[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=4)[N:5]=[C:4]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=4)[C:3]=3[CH3:19])[C:30]([N:33]3[CH2:34][CH2:35][O:36][CH2:37][CH2:38]3)=[N:31][CH:32]=2)[CH2:26]1
Reactant: CC1(C)CN(c2cnc(N3CCOCC3)c(N)c2)CCO1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CN1CCCC1=O
Product: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1Nc1cc(N2CCOC(C)(C)C2)cnc1N1CCOCC1
Temperature: 160 °C

Procedure:
Prepared according to Procedure K, method 2 using 4-chloro-7-fluoro-3-methyl-2-(pyridin-2-yl)quinoline (66.3 mg, 0.24 mmol; described herein), 5-(2,2-dimethylmorpholino)-2-morpholinopyridin-3-amine (71.0 mL, 0.243 mmol, described herein), 4.0M hydrochloric acid in 1,4-dioxane (60 μL, 0.24 mmol), and NMP (350 μL, 3.6 mmol), and heating in a microwave at 160° C. for 3 h. Purification afforded N-(5-(2,2-dimethyl-4-morpholinyl)-2-(4-morpholinyl)-3-pyridinyl)-7-fluoro-3-methyl-2-(2-pyridinyl)-4-quinolinamine as a yellow solid. 1H NMR (400 MHz, chloroform-d) δ ppm 8.74 (1H, dd, J=3.5, 1.2 Hz), 7.86-7.95 (2H, m), 7.78-7.86 (2H, m), 7.58 (1H, d, J=2.7 Hz), 7.40 (1H, ddd, J=6.9, 5.0, 1.8 Hz), 7.28-7.33 (1H, m), 6.83 (1H, s), 6.22 (1H, d, J=2.7 Hz), 3.93 (4H, t, J=4.7 Hz), 3.72-3.84 (3H, m), 3.65 (1H, t, J=5.9 Hz), 3.09-3.33 (4H, m), 2.80-2.93 (2H, m), 2.74 (2H, s), 2.37 (3H, s), 1.25-1.31 (4H, m). Mass Spectrum (ESI) m/e=529.2 (M+1).
Reaction SMILES: C1(=O)[N:5]([CH:6]2[CH2:9][N:8]([CH:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:11][C:12]([O:14][CH3:15])=[O:13])[C:7]2=[O:22])C(=O)C2=CC=CC=C12.CN(C)CCCN.CO.C(Cl)(Cl)Cl>C(OCC)(=O)C>[NH2:5][CH:6]1[CH2:9][N:8]([CH:10]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11][C:12]([O:14][CH3:15])=[O:13])[C:7]1=[O:22]
Reactant: COC(=O)CC(c1ccccc1)N1CC(N2C(=O)c3ccccc3C2=O)C1=O
Agent: CN(C)CCCN
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COC(=O)CC(c1ccccc1)N1CC(N)C1=O
Temperature: 25 °C
Reaction time: 17 h
Yield: 82.6 %

Procedure:
3-Phthalimido-1-(2-methoxycarbonyl-1-phenylethyl)-2-azetidinone (1.90 g.) and N,N-dimethyl-1,3-propanediamine (1.14 g.) were added to a mixture of methanol (20 ml.) and chloroform (5 ml.), whereafter the mixture was stirred at ambient temperature for 17 hours. The reaction mixture was evaporated to dryness under reduced pressure to give a residue, which was dissolved in ethyl acetate (20 ml.). The solution was extracted with three portions of an aqueous solution consisting of 1 N hydrochloric acid (5.3 ml.) and water (11.3 ml.), and then the combined extract was washed with ethyl acetate. The aqueous solution was adjusted to pH 8 with sodium bicarbonate under ice-cooling and then extracted with three 10 ml. portions of chloroform. The extracts were washed with water and then dried over magnesium sulfate. The solvent was removed by distillation from the solution under reduced pressure to give oily 3-amino-1-(2-methoxycarbonyl-1-phenylethyl)-2-azetidinone (1.030 g.).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15](C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C.I[C:38]1[C:39](=[O:59])[C:40]2[CH:45]=[CH:44][N:43]([CH2:46][CH2:47][O:48][CH3:49])[C:42](=[O:50])[C:41]=2[O:51][C:52]=1[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1>>[NH2:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:38]3[C:39](=[O:59])[C:40]4[CH:45]=[CH:44][N:43]([CH2:46][CH2:47][O:48][CH3:49])[C:42](=[O:50])[C:41]=4[O:51][C:52]=3[C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)=[CH:14][CH:13]=2)[CH2:9][CH2:10][CH2:11]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Reactant: COCCn1ccc2c(=O)c(I)c(-c3ccccc3)oc2c1=O
Product: COCCn1ccc2c(=O)c(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)oc2c1=O
Yield: 100 %

Procedure:
(1-{4-[7-(2-Methoxy-ethyl)-4,8-dioxo-2-phenyl-7,8-dihydro-4H-pyrano[2,3-c]pyridin-3-yl]-phenyl}-carbamic acid tert-butyl ester: Following the procedure used to prepare {1-[4-(6-fluoro-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester, 3-iodo-7-(2-methoxy-ethyl)-2-phenyl-7H-pyrano[2,3-c]pyridine-4,8-dione was reacted to give the title compound as a colourless oil (82 mg, 100%). LCMS (Method B): RT=4.63 min, [M+H]+=543.
Reaction SMILES: [C:1]1([C:7]2([C:12]([OH:14])=O)[CH2:11][CH2:10]CC2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:15][C:16]([F:34])([F:33])[C:17]1[CH:18]=[C:19]([CH:30]=[CH:31][CH:32]=1)[CH2:20][N:21]1[CH2:25][C@H:24]2[C@@H:26]([NH2:29])[CH2:27][CH2:28][C@H:23]2[CH2:22]1.[CH2:35](N1C[C@H]2C(N)CC[C@H]2C1)C1C=CC=CC=1>>[CH3:35][CH:11]([CH3:10])[CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:12]([NH:29][C@@H:26]1[C@H:24]2[C@H:23]([CH2:22][N:21]([CH2:20][C:19]3[CH:30]=[CH:31][CH:32]=[C:17]([C:16]([F:33])([F:15])[F:34])[CH:18]=3)[CH2:25]2)[CH2:28][CH2:27]1)=[O:14]
Reactant: O=C(O)C1(c2ccccc2)CCCC1
Reactant: N[C@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21
Reactant: NC1CC[C@H]2CN(Cc3ccccc3)C[C@@H]12
Product: CC(C)C(C(=O)N[C@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21)c1ccccc1

Procedure:
The title compound was prepared by substituting 3-methyl-2-phenylbutanoic acid for 1-phenylcyclopentanecarboxylic acid and (3aS*,4S*,6aR*)-2-(3-(trifluoromethyl)benzyl)octahydrocyclopenta[c]pyrrol-4-amine from Step E for (3aS*,6aR*)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine in Example 1: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.23 (d, J=6.9, 0.5H), 8.13 (d, J=7.1, 0.5H), 7.73 (s, 0.5H), 7.67 (s, 0.5H), 7.63 (dd, J=6.7, 8.0, 2H), 7.56-7.53 (m, 1H), 7.50 (t, J=8.5, 2H), 7.38-7.22 (m, 3H), 4.45-4.38 (m, 0.5H), 4.33-4.26 (m, 0.5H), 3.50 (s, 1H), 3.44 (d, J=13.4, 0.5H), 3.21 (d, J=13.4, 0.5H), 3.17 (d, J=10.5, 0.5H), 3.10 (d, J=10.5, 0.5H), 2.91 (qd, J=3.4, 7.9, 0.5H), 2.79 (dd, J=3.4, 9.5, 0.5H), 2.74-2.56 (m, 1.5H), 2.47-2.31 (m, 2.5H), 2.27 (dd, J=3.1, 8.9, 0.5H), 2.21 (d, J=2.7, 0.5H), 1.98-1.93 (m, 0.5H), 1.89-1.79 (m, 0.5H), 1.74-1.56 (m, 1.5H), 1.53-1.46 (m, 0.5H), 1.46-1.39 (m, 0.5H), 1.30-1.23 (m, 1H), 1.19 (d, J=6.5, 1.5H), 1.17-1.11 (m, 0.5H), 1.08 (d, J=6.5, 1.5H), 0.72 (dd, J=6.7, 9.6, 3H); MS (ESI+) m/z 445 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[C:6](=[S:15])[N:5]([CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[C:4](=[O:23])[C:3]=1[N:24]=O.C1(CN2C(N)=C(N)C(=O)N(CC3CCCCC3)C2=S)CCCCC1.[CH:50]([C:52]1[CH:62]=[CH:61][C:55]([CH:56]=[CH:57][C:58]([OH:60])=[O:59])=[CH:54][CH:53]=1)=O>C(O)C>[CH:17]1([CH2:16][N:5]2[C:4](=[O:23])[C:3]3[N:24]=[C:50]([C:52]4[CH:62]=[CH:61][C:55](/[CH:56]=[CH:57]/[C:58]([OH:60])=[O:59])=[CH:54][CH:53]=4)[NH:1][C:2]=3[N:7]([CH2:8][CH:9]3[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]3)[C:6]2=[S:15])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: Nc1c(N=O)c(=O)n(CC2CCCCC2)c(=S)n1CC1CCCCC1
Reactant: O=Cc1ccc(C=CC(=O)O)cc1
Agent: Nc1c(N)n(CC2CCCCC2)c(=S)n(CC2CCCCC2)c1=O
Solvent: CCO
Product: O=C(O)/C=C/c1ccc(-c2nc3c(=O)n(CC4CCCCC4)c(=S)n(CC4CCCCC4)c3[nH]2)cc1
Temperature: 25 °C
Yield: 55.8 %

Procedure:
In the manner of step (d) of example 8, 6-amino-1,3-bis(cyclohexylmethyl-1,2-dihydro-5-nitroso-2-thioxo-4(3H)-pyrimidinone (from step (c), 3.00 g, 8.20 mmol) was reduced to 1,3-bis(cyclohexylmethyl)-5,6-diamino-1,2-dihydro-2-thioxo-4(3H)-pyrimidinone, which was then combined with 4-formylcinnamic acid (Aldrich, 1.44 g, 8.20 mmol) in ethanol (150 mL). The resulting yellow mixture was dried by evaporation of several portions of absolute ethanol, and the residual yellow powder (Schiff base intermediate) was heated at reflux in nitrobenzene (150 mL) until no more water distilled off. The reaction mixture was then cooled to ambient temperature, and stirred in ether (200 ml). The resulting pale yellow precipitate was filtered off, washed with hot ethanol (100 mL), followed by ether (100 mL), and dried under vacuum at 110° C. to afford (E)-4-(1,3-bis(cyclohexylmethyl)-1,2,3,6-tetrahydro-6-oxo-2-thioxo-9H-purin-8-yl)cinnamic acid as a yellow powder (2.32 g, 65%), m.p. >300° C.; 1H-NMR (DMSO-d6) consistent with structure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7](=O)[CH:8]2[CH3:13].C(O)(=O)C.[CH:19]1([CH2:22][NH2:23])[CH2:21][CH2:20]1>C(O)C>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][C@H:7]([NH:23][CH2:22][CH:19]1[CH2:21][CH2:20]1)[C@@H:8]2[CH3:13]
Reactant: NCC1CC1
Reactant: COc1cccc2c1CCC(=O)C2C
Solvent: CCO
Solvent: CC(=O)O
Product: COc1cccc2c1CC[C@H](NCC1CC1)[C@@H]2C
Temperature: 80 °C

Procedure:
To a solution of 5-methoxy-1-methyl-2-tetralone (2.0 g) in absolute ethanol (50 ml) are added acetic acid (1.9 g), cyclopropylmethylamine (2.0 g) and 4 Å molecular sieves. The mixture is heated in a closed flask at 80° C. for one hour. The molecular sieves are filtered off and the solution is hydrogenated (PtO2) at atmospheric pressure. The catalyst is filtered off (Celite) and the volatiles are evaporated. Dilute hydrochloric acid (50 ml) is added to the solid residue. The resulting acidic solution is washed with ether, made basic 5% sodium hydroxide and extracted twice with ether. The ether extracts are combined, dried (sodium sulfate) and evaporated. The resulting crude base is eluted through an alumina column with ether-light petroleum (1:4).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:16][OH:17])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=1.Cl[C:19]1[CH:35]=[C:23]2[N:24](C(OC(C)(C)C)=O)[CH2:25][CH2:26][CH2:27][N:22]2[C:21](=[O:36])[N:20]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=1)[CH2:16][O:17][C:19]1[CH:35]=[C:23]2[NH:24][CH2:25][CH2:26][CH2:27][N:22]2[C:21](=[O:36])[N:20]=1
Reactant: CC(C)(C)OC(=O)N1CCCn2c1cc(Cl)nc2=O
Reactant: OCc1ccc(Oc2cccc(F)c2)c(F)c1
Product: O=c1nc(OCc2ccc(Oc3cccc(F)c3)c(F)c2)cc2n1CCCN2

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E111 starting from (3-fluoro-4-(3-fluorophenoxyl)phenyl)methanol and tert-butyl 8-chloro-6-oxo-2,3,4,6-tetrahydro-1H-pyrimido[1,6-a]pyrimidine-1-carboxylate.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:5][CH3:6])[CH3:4].[C:7]1([CH3:17])[CH:12]=[CH:11][C:10](S(O)(=O)=O)=[CH:9][CH:8]=1>CCOCC>[CH3:4][CH:3]1[O:5][CH2:6][CH2:17][CH:7]2[CH:1]([CH2:9][CH2:8][CH2:7][CH2:12][CH2:11][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]2)[O:2]1
Reactant: COC(C)OC
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Product: CC1OCCC2CCCCCCCCCCC2O1
Temperature: 70 °C

Procedure:
A mixture of 240 gm (1 mol) of the diol prepared according to (c) above, 90 gm (1 mol) of acetaldehyde dimethyl acetal, and 0.2 gm of p-toluene sulfonic acid was refluxed for five hours at 70° C. After the reaction was completed, the reaction mixture was taken up in ether, washed neutral with 2 N sodium hydroxide solution, washed with water, and then dried over anhydrous sodium sulfate. The ether and methanol were distilled off, and then the residue was distilled in the oil-pump vacuum. The 14-methyl-13,15-dioxabicyclo[10.5.0]heptadecane obtained was a colorless liquid with the following characteristics:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:20]([F:23])([F:22])[F:21])=[C:6]([CH:19]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16](I)=[CH:17][C:9]1=2.[CH2:24]([O:26][C:27]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)=[O:28])[CH3:25]>>[CH2:24]([O:26][C:27](=[O:28])[C:29]1[CH:34]=[CH:33][C:32]([C:16]2[CH:15]=[N:14][C:10]3[NH:11][CH2:12][CH2:13][N:8]([CH2:7][C:6]4[CH:19]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=4[C:20]([F:23])([F:22])[F:21])[C:9]=3[CH:17]=2)=[CH:31][CH:30]=1)[CH3:25]
Reactant: CCOC(=O)c1ccc(B(O)O)cc1
Reactant: FC(F)(F)c1ccc(Cl)cc1CN1CCNc2ncc(I)cc21
Product: CCOC(=O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1

Procedure:
1-[5-Chloro-2-(trifluoromethyl)benzyl]-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (7.0 g) was reacted with 4-ethoxycarbonyl phenyl boronic acid as in General Procedure 4A. The title compound was obtained as a yellow solid (71% yield). M.p.=154° C., LCMS: m/z=476.04 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 1.40, (t, 3H), 3.49 (m, 2H), 3.71 (m, 2H), 4.35 (q, 2H), 4.61 (s, 2H), 5.72 (bs, 1H), 6.62 (s, 1H), 7.44 (m, 3H), 7.50 (s, 1H), 7.63 (d, 1H), 7.72 (s, 1H), 8.07 (d, 2H).
Reaction SMILES: FC(F)(F)C([O-])=O.[C:8]([C:10]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[CH:20][C:11]=1[O:12][CH2:13][C@H:14]1[CH2:19][CH2:18][CH2:17][CH2:16][NH2+:15]1)#[N:9].C(N(CC)CC)C.[N:34]1[CH:39]=[CH:38][C:37]([CH2:40][NH:41][C:42](=O)[O:43]C2C=CC([N+]([O-])=O)=CC=2)=[CH:36][CH:35]=1.O>ClCCl>[C:8]([C:10]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[CH:20][C:11]=1[O:12][CH2:13][C@H:14]1[CH2:19][CH2:18][CH2:17][CH2:16][N:15]1[C:42]([NH:41][CH2:40][C:37]1[CH:38]=[CH:39][N:34]=[CH:35][CH:36]=1)=[O:43])#[N:9]
Reactant: O=C(NCc1ccncc1)Oc1ccc([N+](=O)[O-])cc1
Reactant: N#Cc1c(OC[C@H]2CCCC[NH2+]2)cccc1[N+](=O)[O-]
Agent: O=C([O-])C(F)(F)F
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1c(OC[C@H]2CCCCN2C(=O)NCc2ccncc2)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 23 h
Yield: 30.9 %

Procedure:
To a solution of (R)-2-((2-cyano-3-nitrophenoxy)methyl)piperidinium 2,2,2-trifluoroacetate (Example 16c, 1.12 g, 2.99 mmol) in dichloromethane (5 mL), was added triethylamine (420 uL, 3.01 mmol). To that mixture was added a suspension of 4-nitrophenyl pyridin-4-ylmethylcarbamate (Example 27d, 980 mg, 3.59 mmol) in dichloromethane (5 mL), followed by triethylamine (420 uL, 3.01 mmol). After stirring for 23 h at room temperature, additional portions of 4-nitrophenyl pyridin-4-ylmethylcarbamate (980 mg, 3.59 mmol) and triethylamine (420 uL, 3.01 mmol) were added, and the resulting reaction mixture was stirred for 1 h, at which time it was poured into water, and washed successively with saturated aqueous NaHCO3 water and brine, dried over MgSO4, filtered, concentrated and purified by flash chromatography (0-100% ethyl acetate in hexanes followed by 0-10% methanol in dichloromethane) to provide (R)-2-((2-cyano-3-nitrophenoxy)methyl)-N-(pyridin-4-ylmethyl)piperidine-1-carboxamide (365 mg, 32%). MS=396 (MH+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.[NH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1.CO.[BH4-].[Na+]>O>[N:14]1[CH:15]=[CH:16][CH:17]=[C:12]([CH2:11][CH2:10][NH:9][CH2:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH:13]=1
Reactant: NCCc1cccnc1
Reactant: O=Cc1ccncc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: c1cncc(CCNCc2ccncc2)c1
Temperature: 25 °C
Reaction time: 7 h
Yield: 94.1 %

Procedure:
4-Pyridinecarbaldehyde (5.36 g, 50 mmol) and 3-(2-aminoethyl)pyridine (6.5 ml, 50 mmol) were added to methanol (100 ml), and stirred at room temperature for 7 hours. The resulting mixture was cooled to 0° C. Sodium borohydride (2.8 g, 74 mmol) was added to the mixture, and stirred at 0° C. for 1 hour. Water was then added to the reaction mixture to distill the methanol off under reduced pressure. The residue was extracted with dichloromethane. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate:methanol=95:5→85:5). The purified product was concentrated under reduced pressure to thereby obtain 10.03 g (yield: 94%) of (2-pyridin-3-ylethyl)pyridin-4-ylmethylamine as a colorless oil.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:10])[CH2:5][CH2:6][CH2:7][NH:8][CH3:9].[C:11]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH:17][C:18]([O:20][CH:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][C:29](O)=[O:30])[CH2:23][CH2:22]1)=[O:19].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>C(Cl)Cl.O>[CH3:2][O:3][C:4](=[O:10])[CH2:5][CH2:6][CH2:7][NH:8][CH2:9][C:29](=[O:30])[CH2:28][CH2:27][N:24]1[CH2:25][CH2:26][CH:21]([O:20][C:18](=[O:19])[NH:17][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:22][CH2:23]1
Reactant: O=C(O)CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1
Reactant: CNCCCC(=O)OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)CCCNCC(=O)CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1
Yield: 127.4 %

Procedure:
To a stirred mixture of 4-methylaminobutyric acid methyl ester hydrochloride (546 mg, 3.26 mmol) and 3-[4-(biphenyl-2-ylcarbamoyloxy)piperidin-1-yl]propionic acid (1.20 g, 3.26 mmol) in DCM (15 mL) was added N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (1.36 g, 3.58 mmol) followed by N,N-diisopropylethylamine (1.42 mL, 8.15 mmol). LC-MS (Method 2-90) showed product was present (Rt 3.11 min; m/z 482.4 [M+H]+). Water and DCM were added and the layers were separated. The organic layer was washed with water (2×) and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (2.0 g, 100% yield) as a light yellow oil.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][S:5](=[O:8])[CH2:4][CH2:3]1.[CH2:9]([C:11]1[CH:12]=[C:13]([O:29][C:30]2[CH:31]=[N:32][C:33]([S:36]([CH3:39])(=[O:38])=[O:37])=[CH:34][CH:35]=2)[CH:14]=[C:15]2[C:19]=1[NH:18][C:17]([C:20]1[S:21][CH:22]([CH2:25][C:26](O)=[O:27])[CH2:23][N:24]=1)=[CH:16]2)[CH3:10].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.O.C(N(CC)CC)C>[CH2:9]([C:11]1[CH:12]=[C:13]([O:29][C:30]2[CH:31]=[N:32][C:33]([S:36]([CH3:39])(=[O:37])=[O:38])=[CH:34][CH:35]=2)[CH:14]=[C:15]2[C:19]=1[NH:18][C:17]([C:20]1[S:21][CH:22]([CH2:25][C:26]([N:2]3[CH2:7][CH2:6][S:5](=[O:8])[CH2:4][CH2:3]3)=[O:27])[CH2:23][N:24]=1)=[CH:16]2)[CH3:10]
Reactant: CCc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Reactant: O=S1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(=O)N4CCS(=O)CC4)S3)[nH]c12
Reaction time: 15 h
Yield: 58 %

Procedure:
To a solution of thiomorpholine 1-oxide hydrochloride (340 mg) and triethylamine (0.31 mL) in N,N-dimethylformamide (25 mL) were added [2-(7-ethyl-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]acetic acid (500 mg), 1-hydroxybenzotriazole (300 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (420 mg) under ice-cooling, and the mixture was stirred under ice-cooling and then at room temperature for 15 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:methanol=100:0 to 80:20, volume ratio), and the obtained pale-yellow crystals were recrystallized from tetrahydrofuran-ethyl acetate to give the title compound (354 mg, yield 58%) as colorless crystals. melting point 194-196° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:19]3[CH2:20][CH2:21][CH2:22][CH:12]2[C:13]2[CH:14]=[N:15][NH:16][C:17]=2[CH2:18]3)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:23]([O:26][C:27](Cl)=[O:28])[CH:24]=[CH2:25]>>[CH2:23]([O:26][C:27]([N:15]1[N:16]=[C:17]2[C:13]([CH:12]3[N:11]([S:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)(=[O:9])=[O:10])[CH:19]([CH2:18]2)[CH2:20][CH2:21][CH2:22]3)=[CH:14]1)=[O:28])[CH:24]=[CH2:25]
Reactant: C=CCOC(=O)Cl
Reactant: O=S(=O)(c1ccc(Cl)cc1)N1C2CCCC1c1cn[nH]c1C2
Product: C=CCOC(=O)n1cc2c(n1)CC1CCCC2N1S(=O)(=O)c1ccc(Cl)cc1

Procedure:
Prepared by acylation of 12-(4-chloro-benzenesulfonyl)-4,5,12-triaza-tricyclo[6.3.1.02,6]dodeca-2(6),3-diene using allylchloroformate
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].CO[CH2:12][CH2:13][O:14][CH3:15]>C([O-])(O)=O.[Na+].CCOCC.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>[CH3:6][C:3]1[CH:4]=[CH:12][C:13]2[O:14][C:15]([C:2]3[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=3[C:4]#[N:5])=[CH:8][C:9]=2[CH:2]=1
Reactant: COCCOC
Reactant: N#Cc1ccccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: Cc1ccc2oc(-c3ccccc3C#N)cc2c1
Temperature: 25 °C

Procedure:
Intermediate 1 (20 g) was added to a stirred solution of 2-bromobenzonitrile (10.34 g) and tetrakis(triphenylphosphine)palladium (0) (1.5 g) in DME (200 ml) and 8% NaHCO3 (50 ml) at reflux under nitrogen. Further catalyst (1.5 g) was added and the reaction continued overnight. The reaction was cooled to room temperature and diluted with ether (200 ml). The organic layer was separated, washed with water (3×100 ml) and dried. Filtration and evaporation gave a white solid which was purified by chromatography eluting with System A (1:9) to give the title compound (10.58 g) as a white solid. T.l.c. System A (1:9), Rf 0.45.