Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C@@H:13]3[CH2:15][C@H:14]3[C:16]3[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=3)[C:19]#[N:20])=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.C(N)(=[O:26])C>C1COCC1.O.[Pd](Cl)Cl>[CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C@@H:13]3[CH2:15][C@H:14]3[C:16]3[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=3)[C:19]([NH2:20])=[O:26])=[O:12])[CH2:7][CH2:6]2)[CH2:2][CH2:3][CH2:4]1
Reactant: N#Cc1cccc([C@@H]2C[C@H]2C(=O)N2CCN(C3CCC3)CC2)c1
Reactant: CC(N)=O
Agent: Cl[Pd]Cl
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)c1cccc([C@@H]2C[C@H]2C(=O)N2CCN(C3CCC3)CC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.3 %

Procedure:
33C (180 mg, 0.58 mmol) was dissolved in THF (3 mL) and added to acetamide (687 mg, 11.64 mmol) and palladium(II) chloride (61.9 mg, 0.35 mmol) in H2O (1 mL). This suspension was left stirring at RT for 1 h then the temperature was increased to 50° C. and reaction stirred for 2 h. The reaction mixture was filtered on a Varian C18 reverse phase cartridge and the cartridge was washed with MeOH. The crude material was purified on preparative HPLC MS using the long high pH 25 to 45% gradient method (ACN in H2O ammonium carbonate buffer, 25 min.) on XBridge Prep C18 OBD, 30×150 mm, 5 mm, Waters reverse phase column. Evaporation of the desired pure fractions provided 105 mg 33D (55.1% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.28-1.39 (m, 1H) 1.63-1.79 (m, 3H) 1.80-1.96 (m, 2H) 1.97-2.13 (m, 3H) 2.32 (q, J=4.82 Hz, 4H) 2.56 (ddd, J=9.28, 5.76, 4.10 Hz, 1H) 2.65-2.83 (m, 1H) 3.54-3.77 (m, 4H) 5.58 (br. s., 1H) 6.07 (br. s., 1H) 7.30-7.43 (m, 2H) 7.52-7.61 (m, 2H), ES (M+H)+=328.3.
Reaction SMILES: [CH2:1]([N:4]([CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)[C:5](=[O:34])[C:6]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH:20]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:14][CH2:13]2)[CH:9]=[CH:8][C:7]=1F)[CH:2]=[CH2:3].F[C:42]1[CH:50]=CC([N+]([O-])=O)=C[C:43]=1C(O)=O.C(NC1CCCCC1)C=C>>[CH2:1]([N:4]([CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)[C:5](=[O:34])[C:6]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH:20]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:14][CH2:13]2)[CH:9]=[CH:8][C:7]=1[CH:42]([CH3:50])[CH3:43])[CH:2]=[CH2:3]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1F
Reactant: C=CCN(C(=O)c1cc(N2CCN(CCC(c3ccccc3)c3ccccc3)CC2)ccc1F)C1CCCCC1
Agent: C=CCNC1CCCCC1
Product: C=CCN(C(=O)c1cc(N2CCN(CCC(c3ccccc3)c3ccccc3)CC2)ccc1C(C)C)C1CCCCC1

Procedure:
Steps (a) and (b) of Example 59 were repeated, except that the compound prepared just above in step (a) was used instead of 2-fluoro-5-nitrobenzoic acid. Step (d) of Example 1 was then repeated, except that N-allylcyclohexylamine was used instead of N-methylbenzylamine. Thus, the title compound was prepared.
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:9]=[C:8](I)[N:7]=[CH:6][N:5]=1.[CH3:11][C:12]1[C:17]2[O:18][CH2:19][CH2:20][O:21][C:16]=2[CH:15]=[C:14]([CH:22]=[O:23])[CH:13]=1.[Cl-].C[N+]1C=CN(C)C=1>C1COCC1>[I:3][C:4]1[N:5]=[CH:6][N:7]=[C:8]([C:22]([C:14]2[CH:13]=[C:12]([CH3:11])[C:17]3[O:18][CH2:19][CH2:20][O:21][C:16]=3[CH:15]=2)=[O:23])[CH:9]=1
Reactant: Cc1cc(C=O)cc2c1OCCO2
Reactant: Ic1cc(I)ncn1
Agent: Cn1cc[n+](C)c1
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: Cc1cc(C(=O)c2cc(I)ncn2)cc2c1OCCO2
Temperature: 0 °C

Procedure:
0.131 g (3.00 mmol) sodium hydride (55%, suspension in mineral oil) were added to 0.677 g (2.00 mmol) 4,6-diiodopyrimidine, 0.535 g (3.00 mmol) 8-methyl-2,3-dihydro-benzo[1,4]dioxin-6-carbaldehyde (US2005/256099) and 0.133 g (1.00 mmol) 1,3-dimethylimidazolium chloride in 10 mL THF and the mixture was refluxed for 4 h. Then the reaction mixture was mixed with ice water and extracted with EtOAc. The organic phase was dried on sodium sulphate, evaporated down i. vac. and the residue was purified by preparative HPLC-MS. The fractions containing the product were combined and the organic solvent was evaporated down i. vac. The residue was made alkaline with 1N aqueous sodium hydroxide solution and the grease precipitated was extracted with EtOAc. The organic phase was dried on sodium sulphate, filtered, evaporated down and dried i. vac.
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:3]=1[C:4]([O:6][CH2:7][CH2:8][O:9][CH3:10])=[O:5].S(Cl)([Cl:19])(=O)=O.CC(N=NC(C#N)(C)C)(C#N)C>O>[Cl:19][CH2:1][C:2]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:3]=1[C:4]([O:6][CH2:7][CH2:8][O:9][CH3:10])=[O:5]
Reactant: O=S(=O)(Cl)Cl
Reactant: COCCOC(=O)c1c(C)cccc1C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: O
Product: COCCOC(=O)c1c(C)cccc1CCl

Procedure:
10.4 g of 2-methoxyethyl 2,6-dimethylbenzoate are admixed at room temperature with 5.4 g of sulfuryl chloride and 40 mg of AIBN. The mixture is stirred at 60–90° C. for 1–2 h. Afterwards, the mixture is admixed with 20 ml of water, the phases are separated and the organic phase is dried over magnesium sulfate. The product is distilled under high vacuum (0.02 mbar, 95–103° C.). Yield: 6.4 g (66% of theory; 91.8 area %).
Reaction SMILES: [CH3:1][C:2]1[CH2:11][CH:10]=[C:9]2[C:4]([CH3:14])([CH2:5][CH2:6][CH2:7][C:8]2([CH3:13])[CH3:12])[C:3]=1[CH2:15][CH:16]=[O:17].[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>CCOCC>[CH3:1][C:2]1[CH2:11][CH:10]=[C:9]2[C:4]([CH3:14])([CH2:5][CH2:6][CH2:7][C:8]2([CH3:12])[CH3:13])[C:3]=1[CH2:15][CH2:16][OH:17]
Reactant: CC1=C(CC=O)C2(C)CCCC(C)(C)C2=CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: CC1=C(CCO)C2(C)CCCC(C)(C)C2=CC1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 90 %

Procedure:
A solution of (2,5,5,8a-tetramethyl-3,5,6,7,8,8a-hexahydro-1-naphthalenyl)acetaldehyde obtained in step A) (3.40 g; 14.2 mmol) in Et2O (10 ml) was added drop-wise to a stirred suspension of LiAlH4 (410 mg; 10.7 mmol) in Et2O (20 ml) at such a rate that a gentle reflux was maintained (5 minutes). The suspension was heated at reflux for 30 minutes, cooled at 0° C. and treated successively drop-wise with water (0.4 ml), 5% aqueous NaOH (0.4 ml) and water (3×0.4 ml). After stirring for 5 minutes at room temperature the suspension was filtered over Celite and the filtrate concentrated. Bulb-to-bulb distillation (130° C. (oven temp.)/0.03 mbar) afforded pure 2-(2,5,5,8a-tetramethyl-3,5,6,7,8,8a-hexahydro-1-naphthalenyl)ethanol (1) (3.21 g; yield=90%).
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]#[N:24])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][N:28]=1>>[CH3:33][C:31]1[CH:30]=[CH:29][N:28]=[C:27]([C:4]([C:6]2[N:7]=[CH:8][N:9]([C:11]3[CH:12]=[C:13]([C:17]4[C:18]([C:23]#[N:24])=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:14]=[CH:15][CH:16]=3)[CH:10]=2)=[O:5])[CH:32]=1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3ccccc3C#N)c2)cn1
Reactant: Cc1ccnc(Br)c1
Product: Cc1ccnc(C(=O)c2cn(-c3cccc(-c4ccccc4C#N)c3)cn2)c1

Procedure:
This compound is prepared by method C using compound 12d and 2-bromo-4-methylpyridine.
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([CH:13]=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2].Br[C:18]1[S:22][C:21]2[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:20]=2[C:19]=1[CH3:28].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([C:18]3[S:22][C:21]4[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:20]=4[C:19]=3[CH3:28])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: Cc1c(Br)sc2ccc(F)cc12
Reactant: CCC(CC)c1cc(C)nn2cc(C)nc12
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CCC(CC)c1cc(C)nn2c(-c3sc4ccc(F)cc4c3C)c(C)nc12
Temperature: 130 °C
Reaction time: 24 h
Yield: 59.4 %

Procedure:
A mixture of 8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (435 mg, 2.0 mmol, 1.0 equiv), 2-bromo-5-fluoro-3-methylbenzo[b]thiophene (564 mg, 2.3 mmol, 1.15 equiv), triphenylphosphine (100 mg, 0.38 mmol, 0.19 equiv), Cs2CO3 (1.37 g, 4.2 mmol, 2.1 equiv) and Pd2 dba3 (88 mg, 0.096 mmol, 0.048 equiv) in DMF (4.5 mL, degassed by sparging with nitrogen for 30 min. prior to use) is heated at 130° C. for 4 hr (magnetically-stirred under an atmosphere of N2). The reaction is cooled and partitioned between MTBE (10 mL) and satd. NH4Cl solution (10 mL). The organic phase is washed with satd. NH4Cl solution (2×5 mL), dried (Na2SO4) and concentrated in vacuo to a brown film, which is adsorbed onto silica gel (1.0 g). Material is flash chromatographed (10 g of silica gel; heptane to 5% EtOAc in heptane to 10% EtOAc in heptane) and fractions containing pure product were combined and concentrated. The residue is stirred in warm heptane (6 mL) for 10 min. then refrigerated at −20° C. for 24 hr. Light yellow crystals are separated, washed with cold heptane and dried. The product is recrystallized from MeOH (3 mL) to provide the title compound as light yellow crystals (453 mg, 65%).
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:15]3[S:16][C:17]4[C:23]([O:24][CH3:25])=[CH:22][C:21]([CH3:26])=[CH:20][C:18]=4[CH:19]=3)[C:9]([CH2:13][OH:14])=[C:10]([C:11]#[N:12])[N:6]2[N:5]=[CH:4][N:3]=1.S(Cl)(Cl)=O.[CH3:31][CH2:32]N(C(C)C)C(C)C>ClCCl.C(O)C>[NH2:1][C:2]1[C:7]2=[C:8]([C:15]3[S:16][C:17]4[C:23]([O:24][CH3:25])=[CH:22][C:21]([CH3:26])=[CH:20][C:18]=4[CH:19]=3)[C:9]([CH2:13][O:14][CH2:31][CH3:32])=[C:10]([C:11]#[N:12])[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1cc(C)cc2cc(-c3c(CO)c(C#N)n4ncnc(N)c34)sc12
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CCO
Product: CCOCc1c(-c2cc3cc(C)cc(OC)c3s2)c2c(N)ncnn2c1C#N
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of Example 68 (60 mg, 164 μmol) in dichloromethane (5 ml) was treated with thionyl chloride (18 μl, 246 μmol). The mixture was stirred at rt for 15 min and then evaporated. The residue was dissolved in ethanol (2 ml) and treated with DIPEA (57 μl, 328 μmol). The mixture was stirred at 60° C. overnight and then heated to 150° C. for 30 min in a microwave device. After this, the mixture was evaporated, and the residue was purified by preparative RP-HPLC (Reprosil C18, gradient 10-95% acetonitrile/0.1% aq. TFA). The product thus obtained was dissolved in ethanol (2 ml) and again heated to 150° C. for 30 min in the microwave oven. DIPEA (57 μl, 328 μmol) was added, and heating to 150° C. in the microwave oven was continued for further 30 min. After evaporation, the residue was purified by column chromatography on silica gel (dichloromethane/methanol 95:5) affording 16 mg (23% of th.) of the title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][S:8]([C:11]1[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=1)(=[O:10])=[O:9].[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1B(O)O>>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([C:22]2[CH:21]=[CH:20][C:19]([Cl:18])=[CH:24][C:23]=2[Cl:25])=[CH:13][CH:12]=1)(=[O:10])=[O:9]
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: O=S(=O)(NCCCCCO)c1ccc(Br)cc1
Product: O=S(=O)(NCCCCCO)c1ccc(-c2ccc(Cl)cc2Cl)cc1

Procedure:
Using a method analogous to that described in Example 40, 4-bromophenyl-sulfonic acid-(5-hydroxypentyl)-amide and 2,4-dichlorophenyl boronic acid were reacted to give the title compound as a white solid. δC (DMSO, 62.9 MHz): 22.6, 29.0, 32.0, 42.7, 60.5, 126.5, 127.8, 129.5, 130.0, 132.3, 132.7, 133.7, 137.4, 140.3 and 141.3.
Reaction SMILES: C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+].[CH2:53]([C:55]1[CH:56]([C:61]([O:63][CH2:64][CH3:65])=[O:62])[CH2:57][C:58](=[O:60])[CH:59]=1)[CH3:54].C(O)(C)(C)C>C1(C)C=CC=CC=1.[Cu]Cl>[CH2:53]([CH:55]1[CH2:59][C:58](=[O:60])[CH2:57][CH:56]1[C:61]([O:63][CH2:64][CH3:65])=[O:62])[CH3:54]
Reactant: CCOC(=O)C1CC(=O)C=C1CC
Agent: Cl[Cu]
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CC(=O)CC1CC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
In a 1 L round-bottomed jacketed flask, copper(I) chloride (0.679 g, 6.86 mmol), (S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (4.27 g, 6.86 mmol), and sodium tert-butoxide (0.6.59 g, 6.86 mmol) in toluene (250 mL) were added to give a brown solution. The mixture was stirred at ambient temperature for 15 min after which the solution became brown. The solution was cooled to about 5° C. and polymethylhydrosiloxane (18.29 mL, 274 mmol) was added and the reaction mixture was stirred at about 5° C. for about 40 min. The solution was cooled to about −15° C. and a solution of ethyl 2-ethyl-4-oxocyclopent-2-enecarboxylate (25.00 g, 137 mmol) and tert-butyl alcohol (69.9 mL, 741 mmol) in toluene (250 mL) was added in one portion and the reaction stirred at about −15° C. for about 120 h. The reaction mixture was quenched by the addition of 1:1 ethanol/toluene (350 mL) and Celite® 545 (25 g). The mixture was stirred for about 3 h and allowed to warm to ambient temperature. The reaction mixture was concd in vacuo, chasing with heptane. Heptane (350 mL) was added to the residue and solids were removed by filtration. The filtrate was concd in vacuo and the crude product was purified by silica gel chromatography using a gradient of 10 to 50% EtOAc in heptane over 7 column volumes to give ethyl 2-ethyl-4-oxocyclopentanecarboxylate as a scalemic mixture of diastereomers, predominantly (1S,2R)-ethyl 2-ethyl-4-oxocyclopentanecarboxylate (13.68 g, 54%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 4.17 (qd, J=7.1, 1.5, 2H), 3.25-3.18 (m, 1H), 2.55 (m, J=4.7, 3.5, 1.7, 1H), 2.46-2.29 (m, 3H), 2.21 (m, J=11.6, 9.8, 1.3, 1H), 1.53 (m, J=14.8, 7.4, 6.1, 1H), 1.42-1.30 (m, 1H), 1.27 (t, J=7.1, 3H), 0.98 (t, J=7.4, 3H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@H:11]([N:29]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:12][O:13][C:14]2[S:15][C:16]([C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[CH:25]=[N:24][CH:23]=[CH:22]4)=[N:17][N:18]=2)=[CH:2]1.O.O.NN>C(O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@H:11]([NH2:29])[CH2:12][O:13][C:14]2[S:15][C:16]([C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[CH:25]=[N:24][CH:23]=[CH:22]4)=[N:17][N:18]=2)=[CH:2]1
Reactant: O=C1c2ccccc2C(=O)N1[C@H](COc1nnc(-c2ccc3cnccc3c2)s1)Cc1c[nH]c2ccccc12
Agent: NN
Solvent: CCO
Solvent: O
Product: N[C@H](COc1nnc(-c2ccc3cnccc3c2)s1)Cc1c[nH]c2ccccc12
Temperature: 100 °C

Procedure:
(S)-2-(1-Hydroxy-3-(1H-indol-3-yl)propan-2-yl)isoindoline-1,3-dione (150 mg, 0.47 mmol) and 60% sodium hydride in mineral oil (37.6 mg, 0.94 mmol) was mixed in 2 ml N-methylpyrrolidinone. After stirring for ten minutes, compound 1b suspended in 2 ml N-methylpyrrolidinone was added and the reaction mixture was stirred at 20° C. for an hour. The reaction mixture was partitioned between ethylacetate and saturated aqueous ammonium chloride. The ethylacetate phase was washed with more saturated aqueous ammonium chloride and dried over anhydrous sodium sulfate. After removing the ethylacetate, the remaining residue was subjected to a silica gel column chromatography separation to yield the intermediate 2-((S)-3-(1H-indol-3-yl)-1-(5-(isoquinolin-6-yl)-1,3,4-thiadiazol-2-yloxy)propan-2-yl)isoindoline-1,3-dione (3a). Compound 3a was dissolved in 4 ml ethyl alcohol, 0.5 ml water and 0.5 ml hydrazine monohydrate in a microwave heating tube. The tube was heated at 100° C. under microwave for five minutes. After removing all the solvent, the residue was subjected to a C18 reverse phase HPLC separation to yield (2S)-1-(1H-indol-3-yl)-3-(5-(isoquinolin-6-yl)-1,3,4-thiadiazol-2-yloxy)propan-2-amine (3) (2.4 mg) as a TFA salt. 1H NMR (400 MHz, Methanol-d4): δ 3.08 (m, 1H), 3.12 (m, 1H), 3.58 (m, 2H), 3.74 (m, 1H), 7.33 (t, J=7.2 Hz, 1H), 7.41 (t, J=7.2 Hz, 1H), 7.69 (d, J=7.6 Hz, 1H), 8.32 (m, 2H), 8.46 (d, J=8.8 Hz, 1H), 8.53 (m, 2H), 8.72 (s, 1H), 9.60 (s, 1H); MS (API-ES) m/z (%): 402 (95%, M++1), 424 (100%, M+Na+); HRMS (ESI): calculated for C22H19N5OS [M+1]: 402.1388; found: 402.1394.
Reaction SMILES: C(=O)(O)N.[N:5]1[N:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]2=[C:7]([C:14](OC)=O)[CH:6]=1.[CH:18]([Sn](CCCC)(CCCC)CCCC)=[CH2:19]>C1(C)C=CC=CC=1.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>[CH3:10][N:9]1[C:8]2[C:7](=[CH:14][CH:11]=[CH:12][CH:13]=2)[C:6]([CH:18]=[CH2:19])=[N:5]1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)c1cnn2ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: NC(=O)O
Solvent: Cc1ccccc1
Product: C=Cc1nn(C)c2ccccc12

Procedure:
A solution of compound 1 (1.6 g, 8 mmol) and vinyl tributyl tin (2.6 mL, 11 mmol) in toluene (10 mL) was treated with Pd(PPh3)4 (0.92 g, 0.8 mmol) and heated to reflux overnight. The reaction mixture was concentrated and the resulting material was purified directly by gradient elution on silica gel (0 to 20% EtOAc in hexanes) to afford the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[CH3:39][Si:40]([CH3:45])([CH3:44])[CH2:41][CH2:42]O>CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([O:15][CH2:42][CH2:41][Si:40]([CH3:45])([CH3:44])[CH3:39])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: C[Si](C)(C)CCO
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: ClC(Cl)Cl
Product: C[Si](C)(C)CCOC(=O)CNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of N-[(benzyloxy)carbonyl]glycine (5.33 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.86 g), 1-hydroxybenzotriazole monohydrate (4.68 g) and chloroform (51.0 mL), 2-(trimethylsilyl)ethanol (4.36 mL) was added and the mixture was stirred at room temperature for 8 hours. To the reaction mixture, 2-(trimethylsilyl)ethanol (3.00 mL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.93 g) and 4-dimethylaminopyridine (312 mg) were added and the mixture was stirred at room temperature for 65 hours. After pouring the reaction mixture into a saturated aqueous solution of ammonium chloride, three extractions were conducted with ethyl acetate. The combined organic layers were washed with saturated brine and dried over anhydrous magnesium sulfate. After removing the desiccant by filtration, the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (n-hexane:ethyl acetate=95:5-80:20) to give 2-(trimethylsilyl)ethyl N-[(benzyloxy)carbonyl]glycinate as a colorless oil (6.64 g).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:33][CH3:34])=[C:10]([CH2:19][NH:20][C:21](=[O:32])[C:22]3[CH:27]=[CH:26][CH:25]=[C:24](CC(=O)C)[CH:23]=3)[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[CH:35](C1C=C(C=CC=1)C(O)=O)=[O:36]>>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:33][CH3:34])=[C:10]([CH2:19][NH:20][C:21](=[O:32])[C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH:35]=[O:36])[CH:23]=3)[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: O=Cc1cccc(C(=O)O)c1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(CC(C)=O)c1
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C=O)c1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 29, using 3-formylbenzoic acid in place of 3-(2-oxopropyl)benzoic acid. ES/MS calcd. for C24H30N5O3+ 436.2. found m/z=436.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([O:11][CH3:12])=[CH:4][C:3]=1[N:13]1[CH2:18][CH2:17][CH:16]([N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:15][CH2:14]1>CCO.[Pt]>[N:19]1([CH:16]2[CH2:15][CH2:14][N:13]([C:3]3[C:2]([Cl:1])=[CH:7][C:6]([NH2:8])=[C:5]([O:11][CH3:12])[CH:4]=3)[CH2:18][CH2:17]2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: COc1cc(N2CCC(N3CCCCC3)CC2)c(Cl)cc1[N+](=O)[O-]
Agent: [Pt]
Solvent: CCO
Product: COc1cc(N2CCC(N3CCCCC3)CC2)c(Cl)cc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1′-[2-Chloro-5-(methyloxy)-4-nitrophenyl]-1,4′-bipiperidine was dissolved in EtOH and 5% sulfided platinum on carbon was added. The reaction was placed on a Fischer-Porter Hydrogenator under 50 psi of H2 gas and was allowed to stir at rt overnight. TLC and MS showed the reaction was complete. The catalyst was filtered off and the filtrate was concentrated in vacuo to give the title compound of step D without further purification (2.36 g, 96%). 1H NMR (400 MHz, DMSO-d6) δ ppm 6.56-6.62 (m, 2H), 4.57 (br. s, 2H), 3.70 (d, J=1.3 Hz, 3H), 3.06 (d, J=10.6 Hz, 2H), 2.52 (t, J=11.5 Hz, 2H), 2.39-2.44 (m, 4H), 2.24 (t, J=13.8 Hz, 1H), 1.70 (d, J=11.5 Hz, 2H), 1.54 (t, J=12.4 Hz, 2H), 1.41-1.48 (m, 4H), 1.30-1.38 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:18]=[CH:17][C:5]([CH:6]=[N:7][C@@H:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[CH3:9])=[CH:4][CH:3]=1.[BH4-].[Na+].Cl.[OH-].[Na+]>C(O)C.C(Cl)(Cl)Cl.O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C@@H:8]([C:10]2[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=2)[CH3:9])=[CH:17][CH:18]=1
Reactant: Cc1ccc([C@@H](C)N=Cc2ccc(O)cc2)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: Cc1ccc([C@@H](C)NCc2ccc(O)cc2)cc1
Reaction time: 1 h
Yield: 99.1 %

Procedure:
19.0 g (0.0794 mole) of (R)-(-)-N-(p-hydroxybenzylidene)-1-(p-tolyl)ethylamine were dissolved in 200 ml of ethyl alcohol. The resulting solution was admixed with 1.50 g (0.04 mole) of sodium borohydride at room temperature, stirred at a temperature of from 25° to 30° C. for 1 hours, and then stirred at a temperature of from 55° to 60° C. for 1 hours. After the completion of the reaction, 47 ml of a 10% hydrochloric acid were added at room temperature to the reaction mixture, which was then concentrated under reduced pressure. The residue thus obtained was admixed with 100 ml of water, and thereafter neutralized or weakly alkalized with a 20% aqueous sodium hydroxide solution. Then an extraction operation was carried out three times with 100 ml of chloroform, and the chloroform layer was washed with water, dried over sodium sulfate, and concentrated under reduced pressure to give 18.99 g of (R)-(+)-N-(p-hydroxybenzyl)-1-(p-tolyl)ethylamine. Yield: 99.1%. m.p. 114.5°-116° C.; α!D24 +47.5° (C 1.0, CHCl3) NMR-spectral data (δ ppm, CDCl3) 1.27 (d) 3H; 2.32 (s) 3H; 3.42 (s) 2H; 3.69 (q) 1H; 6.3-7.4 (broad) 2H; 6.5-7.5 (m) 8H
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][N:7]=1.[CH:10]([O:13][CH2:14][C:15](N)=[NH:16])([CH3:12])[CH3:11].C(OCC)(=O)C>C(O)C>[NH2:9][C:8]1[C:3]2[C:2](=[N:7][CH:6]=[CH:5][N:4]=2)[N:1]=[C:15]([CH2:14][O:13][CH:10]([CH3:12])[CH3:11])[N:16]=1
Reactant: N#Cc1nccnc1N
Reactant: CC(C)OCC(=N)N
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)OCc1nc(N)c2nccnc2n1

Procedure:
Obtained using the procedure described in section c of Example 2, starting with 8.8 g (0.073 mole) of 3-amino-2-pyrazinecarbonitrile and 13.0 g (0.11 mole) of 2-isopropoxyacetamidine in 295 ml of absolute ethanol. Refluxing time: 4 hours. Yld: 4.5 g (28%), m.p. 139°-141° C. (ethyl acetate).