Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][O:10][CH3:11])=[CH:4][N:3]=1.[CH2:12]([Mg]Cl)[C:13]([CH3:16])([CH3:15])[CH3:14]>C1COCC1>[CH3:11][O:10][CH2:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[N:3][CH:4]=1
Reactant: CC(C)(C)C[Mg]Cl
Reactant: COCOc1ccc(Br)nc1
Solvent: C1CCOC1
Product: COCOc1ccc(CC(C)(C)C)nc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-bromo-5-(methoxymethoxy)pyridine (30.5 g, 140 mmol) in THF (5 mL) at 0° C. under N2 is added dichloro-((bis-diphenylphosphino)ferrocenyl)-palladium(11)(4.88 g, 5.5 mmol) followed by dropwise addition of neopentylmagnesium chloride (155 mL, 155 mmol) over 2 min. After addition, the cooling bath was removed and the reaction stirred 3 h at rt. The reaction was cooled to 0° C. and saturated NH4Cl (500 mL) was added, and the aqueous layers extracted with EtOAc (3×200 mL). The combined organic layers were washed with saturated NaCl, dried (Na2SO4) and concentrated to give a red oil. Purification by vacuum filtration through a silica plug (9×7 cm, dry load, 10-20%% EtOAc/Hexanes) gives 5-(methoxymethoxy)-2-neopentylpyridine as a light yellow oil.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]2[CH2:14][C@H:15]([CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH2:16][CH2:17][C@H:10]2[CH2:9]1)(OC(C)(C)C)=O>FC(F)(F)C(O)=O.O>[F:26][C:23]1[CH:22]=[CH:21][C:20]([O:19][CH2:18][C@H:15]2[CH2:14][N:11]3[CH2:12][CH2:13][NH:8][CH2:9][C@@H:10]3[CH2:17][CH2:16]2)=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCN2C[C@H](COc3ccc(F)cc3)CC[C@H]2C1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Fc1ccc(OC[C@@H]2CC[C@H]3CNCCN3C2)cc1
Yield: 97.4 %

Procedure:
A solution of 44.4 g (122 mmol) of (7R,9aS)-2-BOC-7-(4-fluorophenoxy)methyl-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine (Preparation 7) in 500 mL of trifluroacetic acid and 200 mL of water was stirred at room temperature for 16 h. The mixture was concentrated by evaporation, the residue dissolved in water, basified with 15% NaOH, and extracted with ethyl acetate (2×). The organic layers were dried (magnesium sulfate), filtered and evaporated to give 31.4 g (96%) of (7R,9aS)-7-(4-fluorophenoxy)methyl-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine which was suitable for use in subsequent reactions. Purification of a 0.40 g sample by flash silica gel chromatography eluting with 90:10 chloroform:methanol gave 0.38 g of colorless crystals. mp (.2 HCl) 200–201° C. 13C NMR (base, CDCl3): δ 27.2, 29.1, 36.3, 45.9, 51.9, 56.0, 59.1, 62.5, 71.7, 115.4 (d, JCF=8). 115.7 (d, JCF=23). HRMS calcd for C15H21FN2O: 264.1638, found: 264.1660.
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:18]=[CH:19][C:20]=2[CH3:21])[C:12](N(OC)C)=[O:13])[C:5]([CH3:22])=[N:4][C:3]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[N:26]=1.[C:32]([Mg]Cl)#[CH:33]>O1CCCC1>[Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([C:12](=[O:13])[C:32]#[CH:33])[CH:18]=[CH:19][C:20]=2[CH3:21])[C:5]([CH3:22])=[N:4][C:3]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[N:26]=1
Reactant: CON(C)C(=O)c1ccc(C)c(-n2c(C)nc(OCc3cccc(F)n3)c(Cl)c2=O)c1
Reactant: C#C[Mg]Cl
Solvent: C1CCOC1
Product: C#CC(=O)c1ccc(C)c(-n2c(C)nc(OCc3cccc(F)n3)c(Cl)c2=O)c1

Procedure:
To a solution of 3-[5-chloro-4-(6-fluoro-pyridin-2-ylmethoxy)-2-methyl-6-oxo-6H-pyrimidin-1-yl]-N-methoxy-4,N-dimethyl-benzamide from Step C (85 mg, 0.19 mmol) in tetrahydrofuran (2 mL), cooled using an ice water bath, was added ethynylmagnesium chloride, 0.5M in tetrahydrofuran, (0.57 mL, 0.28 mmol) in a drop-wise manner. Additional Grignard reagent was added as necessary to ensure full product formation. After thirty minutes, the reaction was quenched into ice cold water and extracted with ethyl acetate. The organic layer was washed with saturated ammonium chloride, water and brine and dried over magnesium sulfate. The slurry was filtered and concentrated. The crude material was used without additional purification.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:5]=[C:6](Br)[CH:7]=[C:8]2[C:12]=1[NH:11][N:10]=[C:9]2[CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)=[O:3].[F:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.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]([C:4]1[CH:5]=[C:6]([C:32]2[CH:31]=[CH:30][CH:29]=[C:28]([F:27])[CH:33]=2)[CH:7]=[C:8]2[C:12]=1[NH:11][N:10]=[C:9]2[CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)=[O:3]
Reactant: CC(C)(C)OC(=O)N1CCC(c2n[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Reactant: OB(O)c1cccc(F)c1
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2n[nH]c3c(C(N)=O)cc(-c4cccc(F)c4)cc23)CC1
Yield: 117.2 %

Procedure:
Following the general procedure of Example 65, a mixture of 1,1-dimethylethyl 4-[7-(aminocarbonyl)-5-bromo-1H-indazol-3-yl]-1-piperidine carboxylate (Intermediate 5) (400 mg, 0.545 mmols), 3-fluorophenyl boronic acid (397 mg, 2.84 mmols), potassium carbonate (782 mg, 5.67 mmol), and Pd(PPh3)4 (218 mg, 0.189 mmol) in dioxane/water (7 mL/1 mL) were reacted. The reaction mixture was concentrated, redissolved in methylene chloride and filtered. The filtrate was concentrated and the residue was purified by using a Gilson semi-preparative HPLC system, eluting with 10% B to 80% B, where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) pumped at 25 mL/min to give the title compound (280 mg, 68%)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([CH3:12])=[CH:9][C:10]=1[NH2:11])=[O:5])[CH3:2].[ClH:13].O1CCOCC1.[C:20](#[N:22])[CH3:21]>>[ClH:13].[C:20]([NH:11][C:10]1[CH:9]=[C:8]([CH3:12])[NH:7][C:6]=1[C:4]([O:3][CH2:1][CH3:2])=[O:5])(=[NH:22])[CH3:21]
Reactant: CC#N
Reactant: CCOC(=O)c1[nH]c(C)cc1N
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)c1[nH]c(C)cc1NC(C)=N
Temperature: 50 °C

Procedure:
Ethyl-3-amino-5-methyl-1H-pyrrole-2-carboxylate (58.87 g; 0.35 mol) prepared according to literature [Gangjee A.; Li W.; Yang J.; Kisliuk R. L.; J. Med. Chem. 2008, 51, 68] is suspended in acetonitrile (1750 mL). To the suspension is added dropwise 4M HCl in dioxane (473 mL; 1.89 mol) within 15 minutes. After complete addition the reaction mixture is heated to 50° C. for 18 hours. The reaction mixture is cooled to 10° C., the solid is collected by suction filtration and washed with cold acetonitrile (400 mL). A second crop of product is obtained from the mother liquor after concentration under reduced pressure. The residue is collected with t-butylmethyl-ether. After the suction filtration the solids are combined and dried in vacuum at 50° C. to yield the title compound as off-white solid.
Reaction SMILES: Br[CH:2]1[CH2:8][CH2:7][O:6][C:5]2[CH:9]=[CH:10][C:11]([Br:13])=[CH:12][C:4]=2[C:3]1=O.[NH2:15][NH:16][C:17]([NH2:19])=[S:18]>>[Br:13][C:11]1[CH:10]=[CH:9][C:5]2[O:6][CH2:7][CH2:8][C:2]3[S:18][C:17]([NH:16][NH2:15])=[N:19][C:3]=3[C:4]=2[CH:12]=1
Reactant: NNC(N)=S
Reactant: O=C1c2cc(Br)ccc2OCCC1Br
Product: NNc1nc2c(s1)CCOc1ccc(Br)cc1-2

Procedure:
Following the procedure for 449, Step 2, 4,7-dibromo-3,4-dihydro-2H-benzo[b]oxepin-5-one was reacted with thiosemicarbazide to afford the title compound as a beige solid. LCMS (Method E): RT=3.85 min, [M+H]+=312 and 314. 1H NMR (DMSO-d6): 10.13 (2H, bs), 9.80 (1H, bs), 8.49 (1H, d, J=2.6 Hz), 7.37 (1H, dd, J=8.6, 2.6 Hz), 6.97 (1H, d, J=8.6 Hz), 4.29 (2H, t, J=5.0 Hz), 3.21 (2H, t, J=5.0 Hz).
Reaction SMILES: [N+](C1C=CC(C[O:11][C:12]([C:14]2[N:15]3[CH:18]([CH:19]([CH3:36])[C:20]=2[S:21][CH:22]2[CH2:26][CH:25]([CH2:27][O:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[O:24][CH2:23]2)[CH:17]([CH:37]([OH:39])[CH3:38])[C:16]3=[O:40])=[O:13])=CC=1)([O-])=O.C(=O)(O)[O-].[Na+:45].O>[Pd].O1CCOCC1>[Na+:45].[OH:39][CH:37]([CH:17]1[C:16](=[O:40])[N:15]2[CH:18]1[CH:19]([CH3:36])[C:20]([S:21][CH:22]1[CH2:26][CH:25]([CH2:27][O:28][CH2:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[O:24][CH2:23]1)=[C:14]2[C:12]([O-:13])=[O:11])[CH3:38]
Reactant: CC(O)C1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3COC(COCc4ccccc4)C3)C(C)C12
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(O)C1C(=O)N2C(C(=O)[O-])=C(SC3COC(COCc4ccccc4)C3)C(C)C12
Yield: 33 %

Procedure:
The title compound is prepared by the procedure of Example 18 using 0.170 g of product from Example 81, 0.0277 g of sodium bicarbonate, 1.2 ml of water, 6.8 ml of dioxane, and 0.055 g of 10% palladium/carbon to give 0.045 g of desired product.
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:3]=1.C1C(=O)N([I:19])C(=O)C1>CN(C)C=O.O>[I:19][C:3]1[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:5][NH:6][C:2]=1[CH3:1]
Reactant: CCOC(=O)c1cc(C)[nH]n1
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1n[nH]c(C)c1I
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.1 %

Procedure:
To a solution of ethyl 5-methyl-1H-pyrazole-3-carboxylate (2 g, 12.97 mmol, 1.00 equiv) in N,N-dimethylformamide (50 mL) was added NIS (3.5 g, 15.56 mmol, 1.20 equiv) in portions. The reaction mixture was stirred at 25° C. for 4 h and then diluted with 30 mL of H2O. The resulting mixture was extracted with 2×30 mL of ethyl acetate. The combined organic layers were washed with 2×50 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with 0-50% of ethyl acetate in petroleum ether to give 3.6 g (99%) of ethyl 4-iodo-5-methyl-1H-pyrazole-3-carboxylate as a white solid. LCMS (method D, ESI): RT=1.27 min, m/z=281.0 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]2([C:18]3[C:10](=[CH:11][C:12]4[CH2:13][CH2:14][NH:15][C:16]=4[CH:17]=3)[O:9][CH2:8]2)[CH2:4][CH2:3]1.[CH3:19][C:20]1[CH:25]=[C:24]([C:26]2[O:27][C:28]([CH3:31])=[N:29][N:30]=2)[CH:23]=[CH:22][C:21]=1[C:32]1[CH:37]=[CH:36][C:35]([C:38](O)=[O:39])=[CH:34][CH:33]=1>>[CH3:1][N:2]1[CH2:3][CH2:4][C:5]2([C:18]3[C:10](=[CH:11][C:12]4[CH2:13][CH2:14][N:15]([C:38]([C:35]5[CH:34]=[CH:33][C:32]([C:21]6[CH:22]=[CH:23][C:24]([C:26]7[O:27][C:28]([CH3:31])=[N:29][N:30]=7)=[CH:25][C:20]=6[CH3:19])=[CH:37][CH:36]=5)=[O:39])[C:16]=4[CH:17]=3)[O:9][CH2:8]2)[CH2:6][CH2:7]1
Reactant: CN1CCC2(CC1)COc1cc3c(cc12)NCC3
Reactant: Cc1nnc(-c2ccc(-c3ccc(C(=O)O)cc3)c(C)c2)o1
Product: Cc1nnc(-c2ccc(-c3ccc(C(=O)N4CCc5cc6c(cc54)C4(CCN(C)CC4)CO6)cc3)c(C)c2)o1

Procedure:
The title compound was prepared from 1'-methyl-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] (D8) and 2'-methyl-4'-(5-methyl-1,3,4-oxadiazol-2-yl)biphenyl-4-carboxylic acid (D11) using a procedure similar to that of Example 1 (23%). This was converted to the oxalate salt which precipitated from acetone/ether as a white solid (mp 232-235° C.), and hydrochloride salt (mp>250° C.).
Reaction SMILES: [OH-].[Na+].[N+:3]([CH3:6])([O-:5])=[O:4].[CH3:7][CH:8]([CH2:11][CH2:12][CH3:13])[CH:9]=[O:10]>O.C(O)C>[CH3:7][CH:8]([CH2:11][CH2:12][CH3:13])[CH:9]([OH:10])[CH2:6][N+:3]([O-:5])=[O:4]
Reactant: C[N+](=O)[O-]
Reactant: CCCC(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCC(C)C(O)C[N+](=O)[O-]
Reaction time: 2 h
Yield: 82.6 %

Procedure:
After dissolving 7.0 g of sodium hydroxide in 50 ml of water and 50 ml of ethanol at 4° C., 10.7 g of nitromethane and 10.0 g of 2-methylpentanal were added thereto. The temperature of the solution was allowed to rise to room temperature, and the solution was stirred for two hours. After concentrating the ethanol under reduced pressure, the solution was neutralized with 1 mol/l of hydrochloric acid so that the pH of the solution was approximately 7. Ethyl acetate was added to the solution, and the organic layer was washed with saturated saline. The organic layer was dried with magnesium sulfate and concentrated, and then purified by silica gel chromatography (hexane/ethyl acetate=8/1), thereby obtaining 13.3 g of 3-methyl-1-nitro-2-hexanol (yield: 94.2%).
Reaction SMILES: [N:1]1([C:10]2[C:15]([Cl:16])=[CH:14][N:13]=[C:12]([NH:17][C@H:18]3[CH2:23][CH2:22][C@H:21]([C:24]([OH:26])=O)[CH2:20][CH2:19]3)[N:11]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[CH2:27]([NH2:29])[CH3:28].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>C1COCC1>[CH2:27]([NH:29][C:24]([C@H:21]1[CH2:22][CH2:23][C@H:18]([NH:17][C:12]2[N:11]=[C:10]([N:1]3[C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[N:3]=[N:2]3)[C:15]([Cl:16])=[CH:14][N:13]=2)[CH2:19][CH2:20]1)=[O:26])[CH3:28]
Reactant: CCN
Reactant: O=C(O)[C@H]1CC[C@H](Nc2ncc(Cl)c(-n3nnc4ccccc43)n2)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)[C@H]1CC[C@H](Nc2ncc(Cl)c(-n3nnc4ccccc43)n2)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of trans-4-(4-benzotriazol-1-yl-5-chloro-pyrimidin-2-ylamino)-cyclohexane-carboxylic acid (70 mg, 0.17 mmol), ethyl amine (21 μL, 0.26 mmol), BOP (114 mg, 0.26 mmol) and DIPEA (59 μL, 0.34 mmol) in THF (60 mL) was stirred at RT for 2 days. The white solid formed was removed by filtration and the filtrate was diluted with water (25 mL) and extracted 3 times with a mixture isopropanol/chloroform (1/1, 20 mL). The combined organic extracts were dried over Na2SO4, filtered and evaporated under reduced pressure to give an off white residue that was purified via flash chromatography (DCM/MeOH, 98/2) to afford 68 mg (quantitative yield) of trans-4-(4-benzotriazol-1-yl-5-chloro-pyrimidin-2-ylamino)-cyclohexane-carboxylic acid ethylamide as a white solid. MS: 400.17 (M+1)+, 372.17 ((M+1)+−28). 1H NMR (250 MHz, CD3OD) δ ppm: 8.55 (1 H, s), 8.09-8.21 (2 H, m), 7.69 (1 H, dd, J=7.50 Hz), 7.55 (1 H, dd, J=7.50 Hz), 3.71-3.88 (1 H, m), 3.18 (2 H, q, J=7.29 Hz), 2.10-2.25 (3 H, m), 1.82-1.95 (2 H, m), 1.50-1.71 (2 H, m), 1.26-1.48 (2 H, m), 1.10 (3 H, t, J=7.29 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2([C:17]#[N:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[N+:19]([O-])([OH:21])=[O:20]>CC(O)=O.CC(OC(C)=O)=O>[CH3:10][O:9][C:8]1[C:3]([O:2][CH3:1])=[CH:4][C:5]([C:11]2([C:17]#[N:18])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]2)=[C:6]([N+:19]([O-:21])=[O:20])[CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: COc1ccc(C2(C#N)CCCCC2)cc1OC
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: COc1cc([N+](=O)[O-])c(C2(C#N)CCCCC2)cc1OC
Temperature: 0 °C
Yield: 28.8 %

Procedure:
1-(3,4-Dimethoxyphenyl)cyclohexanecarbonitrile (0.736 g, 3 mmol), prepared in Step 1, was dissolved in HOAc/Ac2O 1/1 (6 mL) was cooled to 0° C. and treated slowly with nitric acid (0.582 g, 6 mmol, 65%). The reaction was left stirring in the ice bath for 10 min, poured into ice and extracted with EtOAc. Organic layer was dried (MgSO4), filtered and concentrated. Purification by flash chromatography (silica gel, 5-25% EtOAc/hexane) afforded (251 mg, 29%) of 1-(4,5-dimethoxy-2-nitrophenyl)cyclohexanecarbonitrile. MS (ESI) m/z 291 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][NH:11][CH:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:9]1=[O:20])[CH2:4][CH3:5])[CH3:2].[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Cl)=[CH:24][CH:23]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][N:11]2[CH2:12][CH2:13][N:8]([CH2:7][CH2:6][N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[C:9](=[O:20])[CH:10]2[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:24][CH:23]=1
Reactant: CCN(CC)CCN1CCNC(c2ccccc2)C1=O
Reactant: ClCc1ccc(Cl)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCN(CC)CCN1CCN(Cc2ccc(Cl)cc2)C(c2ccccc2)C1=O

Procedure:
80 g. of 1-(diethylamino ethyl)-2-keto-3-phenyl piperazine containing the above mentioned isomer are boiled under reflux with 54 g. of p-chloro benzylchloride, 101 g. of triethylamine, and 300 cc. of toluene for 5 hours. The precipitated triethyl ammonium chloride is removed from the reaction solution by extraction with water while still warm. The separated toluene layer is freed of the solvent, the residue is dissolved in benzene, and insoluble matter is filtered off.
Reaction SMILES: S(C)C.[CH:4]([Li])([CH3:6])[CH3:5].[C:8]([NH:27][C@@H:28]([CH2:31][CH3:32])[CH:29]=[O:30])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[NH4+].[Cl-]>CCOCC>[CH3:5][CH:4]([CH:29]([OH:30])[C@@H:28]([NH:27][C:8]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:31][CH3:32])[CH3:6]
Reactant: [Li]C(C)C
Reactant: CC[C@@H](C=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CSC
Solvent: CCOCC
Product: CC[C@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(O)C(C)C
Temperature: 25 °C

Procedure:
To a stirred suspension of CuBr.SMe2 (1.37 g, 2.2 eq, 6.66 mmol) in Et2O (100 mL) under an argon atmosphere at −78° C., was added isopropyllithium (0.7 M in pentane, 17.29 mL, 4 eq, 12.1 mmol) dropwise and the solution allowed to warm to room temperature. The mixture was recooled to −70° C., to which was added a solution of (S)-2-(trityl-amino)-butyraldehyde (1 g, 1 eq, 3.03 mmol) in Et2O (25 mL) dropwise with stirring. The reaction mixture was stirred at this temperature for 1 h, then allowed to warm to −55° C. and stirred at this temperature for 3 h. To the reaction mixture was added a saturated aqueous solution of NH4Cl (100 mL) and allowed to warm to room temperature over 16 h. The reaction mixture was extracted with Et2O (2×200 mL), and the combined organic phase washed with brine (50 mL), dried (MgSO4) and evaporated in vacuo. The residue was purified by silica gel column chromatography, eluted with hexane:ether (100:0→90:10) to afford the title compound as a colourless oil; Yield: 0.36 g (32%). (50% de 3R,4S: 50% de 3S,4S). 1H-NMR (d6-DMSO, 250 MHz): δ 0.44 (t, 3H, J=6.79 Hz, —NHCH(CH2CH3)CH(CH(CH3)2)OH), 0.52 & 0.76 (2×d, 6H, J=6.63 Hz, —NHCH(CH2CH3)CH(CH(CH3)2)OH), 0.80-1.15 (m, 2H, —NHCH(CH2CH3)CH(CH(CH3)2)OH), 1.70 (m, 1H, —NHCH(CH2CH3)CH(CH (CH3)2)OH), 2.10 (m, 1H, —NHCH(CH2CH3)CH(CH(CH3)2)OH), 2.76 (m, 1H, —NHCH(CH2CH3)CH(CH(CH3)2)OH), 2.99 (m, 1H, —NHCH(CH2CH3)CH(CH(CH3)2)OH), 4.55 (d, 1H, J=5.84 Hz, —NHCH(CH2CH3)CH(CH(CH3)2)OH), 7.17-7.46 (m, 15H, 3×Ph).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1>CC(N(C)C)=O>[O:12]1[CH2:13][CH2:14][N:9]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=2)[CH2:10][CH2:11]1
Reactant: C1COCCN1
Reactant: Nc1cc(Cl)ccn1
Solvent: CC(=O)N(C)C
Product: Nc1cc(N2CCOCC2)ccn1
Temperature: 200 °C

Procedure:
A mixture of 4-chloropyridin-2-amine (400 mg, 3.1 mmol) and morpholine (2 mL) in 2 mL of DMA was heated at 200° C. for 5 min in a microwave reactor. LCMS analysis indicated completion of the reaction. The mixture was partitioned between EtOAc and brine, and the organic layer was dried over Na2SO4 and concentrated under reduced pressure to give crude 4-morpholinopyridin-2-amine as a yellow solid (350 mg). LCMS (ESI) m/z 180 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([OH:28])=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][CH:17]=2)[C:5]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[N:6][C:7]=1[CH3:8].C(=O)([O-])[O-].[K+].[K+].[CH2:35]([CH:37]1[O:39][CH2:38]1)Br.O>CN(C)C=O>[CH3:27][O:26][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][C:22]=1[O:28][CH2:35][CH:37]1[CH2:38][O:39]1)[N:19]=[CH:18][CH:17]=[C:16]2[O:15][C:4]1[C:5]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[N:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=1
Reactant: BrCC1CO1
Reactant: COc1cc2c(Oc3cc(C)c(C)nc3-c3cccnc3)ccnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3cc(C)c(C)nc3-c3cccnc3)ccnc2cc1OCC1CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
4-(5,6-Dimethyl-[2,3′]bipyridin-3-yloxy)-6-methoxy-quinolin-7-ol (compound 345) (146 mg) was dissolved in N,N-dimethylformamide (4 ml) to prepare a solution, potassium carbonate (162 mg) and epibromohydrin (0.1 ml) were added to the solution, and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (98 mg, yield 59%).
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][CH2:10][C@@H:9]1[C:14]([OH:16])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[CH2:18]([O:20][C:21](=[O:33])[CH:22]([OH:32])[CH:23]([NH3+:31])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH3:19]>>[CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][CH2:10][C@@H:9]1[C:14]([NH:31][CH:23]([CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH:22]([OH:32])[C:21]([O:20][CH2:18][CH3:19])=[O:33])=[O:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(O)C([NH3+])Cc1ccccc1
Reactant: O=C(O)[C@H]1CCC(=O)N1Cc1ccccc1
Agent: [Cl-]
Product: CCOC(=O)C(O)C(Cc1ccccc1)NC(=O)[C@H]1CCC(=O)N1Cc1ccccc1

Procedure:
The reaction was carried out in analogy to reaction step 1.1 by reacting (R)-1-benzyl-5-oxopyrrolidine-2-carboxylic acid and 4-ethoxy-3-hydroxy-4-oxo-1-phenylbutan-2-aminium chloride. ESI-MS [M+H]+=425.2.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:10])[CH:9]=1)[CH:5]=O.[OH:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([OH:21])=[O:20])=[CH:14][CH:13]=1.C([O-])(=O)C.[K+].C(OC(=O)C)(=O)C>O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:18]([C:15]2[CH:16]=[CH:17][C:12]([OH:11])=[CH:13][CH:14]=2)[C:19]([OH:21])=[O:20])[CH:7]=[C:8]([CH3:10])[CH:9]=1
Reactant: O=C(O)Cc1ccc(O)cc1
Reactant: Cc1cc(C)cc(C=O)c1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: Cc1cc(C)cc(C=C(C(=O)O)c2ccc(O)cc2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 41.2 %

Procedure:
To a mixture of 43 (3.23 g, 24 mmol), 4-hydroxyphenylacetic acid (3.66 g, 24 mmol) and potassium acetate (2.83 g, 28 mmol) was added acetic anhydride (100 mL). The mixture was heated to reflux for 4 h, cooled to room temperature, and then poured over water (400 mL). After stirring for 1.5 h, a solid gum settled to the bottom and the supernatant was decanted. To the residue was added THF (100 mL) and 1N NaOH (150 mL) and the mixture was stirred for 30 min. The mixture was acidified with 1N HCl (200 mL) and the product was extracted into ethyl acetate (300 mL), washed with water (300 mL), brine (300 mL), dried (MgSO4), filtered and concentrated in vacuo. The crude solid was crystallized in toluene to yield 2.65 g (42%) of a pale yellow solid 44.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH:5]1[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:6]1.[NH2:17][NH2:18].O>CO>[NH:17]([C:3](=[O:2])[CH2:4][CH:5]1[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:6]1)[NH2:18]
Reactant: NN
Reactant: COC(=O)CC1CN(C(=O)OC(C)(C)C)C1
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC(CC(=O)NN)C1
Temperature: 65 °C
Yield: 96 %

Procedure:
To a solution of tert-butyl 3-(2-methoxy-2-oxoethyl)azetidine-1-carboxylate (25.0 g, 109 mmol) in MeOH (150 mL) was added NH2NH2.H2O (27.3 g, 546 mmol) at rt. The mixture was heated at 65° C. for 12 hrs and then concentrated. The residue was diluted with DCM (400 mL), washed with water (2×) and saturated sodium chloride (2×), dried over Na2SO4, and concentrated to give tert-butyl 3-(2-hydrazinyl-2-oxoethyl)azetidine-1-carboxylate (24.0 g, 96%) as a yellow gum. ESI-MS (EI+, m/z): 252 [M+Na]+.