Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[O:4].[OH:7][C:8]([C:10]([F:13])([F:12])[F:11])=[O:9].[F:14][C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[CH:22]([F:43])[CH:23]1[CH2:28][CH2:27][N:26]([C:29]2[N:34]=[C:33]3[CH2:35][NH:36][CH2:37][CH2:38][C:32]3=[N:31][C:30]=2[NH:39][CH:40]([CH3:42])[CH3:41])[CH2:25][CH2:24]1.C(N(CC)CC)C>C(Cl)Cl>[F:14][C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[CH:22]([F:43])[CH:23]1[CH2:28][CH2:27][N:26]([C:29]2[N:34]=[C:33]3[CH2:35][N:36]([C:3]([N:2]([CH3:6])[CH3:1])=[O:4])[CH2:37][CH2:38][C:32]3=[N:31][C:30]=2[NH:39][CH:40]([CH3:41])[CH3:42])[CH2:25][CH2:24]1.[C:8]([OH:9])([C:10]([F:13])([F:12])[F:11])=[O:7]
Reactant: CC(C)Nc1nc2c(nc1N1CCC(C(F)c3ccc(F)cc3F)CC1)CNCC2
Reactant: CN(C)C(=O)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)Nc1nc2c(nc1N1CCC(C(F)c3ccc(F)cc3F)CC1)CN(C(=O)N(C)C)CC2
Reaction time: 1 h

Procedure:
Dimethylcarbamic chloride (8.4 mg, 0.078 mmol) was added to a solution of 3-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine TFA salt (20.8 mg, 0.039 mmol) and triethylamine (16 μL, 0.117 mmol) in DCM (390 μL) at rt. After 1 h, the mixture was purified by HPLC Method A to give the title compound as a TFA salt (20.8 mg, 88%) as a yellow film. 1H NMR (400 MHz, methanol-d4) δ ppm 1.31 (dd, J=6.6, 1.8 Hz, 6H), 1.40-1.48 (m, 1H), 1.58-1.78 (m, 2H), 1.95-2.03 (m, 1H), 2.03-2.18 (m, 1H), 2.71-2.88 (m, 4H), 2.90 (s, 6H), 3.42-3.52 (m, 2H), 3.54 (t, J=5.7 Hz, 2H), 4.07-4.16 (m, 1H), 4.22-4.27 (m, 2H), 5.53 (dd, J=46.5, 7.3 Hz, 1H), 6.97-7.08 (m, 2H), 7.47-7.55 (m, 1H); ESI-MS m/z [M+H]+ 491.4.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]2[S:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.Cl[C:25]([O:27][CH2:28][CH3:29])=[O:26]>C1COCC1>[CH2:28]([O:27][C:25]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]2[S:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)[CH2:10][CH2:9]1)=[O:26])[CH3:29]
Reactant: c1ccc(CN2CCC(Cc3nc4ccccc4s3)CC2)cc1
Reactant: CCOC(=O)Cl
Solvent: C1CCOC1
Product: CCOC(=O)N1CCC(Cc2nc3ccccc3s2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 67.8 %

Procedure:
A solution of 500 mg of 1-benzyl-4-((benzothiazol-2-yl)methyl)piperidine (from EXAMPLE 163, Step D) in 10 mL of THF was added 185 mg of ethyl chloroformate at rt. The reaction was stirred at rt for 5 h. The reaction mixture was partitioned between H2O and EtOAc. The aqueous phase was extracted with EtOAc (3×). The combined organic phases were washed with sat'd NaCl and dried over MgSO4. Concentration afforded 320 mg of the title compound as a oil.
Reaction SMILES: [NH2-].[Li+].N.[CH3:4][O:5][C:6]1([CH2:13][CH2:14][C:15]#[CH:16])[CH:10]=[CH:9][CH:8]([O:11][CH3:12])[O:7]1.Br[CH2:18][CH2:19][CH2:20][C:21]([O:26][CH3:27])([O:24][CH3:25])[O:22][CH3:23]>O1CCCC1>[CH3:4][O:5][C:6]1([CH2:13][CH2:14][C:15]#[C:16][CH2:18][CH2:19][CH2:20][C:21]([O:26][CH3:27])([O:24][CH3:25])[O:22][CH3:23])[CH:10]=[CH:9][CH:8]([O:11][CH3:12])[O:7]1
Reactant: COC(CCCBr)(OC)OC
Reactant: C#CCCC1(OC)C=CC(OC)O1
Agent: N
Agent: [Li+]
Agent: [NH2-]
Solvent: C1CCOC1
Product: COC1C=CC(CCC#CCCCC(OC)(OC)OC)(OC)O1
Yield: 108.2 %

Procedure:
To a stirred mixture of 0.51 g of lithium amide and ml of liquid ammonia was added dropwise a solution of 3.64 g of 2,5-dihydro-2,5-dimethoxy-2-(3-butynyl)furan in 2.5 ml of tetrahydrofuran during 5 minutes. The mixture was stirred under reflux for 30 minutes and then treated dropwise with a solution of 5.0 g of 1-bromo-4,4,4-trimethoxybutane (U.S. Pat. No. 3,864,387) in 5 ml of tetrahydrofuran during 5 minutes. This solution was stirred under reflux for one hour, the ammonia allowed to evaporate during one hour and the resulting solution stirred at 20° C. for 10 minutes. This solution was partitioned with ether and brine. The organic layer was dried, treated with 2 drops of pyridine, and then concentrated, giving 7.1 g of the desired compound as a light amber oil; PMR δ 5.9 (2H, m, vinyl hydrogens).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:15][C:16](Cl)=[N:17][OH:18])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]([C:22]1[C:23]([NH2:29])=[N:24][C:25]([NH2:28])=[CH:26][CH:27]=1)#[CH:21].C(N(CC)CC)C>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=1)[CH2:15][C:16]1[CH:21]=[C:20]([C:22]2[C:23]([NH2:29])=[N:24][C:25]([NH2:28])=[CH:26][CH:27]=2)[O:18][N:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#Cc1ccc(N)nc1N
Reactant: ON=C(Cl)Cc1cccc(OCc2ccccc2)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Nc1ccc(-c2cc(Cc3cccc(OCc4ccccc4)c3)no2)c(N)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.2 %

Procedure:
To a tetrahydrofuran (3 mL) solution of (3-benzyloxy-phenyl)-acetohydroximoyl chloride (200 mg, 0.724 mmol) described in Manufacturing Example 61-1-4 and 3-ethynyl-pyridin-2,6-diamine (61.5 mg, 0.462 mmol) described in Manufacturing Example 13-1-3 was added triethylamine (252 μL, 1.81 mmol). This mixture was stirred for 4 hours at room temperature. This mixture was partitioned into water and ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure. The residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:1˜ethyl acetate) to obtain the title compound (138 mg, 51%).
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:21])[C@@H:15]([NH2:20])[CH2:16][CH:17]([CH3:19])[CH3:18])=[CH:5][CH:4]=1.C(N(CC)C(C)C)(C)C.Br[CH2:39][CH:40]=[C:41]([CH3:43])[CH3:42]>C1COCC1>[ClH:1].[F:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:21])[C@@H:15]([NH:20][CH2:39][CH:40]=[C:41]([CH3:43])[CH3:42])[CH2:16][CH:17]([CH3:19])[CH3:18])=[CH:7][CH:8]=1
Reactant: CC(C)C[C@H](N)C(=O)NCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CC(C)=CCBr
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)=CCN[C@@H](CC(C)C)C(=O)NCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 50 °C
Reaction time: 16 h
Yield: 33.6 %

Procedure:
To a solution of (S)-2-amino-4-methyl-pentanoic acid [4,4-bis-(4-fluoro-phenyl)-butyl]-amide monohydrochloride (0.36 g, 0.88 mmol, Example 7) in THF (15 mL) were added, in succession, N,N-diisopropylethylamine (0.30 mL, 1.7 mmol) and 1-bromo-3-methyl-2-butene (0.10 mL, 0.87 mmol) at ambient temperature under nitrogen atmosphere. The resulting reaction mixture was stirred for 12 hours at that temperature, 16 hours at 50° C., cooled to ambient temperature, and concentrated in vacuo. The desired product was purified by flash chromatography (50% EtOAc in hexanes) and was dissolved in 10 mL of ethyl ether. To this solution was added saturated HCl solution in ethyl ether until no more white precipitate formed. Filtration and drying overnight under vacuum afforded 0.14 g (36%) of the titled compound as a yellow foam; mp 58-72° C. APCI-MS m/z 443.3 (MH+).
Reaction SMILES: [CH3:1][CH:2]1[CH:7]([CH3:8])[NH:6][CH2:5][CH2:4][N:3]1[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].C=O.[C:21](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH3:1][CH:2]1[CH:7]([CH3:8])[N:6]([CH3:21])[CH2:5][CH2:4][N:3]1[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10]
Reactant: CC1NCCN(C(=O)OCc2ccccc2)C1C
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Product: CC1C(C)N(C(=O)OCc2ccccc2)CCN1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of phenylmethyl 2,3-dimethyl-1-piperazinecarboxylate (mixture of four stereoisomers) (3.105 g, 12.5 mmol) in dichloromethane (90 mL) at 0° C. was added formaldehyde (1.409 mL, 37% water solution, 18.75 mmol) followed by sodium triacetoxyborohydride (3.445 g, 16.26 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 2 h before being diluted with dichloromethane and washed with 1N NaOH solution. The organics were washed with brine, dried (MgSO4) and evaporated to yield phenylmethyl 2,3,4-trimethyl-1-piperazinecarboxylate (mixture of all four stereoisomers) (3.04 g, 93%). Phenylmethyl (2R,3R)-2,3,4-trimethyl-1-piperazinecarboxylate (365 mg) and phenylmethyl (2S,3S)-2,3,4-trimethyl-1-piperazinecarboxylate (420 mg) were separated out by a combination of preparative and chiral chromatography. Absolute configuration was assigned using Ab Initio vibrational circular dichroism. LCMS: (M+H)+: 263.3.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([CH:12]([CH3:15])[CH2:13][NH2:14])=[CH:8][CH:7]=2)=[CH:2]1.[N:16]1([C:21](Cl)=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17]1>>[S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([CH:12]([CH3:15])[CH2:13][NH:14][C:21]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:22])=[CH:8][CH:7]=2)=[CH:2]1
Reactant: CC(CN)c1ccc(-c2ccsc2)cc1
Reactant: O=C(Cl)N1CCCC1
Product: CC(CNC(=O)N1CCCC1)c1ccc(-c2ccsc2)cc1

Procedure:
The title compound was prepared from 2-(4-(3-thienyl)phenyl)propylamine (see example 14) and pyrrolidine carbonyl chloride in a manner analogous to the procedure described in example 14. The NMR spectrum was consistent with the proposed title structure.
Reaction SMILES: [S:1]1[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[C:4](=[O:14])[CH:3]=[CH:2]1.[Br:15]Br>C(O)(=O)C>[Br:15][C:10]1[CH:9]=[CH:8][C:7]2[NH:6][C:5]3[C:4](=[O:14])[CH:3]=[CH:2][S:1][C:13]=3[C:12]=2[CH:11]=1
Reactant: BrBr
Reactant: O=c1ccsc2c1[nH]c1ccccc12
Solvent: CC(=O)O
Product: O=c1ccsc2c1[nH]c1ccc(Br)cc12
Reaction time: 0.17 h

Procedure:
-- A solution of 8.04 g (0.04 mole) of thiopyrano[3,2-b]indol-4(5H)-one in 200 ml of acetic acid is treated dropwise with stirring at room temperature with 8.0 g (0.05 mole) of bromine. An immediate heavy precipitate formed. The mixture is concentrated to dryness and the solid residue suspended in 20 ml of pyridine and stirred for 10 minutes at 95°. The reaction mixture is poured onto ice, the solid is filtered and recrystallized from dimethylformamide, mp 334°-337° C.
Reaction SMILES: C(C1C=CC=C(C(C)(C)C)C=1O)(C)(C)C.C([C:20]1[CH:21]=[C:22]([C:31]2[CH:36]=[C:35](C(C)(C)C)[C:34]([OH:41])=[C:33](C(C)(C)C)[CH:32]=2)[CH:23]=[C:24](C(C)(C)C)[C:25]=1[OH:26])(C)(C)C>>[CH:23]1[C:22]([C:31]2[CH:36]=[CH:35][C:34]([OH:41])=[CH:33][CH:32]=2)=[CH:21][CH:20]=[C:25]([OH:26])[CH:24]=1
Reactant: CC(C)(C)c1cc(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc(C(C)(C)C)c1O
Agent: CC(C)(C)c1cccc(C(C)(C)C)c1O
Product: Oc1ccc(-c2ccc(O)cc2)cc1

Procedure:
If a mixture of 2,6-di-t-butylphenol and 3,3',5,5'-tetra-t-butyl-4,4'-diphenoquinone, or a mixture thereof with 3,3',5,5'-tetra-t-butyl-4,4'-dihydroxybiphenyl is treated under the reaction conditions described above concerning catalyst, solvent, temperature and time, the reaction for the synthesis of 3,3',5,5'-tetra-t-butyl-4,4'-dihydroxybiphenyl and that for the dealkylation of this compound will proceed in a balanced and efficient way, thereby allowing p,p'-biphenol to be produced in a satisfactory yield. Stated more specifically, any 3,3',5,5'-tetra-t-butyl-4,4'-diphenoquinone that may be formed on account of excessive oxidation of 3,3',5,5'-tetra-t-butyl 4,4'-dihydroxybiphenyl is reduced with 2,6-di-t-butylphenol to ensure efficient production of 3,3',5,5'-tetra-t-butyl-4,4'-dihydroxybiphenyl therefrom. In addition, the so produced 3,3',5,5'-tetra-t-butyl-4,4'-dihydroxybiphenyl is converted efficiently to p,p'-biphenol by dealkylation.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:3]=1[CH2:4]Cl.[C:11]1([C:13](=[CH:15][CH:16]=[CH:17][CH:18]=1)[OH:14])[OH:12].[OH-].[K+]>C(O)C>[CH3:1][C:2]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:3]=1[CH2:4][O:12][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[OH:14]
Reactant: Oc1ccccc1O
Reactant: Cc1ccc(C)c(CCl)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(C)c(COc2ccccc2O)c1

Procedure:
For the synthesis of V, 15.00 g of 2,5-dimethylbenzyl chloride was added to 10.68 g of catechol dissolved in 10 ml of absolute ethanol under nitrogen. KOH, 5.44 g dissolved in 50 ml of ethanol, is added dropwise over 30 minutes with stirring. The solution is then refluxed under nitrogen for 2 hours. The solution is filtered to remove KCl. The solution is cooled over night and filtered to remove di-substituted product. Ethanol is removed by rotary evaporation, and the oil is dissolved in 50 ml of chloroform. The pH is adjusted to neutrality with HCl and extracted three times with equal volumes of water to remove unreacted catechol and salts. Chloroform is removed by rotary evaporation. The oil is vacuum-distilled at 8 mm Hg and the fraction containing V is collected.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][N:6]([C:8]2([C:11](=[NH:15])OCC)[CH2:10][CH2:9]2)[CH:7]=1.Cl.Cl.[NH2:18][C:19]1[CH:20]=[CH:21][C:22]([N:26]2[CH2:31][CH2:30][CH2:29][C@@H:28]([C:32]([N:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)=[O:33])[CH2:27]2)=[N:23][C:24]=1N.C(O)(=O)C.C(N(CC)CC)C.[Cl-].[NH4+]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[N:5][N:6]([C:8]2([C:11]3[NH:15][C:24]4=[N:23][C:22]([N:26]5[CH2:31][CH2:30][CH2:29][C@@H:28]([C:32]([N:34]6[CH2:38][CH2:37][CH2:36][CH2:35]6)=[O:33])[CH2:27]5)=[CH:21][CH:20]=[C:19]4[N:18]=3)[CH2:9][CH2:10]2)[CH:7]=1
Reactant: Nc1ccc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N
Reactant: CCOC(=N)C1(n2cc(OC)cn2)CC1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1cnn(C2(c3nc4ccc(N5CCC[C@@H](C(=O)N6CCCC6)C5)nc4[nH]3)CC2)c1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
To a solution of crude ethyl 1-(4-methoxy-1H-pyrazol-1-yl)cyclopropanecarbimidate (79.5 mg, 0.380 mmol) in ethanol (1.5 mL) was added (R)-(1-(5,6-diaminopyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone dihydrochloride (151 mg, 0.417 mmol) followed by glacial acetic acid (0.435 mL, 7.59 mmol). The mixture was degassed with nitrogen, and then triethylamine (0.318 mL, 2.28 mmol) was added. The reaction mixture was heated at 100° C. for 20 min and then at 85° C. for 18 h. The mixture was poured into a saturated aqueous solution of ammonium chloride (40 mL) and extracted with dichloromethane (50 mL×3). The combined organics were washed with a saturated aqueous solution of sodium bicarbonate. The aqueous layer was extracted with dichloromethane (40 mL×2). The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified via HPLC to afford the title compound. MS (ESI+) (M+H) 436.2; HPLC retention time 1.85 min (Method A).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([NH:13][C@H:14]([CH2:18][OH:19])[C:15]([OH:17])=[O:16])(=[O:12])=[O:11])=[C:5]([CH3:20])[C:4]=1[CH3:21].C(=O)([O-])[O-].[K+].[K+].[CH2:28]1[O:38][C:37]2[CH:36]=[CH:35][C:32]([CH2:33]Cl)=[CH:31][C:30]=2[O:29]1.[I-].[Li+]>CN(C)C=O.C(Cl)Cl>[CH2:28]1[O:38][C:37]2[CH:36]=[CH:35][C:32]([CH2:33][O:16][C:15](=[O:17])[C@H:14]([NH:13][S:10]([C:6]3[C:7]([CH3:9])=[CH:8][C:3]([O:2][CH3:1])=[C:4]([CH3:21])[C:5]=3[CH3:20])(=[O:11])=[O:12])[CH2:18][OH:19])=[CH:31][C:30]=2[O:29]1
Reactant: COc1cc(C)c(S(=O)(=O)N[C@H](CO)C(=O)O)c(C)c1C
Reactant: ClCc1ccc2c(c1)OCO2
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N[C@H](CO)C(=O)OCc2ccc3c(c2)OCO3)c(C)c1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2(R)-(4-methoxy-2,3,6-trimethylbenzenesulfonylamino)-3-hydroxypropionic acid (27.9 g, 87.9 mmol) in dimethylformamide (280 mL) at 0° C., was added potassium carbonate (72.9 g, 527 mmol) and a solution of 3,4-methylenedioxybenzyl chloride ((60 g, 170.8 mmol, 50% (w/w)) in methylene chloride. After 2 h, lithium iodide (5.88 g, 44 mmol) was added and the reaction mixture was warmed to rt. over 2 h. After 6 h, the reaction mixture was partitioned between ethyl acetate (600 mL) and water (250 mL). The organic layer was separated, dried over magnesium sulfate and concentrated in vacuo. The crude residue was chromatographed (300 g SiO2, 15% ethyl acetate-hexanes) to afford 2(R)-(4-methoxy-2,3,6-trimethylbenzenesulfonylamino)-3-hydroxypropionic acid 3,4-methylenedioxybenzyl ester (38.4 g) which was taken directly into the next reaction without further purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C(=O)([O-])[O-].[Na+].[Na+]>C(O)(C)(C)C>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:2]2[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=2)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: Clc1cncc(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)N1CCN(c2cncc(Cl)n2)CC1

Procedure:
A mixture of 2,6-dichloropyrazine (2.98 g, 20 mmol), piperazine-1-carboxylic acid tert-butyl ester (3.72 g, 20 mmol) and sodium carbonate (2.12 g, 20 mmol) in t-butanol (50 mL) was heated at reflux under nitrogen for 65 h. The solution was concentrated in vacuo. The residue was partitioned between ethyl acetate (50 mL) and water (50 mL). The aqueous phase was extracted with ethyl acetate (3×30 mL). The combined organic extracts were washed with brine (50 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to give the title compound (I-1a) as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([CH3:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N+:13]([O-])([OH:15])=[O:14]>C(O)(=O)C>[C:1]([C:5]1[CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[C:8]([OH:11])=[C:7]([CH3:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(C(C)(C)C)ccc1O
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: Cc1cc(C(C)(C)C)cc([N+](=O)[O-])c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.5 %

Procedure:
4-tert-Butyl-2-methyl-phenol (1.64 g, 10 mmol) was dissolved in 15 mL acetic acid, fuming nitric acid (0.47 mL, 10 mmol) was added and the resulting solution was stirred at rt overnight. The reaction mixture was then poured onto crushed ice, and extracted with chloroform. The organic phase was washed with water, and dried over sodium sulfate. Evaporation gave 2.02 g the nitration product as a red oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](F)=[C:11]([F:33])[C:12]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[Cl:32])=[C:13]([CH:24]=1)[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:35]=[N+:36]=[N-:37].[Na+].O>CN(C=O)C>[N:35]([C:10]1[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:24][C:13]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])=[C:12]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[Cl:32])[C:11]=1[F:33])=[N+:36]=[N-:37]
Reactant: O=C(OCc1ccccc1)c1cc(OCc2ccccc2)c(F)c(F)c1Nc1ccccc1Cl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=Nc1c(OCc2ccccc2)cc(C(=O)OCc2ccccc2)c(Nc2ccccc2Cl)c1F
Temperature: 90 °C
Reaction time: 3 h
Yield: 78.8 %

Procedure:
To a solution of benzyl 5-(benzyloxy)-2-((2-chlorophenyl)amino)-3,4-difluorobenzoate (27.82 g, 57.97 mmol) in DMF (250 mL) was added NaN3 (4.52 g, 69.56 mmol). The mixture was stirred at 90° C. for 3 h. Then water (400 mL) was added. The solution was extracted with ethyl acetate (150 mL×3). The combined organic extracts were washed with water (150 mL) and brine (150 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate, 50:1, v/v) and gave the desired product (pale yellow solid, 22.97 g, 78.8% yield). 1H NMR (400 MHz, CDCl3): δ 8.41 (s, 1H), 7.40 (m, 12H), 7.13 (m, 1H), 6.87 (m, 1H), 6.69 (m, 1H), 5.34 (s, 2H), 5.17 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[OH:9])=[CH:4][CH:3]=1.[Cl:23][CH2:24][CH2:25][CH2:26][C:27]([N:29]([CH3:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:28].C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+].Cl>CN(C)C=O.O>[OH2:9].[ClH:23].[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)([OH:9])[CH:10]2[CH2:11][CH2:12][N:13]([CH2:24][CH2:25][CH2:26][C:27]([N:29]([CH3:36])[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:28])[CH2:14][CH2:15]2)=[CH:4][CH:3]=1
Reactant: CN(C(=O)CCCCl)c1ccccc1
Reactant: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C(=O)CCCN1CCC(C(O)(c2ccc(F)cc2)c2ccc(F)cc2)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 52.5 %

Procedure:
A mixture of 6.1 g (0.020 mole) of α,α-bis(4-fluorophenyl)-4-piperidinemethanol, 6.4 g (0.030 mole) of 4-chloro-N-methyl-N-phenylbutanamide, 8.5 g (0.080 mole) of anhydrous sodium carbonate and 0.4 g (0.002 mole) of potassium iodide in 100 mL of N,N-dimethylformamide was stirred at ambient temperature for 72 h. The mixture was poured into 1.5 L of water and extracted thrice with 250 mL portions of ethyl acetate. The ethyl acetate fractions were combined, washed with water and brine, dried (MgSO4), and concentrated under reduced pressure to give a dark oil. The oil was purified by column chromatography using 250 g of silica gel on a 65 cm×4 cm column eluted with 5% methanol in methylene chloride. The fractions containing the desired product were combined and concentrated under reduced pressure to give a glass. The glass was converted to the hydrochloric acid salt, and the solid was recrystallized from 2-propanol/isopropyl ether to yield 2.8 g (27%) of the title compound as a white solid, mp 107°-110° C.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:14]=2[N+:20]([O-:22])=[O:21])[CH2:9]1)=O)(C)(C)C.[ClH:23]>O1CCOCC1.CCOCC>[ClH:23].[NH:8]1[CH2:11][CH:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:14]=2[N+:20]([O-:22])=[O:21])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC(Nc2ccc(Br)cc2[N+](=O)[O-])C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: O=[N+]([O-])c1cc(Br)ccc1NC1CNC1

Procedure:
Stir a solution of 3-(4-bromo-2-nitro-phenylamino)-azetidine-1-carboxylic acid tert-butyl ester (29.66 mmol, 11.04 g) in 4.0 M hydrogen chloride in dioxane (40 mL) at room temperature under nitrogen overnight. Solids crash out of solution. Dilute with ether (200 mL), filter off solids, rinse with ample ether and dry (8.54 g, 93%). 1H NMR (400 MHz, CD3OD): 4.12 (dd, 2H), 4.45 (dd, 2H), 4.72 (m, 1H), 6.76 (d, 1H), 7.62 (dd, 1H), 8.30 (d, 1H). LC-MS m/z (79Br/81Br) 272.0/274.0 [M+H]+.
Reaction SMILES: Cl.[C:2]1([C:8]2([N:18]3[CH2:21][CH2:20][CH2:19]3)[CH2:17][CH2:16][C:11]3(OCC[O:12]3)[CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CC(C)=O>[N:18]1([C:8]2([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:9][CH2:10][C:11](=[O:12])[CH2:16][CH2:17]2)[CH2:19][CH2:20][CH2:21]1
Reactant: c1ccc(C2(N3CCC3)CCC3(CC2)OCCO3)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: O=C1CCC(c2ccccc2)(N2CCC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6 N Hydrochloric acid (2 ml) was added to a solution of 1-(8-phenyl-1,4-dioxaspiro[4,5]dec-8-yl)azetidine (370 mg, 1.3 mmol) in acetone (30 ml) and the mixture was stirred overnight at room temperature. The pH was adjusted to 10 by the addition of 5 N sodium hydroxide solution and the aqueous phase was extracted with dichloromethane (3×20 ml). The combined organic phases were dried with sodium sulfate and concentrated to small volume under vacuum. Yield: 274 mg (92%), white solid. Melting point: not determinable