Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8]([C:11]3[N:16]=[C:15]([NH2:17])[CH:14]=[CH:13][CH:12]=3)=[CH:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[H-].[Na+].[CH3:20]I.CO>CN(C=O)C>[O:1]1[C:5]2([CH2:10][CH2:9][C:8]([C:11]3[N:16]=[C:15]([NH:17][CH3:20])[CH:14]=[CH:13][CH:12]=3)=[CH:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: CI
Reactant: Nc1cccc(C2=CCC3(CC2)OCCO3)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: CNc1cccc(C2=CCC3(CC2)OCCO3)n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
6-(1,4-Dioxa-spiro[4.5]dec-7-en-8-yl)-pyridin-2-ylamine (as prepared in Example 22, Step A, 2.5 g, 10.8 mmol) in DMF (10 mL) was treated with NaH (Aldrich, 95%, 550 mg, 21.6 mmol) at 0° C. The reaction was stirred for 20 min. and MeI (Aldrich, 810 μL, 12 mmol) was slowly added. The reaction was warmed to room temperature over 2 hours. MeOH (˜1 mL) was added to quench the extra NaH. The reaction solution was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give a yellow oil, which was then purified by silica gel column on a CombiFlash® system using hexanes and ethyl acetate (from 10% ethyl acetate to 100% ethyl acetate) to afford the title compound as white solid.
Reaction SMILES: [CH2:1]([OH:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(N(CC)CC)C.Cl.[CH3:22][N:23]([CH3:28])[CH2:24][C:25](O)=[O:26].C1(N=C=NC2CCCCC2)CCCCC1>CN(C1C=CN=CC=1)C.CN(C)C=O>[CH2:1]([O:13][C:25](=[O:26])[CH2:24][N:23]([CH3:28])[CH3:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCO
Reactant: CN(C)CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCOC(=O)CN(C)C
Temperature: 0 °C
Reaction time: 24 h
Yield: 48.4 %

Procedure:
First, 1-dodecyl alcohol (2.98 g, 0.016 mol), triethylamine (1.62 g, 0.016 mol) and 4-(N,N-dimethylamino)pyridine (DMAP; 0.195 g, 0.0016 mol) were added to a solution of N,N-dimethylglycine hydrochloride (2.23 g, 0.016 mol) in dry N,N-dimethylformamide (DMF; 100 mL) under nitrogen atmosphere, and cooled to 0° C. Then, dicyclohexylcarbodiimide (DCC; 3.63 g, 0.0176 mol) in dry DMF (60 ml) was added thereto at 0° C. The reaction mixture was returned to room temperature and stirred for about one day, then DMF was evaporated under reduced pressure with a pump. The residue was dissolved using ether and aqueous saturated sodium bicarbonate solution, and the ether layer was collected and washed once with water and once with saturated saline, after which it was dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The resultant residue was separated by column chromatography (hexane:ethyl acetate:triethylamine=50:50:1) to give N,N-dimethylamino-acetate-1-dodecyl ester (C12-tertiary amine) (yield 48%, 2.10 g).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([C:16](=[O:18])[CH3:17])=[CH:6][C:7]2[CH:8]=[CH:9][CH2:10][C:11]([CH3:15])([CH3:14])[C:12]=2[CH:13]=1)[CH3:2].[CH:19]([N-]C(C)C)(C)C.[Li+].CI>C1COCC1>[CH2:1]([O:3][C:4]1[C:5]([C:16](=[O:18])[CH2:17][CH3:19])=[CH:6][C:7]2[CH:8]=[CH:9][CH2:10][C:11]([CH3:14])([CH3:15])[C:12]=2[CH:13]=1)[CH3:2]
Reactant: CCOc1cc2c(cc1C(C)=O)C=CCC2(C)C
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CCOc1cc2c(cc1C(=O)CC)C=CCC2(C)C
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of 1-(3-ethoxy-5,5-dimethyl-5,6-dihydro-naphthalen-2-yl)-ethanone (Compound A-25, 0.17 g, 0.68 mmol) in THF (33 mL) at −78° C. was added lithium diisopropylamide (1.5 M in cyclohexane, 0.55 mL 0.82 mmol). The cold bath was removed and the mixture was stirred for 2 h. The mixture was cooled to −78° C. again and methyl iodide (0.13 mL, 2.04 mmol) was added. The mixture was stirred at room temperature for 12 h then quenched with a saturated solution of NH4Cl and extracted with diethyl ether. The combined ethereal layers were washed with water, brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude residue was purified by flash chromatography (silica gel, 2% ethyl acetate in hexane) to give the title compound as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12]([C:14]3[CH:23]=[N:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[N:15]=3)=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:25]1[CH2:30][CH2:29][CH2:28][C@@H:27]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:26]1>CCCCO>[Br:1][C:2]1[C:3]([N:25]2[CH2:30][CH2:29][CH2:28][C@@H:27]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:36])([CH3:35])[CH3:37])[CH2:26]2)=[C:4]2[C:10]([NH:11][C:12]([C:14]3[CH:23]=[N:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[N:15]=3)=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)c1cnc2ccccc2n1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)c4cnc5ccccc5n4)c23)C1
Temperature: 155 °C
Yield: 11.4 %

Procedure:
N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)quinoxaline-2-carboxamide (0.240 g, 0.621 mmol) and (R)-tert-butyl piperidin-3-ylcarbamate (0.373 g, 1.86 mmol) were placed in n-BuOH (3 mL) and heated to 155° C. for 48 hours in a sealed tube. The reaction was then cooled to room temperature and concentrated to dryness. The resulting residue was purified by reverse phase HPLC (5:75 water:ACN gradient, Gilson system) to give (R)-tert-butyl 1-(5-bromo-3-(quinoxaline-2-carboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (0.040 g, 11% yield).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[CH:12]=[C:13]([CH:17]=[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH2:34][CH2:35][CH2:36][C:37]([O:39]CC)=[O:38])[C:28]=4[CH2:42][CH2:43][C:44]([O:46]CC)=[O:45])[CH:19]=3)[C:14](O)=[O:15])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[CH3:49][NH2:50]>>[C:44]([CH2:43][CH2:42][C:28]1[C:27]([CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][O:20][C:18]2[CH:17]=[C:13]([C:14](=[O:15])[NH:50][CH3:49])[CH:12]=[C:11]([C:9]3[CH:8]=[CH:7][C:6]4[O:1][CH2:2][CH2:3][O:4][C:5]=4[CH:10]=3)[CH:19]=2)=[CH:32][CH:31]=[CH:30][C:29]=1[O:33][CH2:34][CH2:35][CH2:36][C:37]([OH:39])=[O:38])([OH:46])=[O:45]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(=O)O)cc(-c3ccc4c(c3)OCCO4)c2)c1CCC(=O)OCC
Reactant: CN
Product: CNC(=O)c1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2ccc3c(c2)OCCO3)c1

Procedure:
The title compound was prepared according to the general procedure described in Example 74 starting from 3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-5-{6-[2-(2-ethoxycarbonyl-ethyl)-3-(3-ethoxycarbonyl-propoxy)-phenyl]-hexyloxy}-benzoic acid and methylamine.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([F:10])([F:9])[F:8])=[CH:5][C:4]([O:11][C:12]2[CH:13]=[CH:14][C:15]([N+:19]([O-])=O)=[C:16]([CH:18]=2)[NH2:17])=[N:3]1.S(S([O-])=O)([O-])=O.[Na+].[Na+].O.C(=O)(O)[O-].[Na+]>C(O)C>[CH3:1][N:2]1[C:6]([C:7]([F:9])([F:10])[F:8])=[CH:5][C:4]([O:11][C:12]2[CH:13]=[CH:14][C:15]([NH2:19])=[C:16]([NH2:17])[CH:18]=2)=[N:3]1
Reactant: Cn1nc(Oc2ccc([N+](=O)[O-])c(N)c2)cc1C(F)(F)F
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cn1nc(Oc2ccc(N)c(N)c2)cc1C(F)(F)F
Reaction time: 1.5 h

Procedure:
The nitroaniline obtained in step A (2 g, 6.6 mmol) was dissolved in 50% aqueous ethanol (100 cm3) and sodium dithionite (4.61 g 26.5 mmol) added portionwise over 20 minutes to the stirred solution, each portion being allowed to dissolve before adding the next. The reaction mixture was heated under reflux with stirring for 1.5 hours and after cooling was poured into water (50 cm3) and neutralised with aqueous sodium bicarbonate before being extracted with ethyl acetate (2×100 cm3). The combined extracts were dried (MgSO4) and the solvent removed in vacuo leaving a light brown solid which was triturated with hexane, filtered and dried, to give 4-(1-methyl-5-trifluoromethyl-1H-pyrazol-3-yloxy)-o-phenylenediamine m.p. 109°-111° C.
Reaction SMILES: [Li].[OH:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[CH:8]2.[Cl-:13].[Cl-].[Cl-].[Cr+3:16]>O1CCCC1>[Cl-:13].[Cl-:13].[N:11]1[C:12]2[C:7](=[CH:6][CH:5]=[CH:4][C:3]=2[O:2][Cr+2:16])[CH:8]=[CH:9][CH:10]=1
Reactant: [Cr+3]
Reactant: Oc1cccc2cccnc12
Agent: [Cl-]
Agent: [Li]
Solvent: C1CCOC1
Product: [Cr+2]Oc1cccc2cccnc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 0.01 moles of the lithium salt of 8-hydroxyquinoline (prepared as described in Example 3) in 50 mL of tetrahydrofuran is added dropwise to a solution of 0.01 moles of chromium trichloride in 50 mL of tetrahydrofuran at −78° C. After warming to room temperature and stirring overnight, the suspension is filtered and the solvent evaporated under vacuum. The product is recovered from the solids by extraction with toluene and then isolated by evaporating the toluene. Polymers may be produced using this catalyst by following the procedure of Example 4.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:9][CH2:8][C:5]2([CH2:7][CH2:6]2)[O:4]1.CCN(CC)CC.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C(Cl)Cl>[CH3:17][S:18]([O:1][CH2:2][C@H:3]1[CH2:9][CH2:8][C:5]2([CH2:7][CH2:6]2)[O:4]1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: OC[C@H]1CCC2(CC2)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC[C@H]1CCC2(CC2)O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of (5R)-5-(hydroxymethyl)-4-oxaspiro[2.4]heptane (116 mg, 0.9 mmol) and Et3N (183.8 mg, 1.82 mmol, Shantou Xilong chemical factory) in dry CH2Cl2 (6 mL) at −10° C. under N2, was added MsCl (203 mg, 1.4 mmol, Shanghai Haiqu chemical Ltd.) dropwise via a syringe. After stirring for 2 hrs at rt, the reaction was quenched with water ice (3 mL), and the water phases were extracted with CH2Cl2 (20 mL×2). The combined organic phases were dried over Na2SO4, and concentrated in vacuo to give ((5R)-4-oxaspiro[2.4]heptane-5-yl)methyl methanesulfonate as pale yellow oil.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.O=S(Cl)[Cl:12]>C1COCC1>[C:1]([Cl:12])(=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cccnc1
Solvent: C1CCOC1
Product: O=C(Cl)c1cccnc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of nicotinic acid (2 g, 16.2 mmol) in anhydrous THF (30 mL) was added SOCl2 (2.4 mL, 32.5 mmol). After stirring at 80° C. for 2 hours, the mixture was concentrated in vacuo
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([Cl:16])[CH:10]=2)[CH:5]=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1.[C:23](Cl)(=[O:29])[CH2:24][CH2:25][C:26](Cl)=[O:27]>CN(C)C=O.CN(C1C=CN=CC=1)C.O>[Cl:16][C:11]1[CH:10]=[C:9]([NH:8][C:6]2[CH:5]=[C:4]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:3]=[C:2]([N:1]3[C:26](=[O:27])[CH2:25][CH2:24][C:23]3=[O:29])[N:7]=2)[CH:14]=[CH:13][C:12]=1[OH:15]
Reactant: Nc1nc(Nc2ccc(O)c(Cl)c2)cc(-c2ccccc2)n1
Reactant: O=C(Cl)CCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CCC(=O)N1c1nc(Nc2ccc(O)c(Cl)c2)cc(-c2ccccc2)n1

Procedure:
To a solution of compound 4-(2-amino-6-phenyl-pyrimidin-4-ylamino)-2-chloro-phenol (0.5 g, 1.6 mmol) in dry dimethylformamide (10 mL) was added 4-(N,N-dimethylamino)pyridine (0.39 g, 3.2 mmol) at 0° C. with stirring under nitrogen atmosphere. To this was added freshly prepared succinyl chloride (0.62 g, 4 mmol). The mixture was then stirred at 80° C. for 20 hours. After completion of the reaction the mixture was diluted with water (75 mL), the solid separated was filtered off, washed with cold water (200 mL) and dried. The solid was purified further by column chromatography using petroleum ether-ethyl acetate to give the desired product as a light brown solid.
Reaction SMILES: Br[CH:2]([CH3:6])[C:3]([NH2:5])=[O:4].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]([NH:17][C:18]2[CH:19]=[N:20][CH:21]=[C:22]([C:24]([C:26]3[C:34]4[CH:33]=[N:32][CH:31]=[N:30][C:29]=4[NH:28][CH:27]=3)=[O:25])[CH:23]=2)=[O:16])=[CH:10][CH:9]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]([NH:17][C:18]2[CH:23]=[C:22]([C:24]([C:26]3[C:34]4[CH:33]=[N:32][CH:31]=[N:30][C:29]=4[N:28]([CH:2]([CH3:6])[C:3]([NH2:5])=[O:4])[CH:27]=3)=[O:25])[CH:21]=[N:20][CH:19]=2)=[O:16])=[CH:10][CH:9]=1
Reactant: O=C(Cc1ccc(Cl)cc1)Nc1cncc(C(=O)c2c[nH]c3ncncc23)c1
Reactant: CC(Br)C(N)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C(N)=O)n1cc(C(=O)c2cncc(NC(=O)Cc3ccc(Cl)cc3)c2)c2cncnc21
Temperature: 60 °C
Reaction time: 3 h
Yield: 34 %

Procedure:
2-bromopropionamide (46.5 mg, 0.31 mmol) was added to a mixture of 2-(4-chlorophenyl)-N-[5-(7H-pyrrolo[2,3-d]pyrimidin-5-ylcarbonyl)pyridin-3-yl]acetamide (Example 308, 100 mg, 0.26 mmol) and cesium carbonate (150 mg, 0.46 mmol) in DMF (1.3 mL). The mixture was stirred at 60° C. for 3 hours. The reaction mixture was cooled and water (10 mL) was added. The mixture was extracted with EtOAc (3×10 mL) and the combined organic phases were passed through a phase separator and evaporated in vacuo. Purification by preparative HPLC gave the title compound as a white solid in 34% yield, 15 mg.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:18])[CH:11]=[C:12]([CH:15]([F:17])[F:16])O[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]([NH2:22])[CH:20]=[CH2:21]>CO>[CH2:19]([N:22]1[CH:14]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:10](=[O:18])[CH:11]=[C:12]1[CH:15]([F:16])[F:17])[CH:20]=[CH2:21]
Reactant: O=c1cc(C(F)F)occ1OCc1ccccc1
Reactant: C=CCN
Solvent: CO
Product: C=CCn1cc(OCc2ccccc2)c(=O)cc1C(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.4 %

Procedure:
A mixture of 5-benzyloxy-2-difluoromethyl-pyran-4-one (4.00 g, 15.8 mmol), allylamine (3.60 mL, 47.5 mmol) in methanol (40 mL) was stirred at room temperature for 1 hour. The reaction mixture was evaporated to dryness, and the residual solid was dissolved in 10 mL of ethyl acetate, and again concentrated in vacuo. The solid was suspended in a mixture of ethyl acetate and ether, then collected by suction filtration and thoroughly washed with ether. The off-white solid was dried to constant weight in a vacuum oven at 40° C. to afford the title product (3.38 g, 73% yield). HPLC purity (peak area percent) is 98.9% at λ=278 nm using HPLC Method 1 as described above. 1H NMR (400 MHz, CDCl3) δ (ppm): 7.35-7.43 (m, 5H, ArH), 7.16 (s, 1H), 6.79 (s, 1H), 6.48 (t, J=53.1 Hz, 1H, CF2H), 5.80-5.86 (m, 1H), 5.29 (d, J=10.4 Hz, 1H), 5.22 (s, 2H, OCH2), 5.10 (d, J=17.1 Hz, 1H), 4.58 (d, J=5.2 Hz, 2H); MS-ESI (m/z): 291.9 [M+1]+, 91.0.
Reaction SMILES: IC1C=C(N[C:10](=[O:23])[CH2:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([I:22])[CH:16]=2)=[O:13])C=CC=1C.[Cl-].[Al+3].[Cl-].[Cl-].[Cl-].[Na+]>O>[OH:23][C:10]1[C:20]2[C:15](=[CH:16][C:17]([I:22])=[C:18]([CH3:21])[CH:19]=2)[NH:14][C:12](=[O:13])[CH:11]=1
Reactant: Cc1ccc(NC(=O)CC(=O)Nc2ccc(C)c(I)c2)cc1I
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: Cc1cc2c(O)cc(=O)[nH]c2cc1I
Temperature: 250 °C
Yield: 28 %

Procedure:
N,N′-Bis-(3-iodo-4-methyl-phenyl)-malonamide (43.4 g, 81.3 mmol) was added portionwise to a melt of aluminum chloride (32.5 g, 244 mmol) and sodium chloride (9.50 g, 163 mmol) at 150° C., then the mixture was heated at 250° C. for 20 min. After cooling the solid formed was suspended in hot water and collected by filtration. This crude material was suspended in hot 0.5 M aq. sodium hydroxide solution, insoluble material was removed by filtration, and the filtrate was acidified with 25% aq. hydrochloric acid solution. The precipitate was collected by filtration, washed with water and ethyl acetate, and dried to afford the title compound (6.85 g, 28%). Light brown solid, EI-MS: m/e=301.2 (M+).
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][C:6]([NH:17][C@H:18]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:19]([NH2:21])=[O:20])=[N:7][C:8]=1[NH:9][C:10]1[CH:11]=[C:12]([CH3:16])[CH:13]=[CH:14][CH:15]=1)#[N:2].C([O-])([O-])=[O:27].[K+].[K+]>CO.OO>[NH2:21][C:19](=[O:20])[C@H:18]([NH:17][C:6]1[N:7]=[C:8]([NH:9][C:10]2[CH:11]=[C:12]([CH3:16])[CH:13]=[CH:14][CH:15]=2)[C:3]([C:1]([NH2:2])=[O:27])=[N:4][CH:5]=1)[CH2:22][CH:23]([CH3:25])[CH3:24]
Reactant: Cc1cccc(Nc2nc(N[C@H](CC(C)C)C(N)=O)cnc2C#N)c1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CO
Product: Cc1cccc(Nc2nc(N[C@H](CC(C)C)C(N)=O)cnc2C(N)=O)c1

Procedure:
To a mixture of (R)-2-(5-cyano-6-(m-tolylamino)pyrazin-2-ylamino)-4-methylpentanamide in methanol (1 ml) was added K2CO3 (excess)) and H2O2 (50%, a few drops). After completion, it was concentrated and purified by preparative HPLC to give (R)-5-(1-amino-4-methyl-1-oxopentan-2-ylamino)-3-(m-tolylamino)pyrazine-2-carboxamide (6 mg). MS found for C18H24N6O2 as (M+H)+357.3, UV: λ=253.4, 304.5.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:10]([O:12]N1C(=O)CCC1=O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:28][CH2:29][CH2:30][N:31]([CH2:40][CH2:41][Cl:42])[C:32]1[CH:37]=[CH:36][C:35]([CH3:38])=[C:34]([NH2:39])[CH:33]=1.C(N(CC)CC)C>C(#N)C>[Cl:28][CH2:29][CH2:30][N:31]([CH2:40][CH2:41][Cl:42])[C:32]1[CH:37]=[CH:36][C:35]([CH3:38])=[C:34]([NH:39][C:10](=[O:12])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:20][C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[CH:33]=1
Reactant: Cc1ccc(N(CCCl)CCCl)cc1N
Reactant: CC(C)(C)OC(=O)C[C@H](NC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1ccc(N(CCCl)CCCl)cc1NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Adapting a literature known protocol (Levi and Weed, U.S. Pat. No. 3,235,594 (1966)), to a solution of O1-(2,5-Dioxopyrrolidin-1-yl)O4-tert-butyl(2S)-2-(tert-butoxycarbonylamino)-butanedioate (Boc-L-Asp(Osu)-OtBu) (6a) (386 mg, 1.0 mmol) in anhydrous acetonitrile (MeCN) (10 mL) is added N,N-bis(2-chloroethyl)-4-methyl-benzene-1,3-diamine (16b) as a bis hydrochloride salt (320 mg, 1.0 mmol) followed by neat triethylamine (Et3N, TEA) (321 μL, 233 mg, 2.3 mmol). The reaction mixture is stirred for about 12 h at room temperature. The reaction is followed by TLC and/or LC/MS to completion. The volatile solvents are removed under reduced pressure using a rotary evaporator. Aqueous work-up and purification by silica gel column chromatography furnish the target compound (16c).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[CH:4][C:3]=1[CH3:10].[C-:11]#[N:12].[K+]>C(Cl)Cl.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:11]#[N:12])=[CH:4][C:3]=1[CH3:10]
Reactant: [C-]#N
Reactant: Cc1cc(CBr)ccc1Br
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: Cc1cc(CC#N)ccc1Br
Reaction time: 6 h
Yield: 86.6 %

Procedure:
1-Bromo-4-(bromomethyl)-2-methylbenzene (45 of crude from step b, 68.2 mmol) dissolved in CH2Cl2 (500 mL) is mixed and stirred with potassium cyanide (24 g, 364 mmol) and N-tetra(n-butyl)ammonium bromide (1.2 g, 3.64 mmol) in distilled water (500 mL). This reaction mixture is stirred vigorously for 6 h. The organic phase is separated, dried over MgSO4, filtered and concentrated. The resulting residue is purified on silica gel using a 0 to 30% gradient of ethyl acetate in heptane to provide the expected product 2-(4-bromo-3-methylphenyl)acetonitrile (12.4 g, 87% over two steps) as a clear yellow oil. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 2.41 (s, 3H) 3.68 (s, 2H) 7.01 (dd, J=8.50, 2.05 Hz, 1H) 7.21 (d, J=1.37 Hz, 1H) 7.53 (d, J=8.20 Hz, 1H)
Reaction SMILES: [Cl:1][C:2]1[C:14]([NH:15][CH2:16][C:17]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)[CH:20]=[CH:19][C:18]=2[F:30])=[C:13]([Cl:31])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([O:8]CC)=[O:7].O[Li].O.O>C1COCC1>[Cl:1][C:2]1[C:14]([NH:15][CH2:16][C:17]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)[CH:20]=[CH:19][C:18]=2[F:30])=[C:13]([Cl:31])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)COc1ccc(Cl)c(NCc2cc(-c3cccc(F)c3)ccc2F)c1Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)COc1ccc(Cl)c(NCc2cc(-c3cccc(F)c3)ccc2F)c1Cl
Temperature: 60 °C
Yield: 65.2 %

Procedure:
To a solution of ethyl 2-[2,4-dichloro-3-[[2-fluoro-5-(3-fluorophenyl)phenyl]methylamino]phenoxy]acetate (130 mg, 0.28 mmol, 1.0 eq) in THF (20 mL), LiOH.H2O (50 mg, 1.1 mmol, 4.0 eq) was added. After the addition of water (10 mL), the mixture was heated to 60° C. overnight. The THF was then removed in vacuo and the water phase was adjusted to pH 6 by addition of 1M HCl. The precipitate was collected by filtration, washed with water and dried in vacuo to give the title compound as a solid (80 mg, 65%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:10]=[C:11]2[N:16]=CC=C[N:12]2[CH:17]=1.NN.O>CCO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:10]=[C:11]([NH2:16])[NH:12][CH:17]=1
Reactant: COc1ccccc1-c1cn2cccnc2n1
Agent: NN
Solvent: O
Solvent: CCO
Product: COc1ccccc1-c1c[nH]c(N)n1
Temperature: 75 °C

Procedure:
To a stirred solution of 2-(2-methoxyphenyl)imidazo[1,2-α]pyrimidine (1.24 g, 5.5 mmol) in EtOH (8 mL) was added NH2NH2.H2O (0.3 mL, 6.1 mmol). After heating to 75° C. for 24 h, the reaction was concentrated under reduced pressure. The residue was suspended in Et2O and filtered to collect 4-(2-methoxyphenyl)-1H-imidazol-2-amine (1 g, 96%) as a light yellow solid.
Reaction SMILES: [CH3:1][C:2]([CH3:12])=[CH:3][C@H:4]1[C:6]([CH3:8])([CH3:7])[C@H:5]1[C:9]([OH:11])=[O:10].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.BrBr>C1(C)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[CH3:1][C:2]([CH3:12])=[CH:3][CH:4]1[C:6]([CH3:7])([CH3:8])[CH:5]1[C:9]([OH:11])=[O:10]
Reactant: CC(C)=C[C@@H]1[C@H](C(=O)O)C1(C)C
Agent: BrBr
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)=CC1C(C(=O)O)C1(C)C
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 93.5 %

Procedure:
2.0 g of cis-chrysanthemic acid and 43 mg of benzoyl peroxide were dissolved in 20 ml of toluene and thereto was added dropwise a solution of bromine (28 mg) in carbon tetrachloride with stirring at 80° C. over a period of 20 minutes, and the reaction mixture was stirred at the same temperature for 20 minutes. Then, a post-treatment similar to Example 1 was effected to obtain 1.87 g of chrysanthemic acid. Gas chromatographic assay thereof showed the composition: cis, 5.9%; and trans, 94.1%.
Reaction SMILES: Cl[C:2]1[N:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH:15]=[N:16][N:17]([CH3:28])[C:18]2[C:23]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:21]=[CH:20][N:19]=2)[C:4](=[O:8])[N:5]([CH3:7])[N:6]=1.[CH3:29][O-:30].[Na+]>C1COCC1.O>[CH3:29][O:30][C:2]1[N:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH:15]=[N:16][N:17]([CH3:28])[C:18]2[C:23]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:21]=[CH:20][N:19]=2)[C:4](=[O:8])[N:5]([CH3:7])[N:6]=1
Reactant: C[O-]
Reactant: CN(N=Cc1ccccc1-n1c(Cl)nn(C)c1=O)c1ncccc1C(F)(F)F
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1nn(C)c(=O)n1-c1ccccc1C=NN(C)c1ncccc1C(F)(F)F
Temperature: 25 °C

Procedure:
The title compound of Step B (0.38 g, 0.93 mmol) was dissolved in THF (10 mL) and then sodium methoxide (25% in methanol, 0.56 mL) was added dropwise. The mixture was heated at reflux for 1 h, cooled to room temperature and then diluted with water and extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous NaCl, dried (MgSO4), filtered and concentrated to an oil which was purified by flash column chromatography on silica gel to afford 0.27 g of the title compound of Step C, a compound of the invention, as a pale yellow solid melting at 185-187° C. 1H NMR (300 MHz, CDCl3): δ 8.41 (dd,1H, J=5, 1.5 Hz), 8.12 (dd,1H, J=8, 1.5 Hz), 8.01 (dd,1H, J=8, 1.5Hz), 7.42 (m,3H), 7.23 (d,1H J=8 Hz), 15 7.02 (dd,1H, J=8, 5Hz), 3.93 (s,3H), 3.56 (s,3H), 3.48 (s,3H).