Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12]([C:14]2[N:19]=[C:18]([NH:20][C@H:21]([CH3:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[C:17]([N+:27]([O-])=O)=[CH:16][CH:15]=2)=[C:11]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[N:10]=1.O.O.[Sn](Cl)Cl.[N:42]#[C:43]Br>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12]([C:14]2[N:19]=[C:18]3[N:20]([C@H:21]([CH3:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[C:43]([NH2:42])=[N:27][C:17]3=[CH:16][CH:15]=2)=[C:11]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[N:10]=1
Reactant: N#CBr
Reactant: C[C@@H](Nc1nc(-c2[nH]c(-c3c(F)cccc3F)nc2-c2ccc(F)cc2)ccc1[N+](=O)[O-])C(C)(C)C
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: C[C@@H](n1c(N)nc2ccc(-c3[nH]c(-c4c(F)cccc4F)nc3-c3ccc(F)cc3)nc21)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.1 %

Procedure:
Dissolve {6-[2-(2,6-difluoro-phenyl)-5-(4-fluoro-phenyl)-3H-imidazol-4-yl]-3-nitro-pyridin-2-yl}-(1(R),2,2-trimethyl-propyl)-amine (673 mg, 1.4 mmol) in 100% ethanol (15 mL) and add tin(II) dichloride dihydrate (1.5 g, 6.8 mmol, 5 equiv). Heat the reaction mixture until starting material is consumed. Cool the reaction solution to room temperature, quench slowly with saturated aqueous NaHCO3. Add Celite® to the quenched reaction and filter the suspension on a Celite® pad, washing with water and ethyl acetate. Separate the layers and wash the organic layer with saturated aqueous NaCl. Dry the organic layer with Na2SO4, filter, and concentrated under reduced pressure. Add 10% aqueous ethanol (14 mL) and cyanogen bromide (216 mg, 2.04 mmol, 1.5 equiv) to the residue and stir overnight. Quench with saturated aqueous NaHCO3 (20 mL). Add ethyl acetate and water to dissolve all solids. Wash the organic layer is with saturated aqueous NaCl, dry with Na2SO4, filter, and concentrate under reduced pressure. Subject the residue to medium pressure silica gel chromatography eluting with a gradient of 1.5-3% (2M ammonia in MeOH)/CH2Cl2 to provide 5-[2-(2,6-difluoro-phenyl)-5-(4-fluoro-phenyl)-3H-imidazol-4-yl]-3-(1(R),2,2-trimethyl-propyl)-3H-imidazo[4,5-b]pyridin-2-ylamine as a tan glass (289 mg, 43% yield).
Reaction SMILES: [OH:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]([Cl:12])([Cl:11])[Cl:10])[N:3]=1.C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>ClCCl>[CH3:20][S:21]([O:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]([Cl:12])([Cl:11])[Cl:10])[N:3]=1)(=[O:23])=[O:22]
Reactant: Cc1nc(O)nc(C(Cl)(Cl)Cl)n1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc(OS(C)(=O)=O)nc(C(Cl)(Cl)Cl)n1

Procedure:
To a solution of 2-hydroxy-4-methyl-6-trichloromethyl-[1,3,5]triazine (1.14 g, 5.0 mmol; J. Amer. Chem. Soc. 1956, 78, 2447) and triethylamine (0.51 g, 5.5 mmol) in dichloromethane was added methanesulfonyl chloride (0.57 g, 5.0 mmol) at 0° C. and stirred ford h then quenched in saturated aqueous sodium bicarbonate. The separated organic layer was washed once with saturated sodium chloride, dried over magnesium sulfate and filtered. The filtrate was evaporated to give the title compound of Example 242, Step A as an orange oil, 0.98 g (65%) which was used directly without any further purification. MS (CI) 291, 293 (MH+).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.Cl[C:16]([O:18][CH3:19])=[O:17].C(N(CC)CC)C>C(Cl)Cl>[CH3:19][O:18][C:16]([NH:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1)=[O:17]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)NC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 2 h

Procedure:
tert-Butyl 4-aminopiperidine-1-carboxylate (0.1 g, 0.5 mmol) was combined with methyl chloroformate (0.046 mL, 0.59 mmol) and triethylamine (0.22 mL, 1.6 mmol) in methylene chloride (2 mL) at room temperature and stirred for 2 hours. The reaction was diluted with dichloromethane, washed with water, dried over MgSO4, and then concentrated. The resulting residue was purified on silica gel (eluting with 0 to 5% methanol in dichloromethane) to give tert-butyl 4-[(methoxycarbonyl)amino]piperidine-1-carboxylate, LCMS [M+Na] 281.1. The later was treated with 4.57 M hydrogen chloride in 1,4-dioxane (1 mL, 4 mmol) at room temperature for 1 hour. The mixture was concentrated to give crude product which was used directly in the next step. LCMS calculated for C7H15N2O2 (M+H)+: m/z=159.1; Found: 159.1.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[O:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]1[O:25][CH:26]([C:35]1[CH:40]=[CH:39][C:38]([CH2:41][O:42][Si](C(C)C)(C(C)C)C(C)C)=[CH:37][CH:36]=1)[C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[C:30]#[N:31]>O1CCCC1.O>[OH:42][CH2:41][C:38]1[CH:39]=[CH:40][C:35]([CH:26]([O:25][CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][O:19]2)[C:27]2[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=2)[C:30]#[N:31])=[CH:36][CH:37]=1
Reactant: CC(C)[Si](OCc1ccc(C(OC2CCCCO2)c2cccc(C#N)c2)cc1)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1cccc(C(OC2CCCCO2)c2ccc(CO)cc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.4 %

Procedure:
Add a 1M solution in tetrahydrofuran of tetrabutylammonium fluoride (37 mL, 37 mmol) to a solution of 3-[(tetrahydro-pyran-2-yloxy)-(4-triisopropylsilanyloxymethyl-phenyl)-methyl]-benzonitrile (14.6 g, 30.4 mmol) in tetrahydrofuran (50 mL) and tetrahydrofuran stir at room temperature for 2 hours. Concentrate the reaction, dilute with water (200 mL), and extract with ethyl acetate (2×100 mL). Combine the extracts, dry over magnesium sulfate, filter, and concentrate. Purify the residue via silica chromatography eluting with 9:1 hexanes:ethyl acetate to 1:1 hexanes ethyl acetate to afford the title compound (8.0 g, 82%), as a colorless thick oil. LCMS (m/z) 323 M+1.
Reaction SMILES: [I:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:9]([O-])=O.[OH-].[Na+].[ClH:14]>O1CCCC1>[ClH:14].[I:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH2:9]
Reactant: O=[N+]([O-])c1cccc(F)c1I
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Nc1cccc(F)c1I

Procedure:
A solution of 2-iodo-3-fluoronitrobenzene (27.0 g, 0.101 mol) in tetrahydrofuran (200 mL) was added dropwise over a 10 minute period to a stirring solution of stannous chloride dihydrate (68.0 g, 0.302 mol) in concentrated hydrochloric acid (200 mL). After 3 hours at room temperature the reaction was poured onto ice, made alkaline (pH 11) with 50% NaOH, and extracted with diethyl ether. The combined organic phases were washed with water, brine, dried (MgSO4), filtered, and concentrated to almost dryness. Ethereal HCl was added (pH 1-2), and the resulting precipitate filtered and dried to afford 25.0 g of the title compound, m.p. 197°-198° C. (dec.).
Reaction SMILES: Cl.[C:2]([CH2:7][NH2:8])(=[O:6])[CH:3]([CH3:5])[CH3:4].C(=O)(O)[O-].[Na+].[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:14]([NH:8][CH2:7][C:2](=[O:6])[CH:3]([CH3:5])[CH3:4])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)C(=O)CN
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(C)C(=O)CNC(=O)c1ccccc1
Yield: 90.4 %

Procedure:
4.5 g of isobutyrylmethylamine hydrochloride, 11 g of sodium bicarbonate and 4.81 g of benzoyl chloride are treated in the same manner as described in Preparation 1-(4). 6.07 g of N-benzoylisobutyrylmethylamine are thereby obtained. Yield: 90.5%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[Cl:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=1.Cl>CC(O)C>[ClH:1].[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:14][C:13]2[CH:15]=[CH:16][C:10]([Cl:9])=[CH:11][CH:12]=2)[CH:7]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: Nc1ccc(Cl)cc1
Agent: Cl
Solvent: CC(C)O
Product: Clc1ccc(Nc2cc(Cl)ncn2)cc1
Temperature: 84 °C
Yield: 75 %

Procedure:
250 mg of 4,6-dichloropyrimidine and 165 mg of p-chloroaniline were dissolved in 2.5 mL of i-PrOH and 0.25 mL of 37% HCl were added. The mixture obtained was refluxed (84° C.) for 2.5 hours under nitrogen atmosphere. A colorless precipitate was formed which was collected by filtration. 6-Chloro-N-(4-chlorophenyl)pyrimidin-4-amine hydrochloride in the form of colorless crystals was obtained.
Reaction SMILES: [CH3:1][C:2]1[C:24]([CH3:25])=[CH:23][C:5]2[N:6]([C:10]3[CH2:11][CH2:12][N:13](CC4C=CC=CC=4)[CH2:14][CH:15]=3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.[H][H]>C(O)C.C(O)(=O)C.[Pd]>[CH3:1][C:2]1[C:24]([CH3:25])=[CH:23][C:5]2[N:6]([C:10]3[CH2:11][CH2:12][NH:13][CH2:14][CH:15]=3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1
Reactant: Cc1cc2[nH]c(=O)n(C3=CCN(Cc4ccccc4)CC3)c2cc1C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1cc2[nH]c(=O)n(C3=CCNCC3)c2cc1C

Procedure:
A solution of 5,6-dimethyl-1-[1-(phenylmethyl)-1,2,3,6-tetrahydro-4-pyridinyl]-1,3-dihydro-2H-benzimidazol-2-one (D99) (1.05 mmol, 350 mg) in ethanol (10 mL) and acetic acid (2 mL) was treated with 10% palladium on charcoal (0.25 eq wt, 90 mg) then shaken under 50 PSI of hydrogen pressure for 24 h. The catalyst was filtered off and the filtrate was concentrated under reduced pressure to give the acetate salt of the title compound also containing some saturated analogue (reduction of the C═C double bond in the piperidine core) as a beige solid (1.2 mmol, 370 mg, >100% yield) M+H 246.2, M−H 242.3.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10]3[CH:29]=[CH:28][CH:27]=[CH:26][C:11]=3[C:12]3[CH2:13][N:14]([C@H:19]4[CH2:24][CH2:23][CH2:22][CH2:21][C@@H:20]4[OH:25])[C:15](=[O:18])[C:16]=3[CH:17]=2)=[CH:4][CH:3]=1.[CH3:30][Zn]C.ClCCl>O1CCCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[OH:25][C@H:20]1[CH2:21][CH2:22][CH2:23][CH2:24][C@@H:19]1[N:14]1[CH2:13][C:12]2[C:11]3[CH:26]=[CH:27][CH:28]=[CH:29][C:10]=3[C:9]([CH2:8][C:5]3[CH:6]=[N:7][C:2]([CH3:30])=[CH:3][CH:4]=3)=[CH:17][C:16]=2[C:15]1=[O:18]
Reactant: C[Zn]C
Reactant: O=C1c2cc(Cc3ccc(Cl)nc3)c3ccccc3c2CN1[C@H]1CCCC[C@@H]1O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1ccc(Cc2cc3c(c4ccccc24)CN([C@H]2CCCC[C@@H]2O)C3=O)cn1
Temperature: 50 °C

Procedure:
To a solution of 5-[(6-chloropyridin-3-yl)methyl]-2-[(1S,2S)-2-hydroxycyclohexyl]-1,2-dihydro-3H-benzo[e]isoindol-3-one (0.040 g, 0.098 mmol) in 3 mL of tetrahydrofuran under an atmosphere of nitrogen was added dimethylzinc (1.2 M in tetrahydrofuran, 0.16 mL, 0.20 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloro-palladium(II), 1:1 complex with dichloromethane (7.2 mg, 0.0098 mmol). The mixture was heated at 50° C. for 3 hr and then cooled to ambient temperature. Additional dimethyl zinc (1.2 M in tetrahydrofuran, 0.16 mL, 0.20 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloro-palladium(II), 1:1 complex with dichloromethane (7.2 mg, 0.0098 mmol) were added and the mixture was heated at 50° C. for an additional 12 hr. The mixture was cooled to ambient temperature and concentrated in vacuo. The residue was purified via preparative reverse phase HPLC to provide the title compound that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 387.4 for [M+H]+: 1H NMR (400 MHz, CDCl3) δ 8.79 (s, 1H), 7.92-7.84 (m, 3H), 7.69 (s, 1H), 7.65-7.61 (m, 2H), 7.41 (d, J=8.1 Hz, 1H), 4.87-4.73 (m, 2H), 4.53 (s, 2H), 4.23-4.16 (m, 1H), 3.81-3.75 (m, 1H), 2.77 (s, 3H), 2.23-2.20 (m, 1H), 2.02-1.99 (m, 1H), 1.87-1.84 (m, 2H), 1.84-1.64 (m, 1H), 1.55-1.33 (m, 3H) ppm.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:8]([C:21](=[O:23])[CH3:22])[C:9]3[C:14]([S:15][C:16]=2[CH:17]=1)=[CH:13][C:12]([N+:18]([O-])=O)=[CH:11][CH:10]=3)([O-])=O.O.O.[Sn](Cl)Cl.C(=O)([O-])O.[Na+]>C(O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[N:8]([C:21](=[O:23])[CH3:22])[C:9]3[C:14]([S:15][C:16]=2[CH:17]=1)=[CH:13][C:12]([NH2:18])=[CH:11][CH:10]=3
Reactant: CC(=O)N1c2ccc([N+](=O)[O-])cc2Sc2cc([N+](=O)[O-])ccc21
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(=O)N1c2ccc(N)cc2Sc2cc(N)ccc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 100.1 %

Procedure:
A mixture of 1-(3,7-dinitro-phenothiazin-10-yl)-ethanone (2 g, 6.04 mmol), tin (II) chloride dihydrate (14.17 g, 62.8 mmol), and ethanol (50 cm3) was heated to reflux and stirred at this temperature for 5 hours. The mixture was then cooled to room temperature and poured over ice water. The pH was adjusted to 7 with 5% sodium hydrogen carbonate before the product was extracted with ethyl acetate (3×50 cm3). The extracts were washed with brine and dried over magnesium sulphate, filtered, and concentrated to give the title compound (1.64 g, 100%) as a purple blue solid; vmax(KBr)/cm−1: 3445 (NH), 3424 (NH), 3368 (NH), 3322 (NH), 3203 (NH), 3054 (CH), 2995 (CH), 1706 (C═O), 1650 (NO2), 1590 (NO2); δH (250 MHz; CDCl3): 2.01 (3H, s, CH3), 5.09-5.43 (4H, brd s, NH), 6.47-6.51 (2H, dd, J 1.5, 8.25, ArH), 6.61 (2H, s, ArH), 7.11-7.15 (2H, d, J 8, ArH); δC (62.9 MHz; CDCl3): 169.1 (C═O), 147.2 (ArC), 128.1 (ArC), 127.6 (ArC), 127.3 (ArC), 112.3 (ArC), 111.5 (ArC), 22.6 (CH3); m/z (ES) 293.9 (95%, [M+H, Na]+), 272.0 (20%, [M+H]+), 227.9 (100%, [M+H, —Ac]+).
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][C:30]4[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[CH:32][N:31]=4)=[O:28])=[C:22]([F:40])[CH:21]=3)[C:9]([CH2:18]O)=[C:10]([CH2:11][N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[N:6]2[N:5]=[CH:4][N:3]=1.NC1C2=C(C3C=CC(NC(NC4C=C(C(F)(F)[F:77])C=CN=4)=O)=CC=3)C(C=O)=C(CN3CCOCC3)N2N=CN=1>>[NH2:1][C:2]1[C:7]2=[C:8]([C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][C:30]4[CH:35]=[C:34]([C:36]([F:37])([F:39])[F:38])[CH:33]=[CH:32][N:31]=4)=[O:28])=[C:22]([F:40])[CH:21]=3)[C:9]([CH2:18][F:77])=[C:10]([CH2:11][N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: Nc1ncnn2c(CN3CCOCC3)c(C=O)c(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccn4)cc3)c12
Reactant: Nc1ncnn2c(CN3CCOCC3)c(CO)c(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccn4)c(F)c3)c12
Product: Nc1ncnn2c(CN3CCOCC3)c(CF)c(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccn4)c(F)c3)c12
Yield: 23 %

Procedure:
The title compound was prepared in a manner similar to the procedure described for the preparation of Example 87, using N-{4-[4-amino-6-(hydroxymethyl)-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f]-[1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[4-(trifluoro-methyl)-pyridin-2-yl]urea (which can be prepared using the procedure used for the preparation of Example 62 substituting Intermediate AJ for Intermediate Y) in place of Example 85 (N-{4-[4-amino-6-formyl-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f]-[1,2,4]triazin-5-yl]phenyl}-N′-[4-(trifluoro-methyl)pyridin-2-yl]urea), 45 mg (23%) of the desired product was isolated. 1H-NMR (DMSO-d6) δ 10.16-10.10 (m, 2H), 8.54 (d, J=5.1 Hz, 1H), 8.31 (t, J=8.4 Hz, 1H), 8.01 (s, 1H), 7.95 (s, 1H), 7.39-7.19 (m, 3H), 5.35 (d, J=49.8 Hz, 2H), 3.92 (s, 2H), 3.53-3.52 (m, 4H), 2.48-2.43 (m, 4H); MS [M+H]+=562.7; LCMS RT=2.50.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH:4]([NH:8][C:9](=[O:39])[C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[N:18]=[CH:19][C:20]4[N:26]([CH3:27])[C:25](=[O:28])[C:24]([F:30])([F:29])[CH2:23][N:22]([CH:31]5[CH2:35][CH2:34][CH2:33][CH2:32]5)[C:21]=4[N:36]=3)=[C:12]([O:37][CH3:38])[CH:11]=2)[CH2:3][CH2:2]1.[CH3:40]I>>[CH:31]1([N:22]2[CH2:23][C:24]([F:30])([F:29])[C:25](=[O:28])[N:26]([CH3:27])[C:20]3[CH:19]=[N:18][C:17]([NH:16][C:13]4[CH:14]=[CH:15][C:10]([C:9]([NH:8][CH:4]5[CH2:5][CH2:6][CH2:7][N:1]([CH3:40])[CH2:2][CH2:3]5)=[O:39])=[CH:11][C:12]=4[O:37][CH3:38])=[N:36][C:21]2=3)[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: CI
Reactant: COc1cc(C(=O)NC2CCCNCC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Product: COc1cc(C(=O)NC2CCCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized by methylating N-(Azepan-4-yl)-4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzamide using methyl iodide. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.58-1.93 (m, 17 H) 2.28 (br. s., 3 H) 2.33 (br. s., 1 H) 3.93 (s, 3 H) 4.05 (t, J=14.0 Hz, 3 H) 4.75 (d, J=7.1 Hz, 1 H) 7.37-7.53 (m, 2 H) 7.96 (s, 1 H) 8.15 (d, J=7.8 Hz, 1 H) 8.26 (t, J=4.0 Hz, 2 H). [M+H] calc'd for C28H37F2N7O3, 558; found 558.
Reaction SMILES: [N+:1]([C:4]1[CH:42]=[CH:41][C:7]([CH2:8][O:9][C:10](=[O:40])[CH:11]([N:13]2[CH:16]([S:17][C:18](=[O:36])[CH2:19][CH2:20][CH2:21][NH:22][C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=3)=[O:24])[CH:15]([CH2:37][CH3:38])[C:14]2=[O:39])Cl)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:43]1([P:49]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>O1CCCC1.C(Cl)Cl>[N+:1]([C:4]1[CH:42]=[CH:41][C:7]([CH2:8][O:9][C:10](=[O:40])[C:11]([N:13]2[CH:16]([S:17][C:18](=[O:36])[CH2:19][CH2:20][CH2:21][NH:22][C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=3)=[O:24])[CH:15]([CH2:37][CH3:38])[C:14]2=[O:39])=[P:49]([C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CCC1C(=O)N(C(Cl)C(=O)OCc2ccc([N+](=O)[O-])cc2)C1SC(=O)CCCNC(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCC1C(=O)N(C(C(=O)OCc2ccc([N+](=O)[O-])cc2)=P(c2ccccc2)(c2ccccc2)c2ccccc2)C1SC(=O)CCCNC(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The resulting crude 2-[3-ethyl-4-(4-p-nitrobenzyloxycarbonylaminobutyrylthio)-2-oxoazetidin-1-yl]-2-chloroacetic acid p-nitrobenzyl ester is dissolved in a minimum amount of tetrahydrofuran, 9 g of triphenylphosphine are added and the mixture is stirred overnight at room temperature under nitrogen. The reaction mixture is diluted with 250 ml of methylene chloride, washed with saturated aqueous sodium bicarbonate solution, dried and concentrated by evaporation in vacuo. The residue is chromatographed over silica gel with toluene/ethyl acetate (1:1) and yields the title compound with the following physico-chemical properties:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][CH2:8][CH2:9][CH2:10][NH2:11])[CH:2]=1.[C:12]1(=O)[O:17][C:15](=[O:16])[CH:14]=[CH:13]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1COCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][CH2:8][CH2:9][CH2:10][N:11]2[C:15](=[O:16])[CH:14]=[CH:13][C:12]2=[O:17])[CH:2]=1
Reactant: O=C1C=CC(=O)O1
Reactant: NCCCOc1cccnc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: O
Product: O=C1C=CC(=O)N1CCCOc1cccnc1

Procedure:
From 2 to 3 mmol of the appropriate 3-(pyridin-3-yloxy)propylamine in 5 ml of THF are admixed in succession with 500 mg of maleic anhydride (molecular mass: 98.06; 5.1 mmol) and 200 mg of p-toluenesulphonic acid hydrate (molecular mass: 190.22; 1.0 mmol). The solution is refluxed for 24 hours and concentrated to dryness. The residue is chromatographed on silica gel to give the desired 1-[3-(pyridin-3-yloxy)propyl]-pyrrole-2,5-dione derivative.
Reaction SMILES: [CH3:1]N(C)C=O.[ClH:6].[C:7]1(/[CH:13]=[CH:14]/[C:15]([NH:17][CH2:18][CH2:19][CH:20]2[CH2:25][CH2:24][N:23]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:22][CH2:21]2)=[O:16])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[H-].[Na+].CI>O>[ClH:6].[C:7]1(/[CH:13]=[CH:14]/[C:15]([N:17]([CH3:1])[CH2:18][CH2:19][CH:20]2[CH2:25][CH2:24][N:23]([CH2:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:22][CH2:21]2)=[O:16])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CN(C)C=O
Reactant: O=C(/C=C/c1ccccc1)NCCC1CCN(Cc2ccccc2)CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: CN(CCC1CCN(Cc2ccccc2)CC1)C(=O)/C=C/c1ccccc1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a dimethylformamide solution (5 ml) of (E)-3-phenyl-N-[2-(1-benzylpiperidin-4-yl)ethyl]-2-propenamide.hydrochloride (0.6 g) obtained in Example 1 was gradually added sodium hydride (80 mg) at room temperature and the mixture was stirred at 60° C. for 30 minutes. The reaction mixture was cooled on an ice-bath and there was added methyl iodide (0.21 g), followed by stirring at room temperature for one hour. To the resultant mixture was added water and the mixture was subjected to extraction with dichloromethane. The dichloromethane solution was washed with water and dried over anhydrous sodium sulfate, then the solvent was distilled off. The oily residue was subjected to a silica gel column chromatography [developing solvent : ethyl acetate - methanol=10 : 1(V/V)]. Then the solvent of the solution containing the object compound was distilled off. To the residue was added an ethanolic solution (0.5 ml) of 3N hydrogen chloride, followed by distilling off the solvent to obtain an amorphous powder (0.2 g).
Reaction SMILES: FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[CH3:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[N+:25]([O-:27])=[O:26])[CH2:20]O.C(N(CC)C(C)C)(C)C.[CH3:37][O:38][C:39](=[O:62])[C@H:40]([CH2:49][C:50]1[N:54]=[CH:53][N:52](C(OC(C)(C)C)=O)[CH:51]=1)[NH:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43].P([O-])([O-])([O-])=O>C(Cl)Cl>[CH3:37][O:38][C:39](=[O:62])[C@H:40]([CH2:49][C:50]1[N:54]([CH2:20][C:19]2[CH:22]=[CH:23][C:24]([N+:25]([O-:27])=[O:26])=[C:17]([CH3:16])[CH:18]=2)[CH:53]=[N:52][CH:51]=1)[NH:41][C:42]([O:44][C:45]([CH3:48])([CH3:46])[CH3:47])=[O:43]
Reactant: Cc1cc(CO)ccc1[N+](=O)[O-]
Reactant: COC(=O)[C@H](Cc1cn(C(=O)OC(C)(C)C)cn1)NC(=O)OC(C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](Cc1cncn1Cc1ccc([N+](=O)[O-])c(C)c1)NC(=O)OC(C)(C)C
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 106.4 %

Procedure:
Trifluoromethanesulfonic anhydride (10.00 g, 0.0354 mol) and dry methylene chloride (60 ml) were placed into a 500 ml separable flask having its interior atmosphere replaced with well dried nitrogen gas, and cooled to -70° C. Then a solution of 3-methyl-4-nitrobenzyl alcohol (5.34 g, 0.0325 mol) and N,N-diisopropylethylamine (6.2 ml, 0.0356 mol) in dry methylene chloride (40 ml) was added dropwise over a period of 15 minutes, followed by stirring for 30 minutes, after which a solution of N,1-bis-t-butoxycarbonyl-L-histidine methyl ester (XI-2) (10.00 g, 0.0271 mol) in dry methylene chloride (40 ml) was further added dropwise over a period of 20 minutes. Thereafter, the reaction flask was taken out of the cooling bath and the mixture was stirred at room temperature for 6 hours. The reaction mixture during rapid stirring was poured into a 0.2M phosphate buffer solution (about 400 ml) to separate the methylene chloride layer, and the residue was washed with a 0.2M phosphate buffer solution (about 400 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain an orange-colored oily material (12.07 g). This crude oily material was purified by silica gel column chromatography (LiChroprep Si60, 300 g, chloroform/methanol=30/1) to obtain the objective compound (IX-2) (4.45 g; yield: 39.3%) as a light-yellow oily material.