Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]1[OH:9].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[N:32]1[CH:37]=[C:36]([CH2:38][CH2:39][C:40]2[C:48]([C:49]3[CH:54]=[CH:53][C:52]([C:55]([F:58])([F:57])[F:56])=[CH:51][CH:50]=3)=[CH:47][C:43]([C:44](O)=[O:45])=[CH:42][N:41]=2)[CH:35]=[N:34][CH:33]=1.C(N(C(C)C)C(C)C)C>CN(C)C=O>[OH:9][C@@H:4]1[CH2:5][CH2:6][CH2:7][CH2:8][C@H:3]1[NH:2][C:44](=[O:45])[C:43]1[CH:47]=[C:48]([C:49]2[CH:50]=[CH:51][C:52]([C:55]([F:56])([F:57])[F:58])=[CH:53][CH:54]=2)[C:40]([CH2:39][CH2:38][C:36]2[CH:35]=[N:34][CH:33]=[N:32][CH:37]=2)=[N:41][CH:42]=1
Reactant: N[C@@H]1CCCC[C@H]1O
Reactant: O=C(O)c1cnc(CCc2cncnc2)c(-c2ccc(C(F)(F)F)cc2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@@H]1CCCC[C@H]1O)c1cnc(CCc2cncnc2)c(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 44 %

Procedure:
A solution of (1R,2R)-2-amino-cyclohexanol hydrochloride (41 mg, 0.27 mmol) in N,N-dimethylformamide (1.2 ml) was added to a suspension of TBTU (234 mg, 0.73 mmol), 6-(2-pyrimidin-5-yl-ethyl)-5-(4-trifluoromethyl-phenyl)-nicotinic acid (0.24 mmol) and N-ethyldiisopropylamine (0.21 ml, 1.22 mmol) in N,N-dimethylformamide (1.7 ml). The reaction mixture was shaken at room temperature for 20 hours then concentrated in vacuo. The residue was then dissolved in dichloromethane (2 ml) and washed with water (2 ml). The aqueous layer was separated and extracted with dichloromethane (2 ml), the organics were combined and the whole was dried over MgSO4 and concentrated in vacuo. The residue was purified by preparative HPLC to afford N-((1R,2R)-2-hydroxy-cyclohexyl)-6-(2-pyrimidin-5-yl-ethyl)-5-(4-trifluoromethyl-phenyl)-nicotinamide, 49 mg (44% yield over 2 steps). LC at 215 nm; Rt 3.92: 92%, m/z (ES+): 471 (M+H).
Reaction SMILES: CC([O-])(C)C.[Li+].[Br:7][C:8]1[CH:9]=[CH:10][C:11]([C:15]([O:17][CH3:18])=[O:16])=[N:12][C:13]=1Cl.[F:19][CH2:20][CH2:21][OH:22].Cl>CN(C=O)C.O>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([C:15]([O:17][CH3:18])=[O:16])=[N:12][C:13]=1[O:22][CH2:21][CH2:20][F:19]
Reactant: OCCF
Reactant: COC(=O)c1ccc(Br)c(Cl)n1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Br)c(OCCF)n1
Temperature: 70 °C
Reaction time: 6 h
Yield: 11.9 %

Procedure:
Lithium 2-methylpropan-2-olate (4.17 mL, 9.18 mmol) was added within 30 minutes at ambient temperature to a solution of methyl 5-bromo-6-chloro-pyridine-2-carboxylate (CAN 1214353-79-3, 1 g, 3.99 mmol) and 2-fluoroethanol (CAN 371-62-0, 332 mg, 300 μL, 5.19 mmol) in DMF (6.67 mL). The reaction mixture was heated to 70° C. and stirred for 6 h. After cooling to ambient temperature, water (5 mL) and 2N HCl (5 mL) were added. The mixture was poured onto ice/brine (50 mL) and extracted with EtOAc (2×50 mL). The combined extracts were washed with ice/brine (50 mL), dried over Na2SO4, filtered and evaporated to dryness. The crude product was purified by flash-chromatography (50 g SiO2, heptane/0-30% EtOAc in 120 min.) to give the title compound (132 mg, 12%) as light brown solid, MS (ESI) m/e=278.0 [MH+].
Reaction SMILES: Cl.[Cl:2][C:3]1[N:4]=[C:5]([C@@H:19]2[CH2:23][C@H:22]([CH:24]3[CH2:29][CH2:28][N:27]([S:30]([CH3:33])(=[O:32])=[O:31])[CH2:26][CH2:25]3)[CH2:21][NH:20]2)[NH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:18])[O:16][CH3:17])=[CH:10][CH:9]=1.[CH3:34][C:35]([O:38][C:39]([NH:41][C@H:42]([C@H:44]1[CH2:49][CH2:48][C@H:47]([C:50](O)=[O:51])[CH2:46][CH2:45]1)[CH3:43])=[O:40])([CH3:37])[CH3:36]>>[Cl:2][C:3]1[N:4]=[C:5]([C@@H:19]2[CH2:23][C@H:22]([CH:24]3[CH2:29][CH2:28][N:27]([S:30]([CH3:33])(=[O:32])=[O:31])[CH2:26][CH2:25]3)[CH2:21][N:20]2[C:50]([C@H:47]2[CH2:46][CH2:45][C@H:44]([C@@H:42]([NH:41][C:39](=[O:40])[O:38][C:35]([CH3:37])([CH3:36])[CH3:34])[CH3:43])[CH2:49][CH2:48]2)=[O:51])[NH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([O:16][CH3:17])=[O:18])=[CH:10][CH:9]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)[C@H]1CC[C@H](C(=O)O)CC1
Reactant: COC(=O)Nc1ccc(-c2[nH]c([C@@H]3C[C@H](C4CCN(S(C)(=O)=O)CC4)CN3)nc2Cl)cc1
Agent: Cl
Product: COC(=O)Nc1ccc(-c2[nH]c([C@@H]3C[C@H](C4CCN(S(C)(=O)=O)CC4)CN3C(=O)[C@H]3CC[C@H]([C@H](C)NC(=O)OC(C)(C)C)CC3)nc2Cl)cc1

Procedure:
Following the procedure described in Example 8, the compound prepared in Example 67 was treated with trans-4-[(1S)-1-({[(2-methyl-2-propanyl)oxy]carbonyl}amino)ethyl]cyclohexanecarboxylic acid to give the title compound as a light brown solid.
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].Br[CH:34]([CH3:37])[CH2:35][OH:36]>>[CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:21][CH2:22][N:23]([CH:34]([CH3:37])[CH2:35][OH:36])[CH2:24][CH2:25]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: CC(Br)CO
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCNCC4)cn3)nc2n1C1CCCC1
Product: CC(CO)N1CCN(c2ccc(Nc3ncc4cc(C(=O)N(C)C)n(C5CCCC5)c4n3)nc2)CC1
Yield: 24.7 %

Procedure:
Following General Procedure D, 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (100 mg, 0.230 mmol) and 2-bromo propan-1-ol (96 mg, 0.690 mmol) gave 7-cyclopentyl-2-{5-[4-(2-hydroxy-1-methyl-ethyl)-piperazin-1-yl]-pyridin-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (28 mg, 25%). MS (ESI) m/z 493.4 (M+H)+
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][CH2:26][C:27]1[C:28]([F:44])=[C:29]([O:34][C:35]2[CH:36]=[C:37]([CH:40]=[C:41]([Cl:43])[CH:42]=2)[C:38]#[N:39])[C:30]([Cl:33])=[CH:31][CH:32]=1.[CH3:45][C:46]1[N:47]=[C:48]([CH:62]([CH3:64])[CH3:63])[N:49](COCC[Si](C)(C)C)[C:50]=1[C:51](O)=[O:52].C(N(C(C)C)CC)(C)C>CN(C=O)C>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][NH:25][C:51]([C:50]2[NH:49][C:48]([CH:62]([CH3:63])[CH3:64])=[N:47][C:46]=2[CH3:45])=[O:52])=[C:28]([F:44])[C:29]=1[O:34][C:35]1[CH:36]=[C:37]([C:38]#[N:39])[CH:40]=[C:41]([Cl:43])[CH:42]=1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Reactant: Cc1nc(C(C)C)n(COCC[Si](C)(C)C)c1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(C(C)C)[nH]c1C(=O)NCc1ccc(Cl)c(Oc2cc(Cl)cc(C#N)c2)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.2 %

Procedure:
HATU (103 mg, 0.27 mmol) was added to a solution of 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (56.2 mg, 0.18 mmol), 4-methyl-2-(1-methylethyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxylic acid (54 mg, 0.18 mmol) and diisopropylethylamine (47 uL, 0.27 mmol) in DMF (1 mL). The reaction mixture was stirred at RT overnight and the solvent was removed under vacuum. The residue was dried in vacuo and the residue was treated with TFA (0.5 mL) in DCM (1.0 mL) at RT and stirred overnight. Neutralized with saturated NaHCO3 and extracted with 10% MeOH in DCM. The organic layer was dried over sodium sulfate and concentrated. The residue was purified by flash chromatography (0-5% 2M NH3 solution of MeOH in DCM) and HPLC to afford the title compound (50 mg, 60%) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.68 (1H, br. s.) 7.56 (1H, br. s.) 7.31-7.40 (2H, m) 7.23 (1H, s) 7.14 (1H, d, J=1.3 Hz) 7.02 (1H, s) 4.62 (2H, d, J=6.4 Hz) 2.96 (1H, dt, J=13.7, 6.8 Hz) 2.56 (3H, s) 1.30 (6H, d, J=7.0 Hz). LCMS: m/z 461 (M+1).
Reaction SMILES: Br[C:2]1[C:7]([N:8]([CH2:23][O:24][CH3:25])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([Cl:26])=[CH:4][N:3]=1.C([Mg]Cl)(C)C.[C:32]1(=[O:42])[O:37][C:35](=[O:36])[C:34]2=[CH:38][CH:39]=[CH:40][CH:41]=[C:33]12>C1COCC1.C(Cl)Cl>[Cl:26][C:5]1[CH:6]=[C:7]([N:8]([S:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=2)(=[O:11])=[O:10])[CH2:23][O:24][CH3:25])[C:2]([C:32]([C:33]2[CH:41]=[CH:40][CH:39]=[CH:38][C:34]=2[C:35]([OH:37])=[O:36])=[O:42])=[N:3][CH:4]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: COCN(c1cc(Cl)cnc1Br)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: CC(C)[Mg]Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: COCN(c1cc(Cl)cnc1C(=O)c1ccccc1C(=O)O)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 28.4 %

Procedure:
To a solution of N-(2-Bromo-5-chloro-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (250 mg, 0.50 mmol) in 4.0 ml of THF under nitrogen atmosphere at 0° C. was added drop-wise 0.6 ml (1.2 mmol) of isopropylmagnesium chloride. The mixture was then stirred for 20 min at 0° C. followed by addition of a solution of phthalic anhydride (148 mg, 1.0 mmol) in 1 ml of DCM. The mixture was stirred at room temperature overnight, quenched with saturated ammonium chloride and extracted with ethyl acetate. After concentration the residue was purified by flash chromatograph (70% ethyl acetate in hexane) to afford 80 mg of title compound as an off white solid. MS: (M+H)/z=564.0, (M-32)/z=532.0.
Reaction SMILES: C[Al](C)C.[F:5][C:6]([F:10])([F:9])[CH2:7][NH2:8].C[O:12][C:13](=O)[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]2[C:23]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)=[N:24][O:25][C:26]=2[CH3:27])=[N:16][CH:15]=1.O>O1CCOCC1>[Cl:34][C:31]1[CH:30]=[CH:29][C:28]([C:23]2[C:22]([CH2:21][O:20][C:17]3[CH:18]=[CH:19][C:14]([C:13]([NH:8][CH2:7][C:6]([F:10])([F:9])[F:5])=[O:12])=[CH:15][N:16]=3)=[C:26]([CH3:27])[O:25][N:24]=2)=[CH:33][CH:32]=1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(Cl)cc3)noc2C)nc1
Reactant: NCC(F)(F)F
Agent: C[Al](C)C
Solvent: O
Solvent: C1COCCO1
Product: Cc1onc(-c2ccc(Cl)cc2)c1COc1ccc(C(=O)NCC(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.5 %

Procedure:
A solution of trimethylaluminium (2 M in toluene, 401 μL, 0.8 mmol) was added dropwise (exothermic) to a solution of 2,2,2-trifluoroethylamine (79 mg, 63 μL, 0.8 mmol) in dioxane (5 mL) and the resulting mixture was stirred at room temperature for 1 h. Then a solution of 6-[3-(4-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (72 mg, 0.2 mmol) in dioxane (2.5 mL) was added. The resulting mixture was then heated at 85-95° C. for 1 h and then cooled to room temperature and then poured into water and extracted with ethyl acetate which was then washed with brine, dried over sodium sulfate and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 1:1) afforded the title compound (66 mg, 77%) which was obtained as a white solid. MS: m/e=426.0 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11](OS(C)(=O)=O)[CH2:10][C@@H:9]1[CH2:18][OH:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:20]([O-:23])(=[S:22])[CH3:21].[K+].C(OCC)(=O)C.Cl>CN(C)C=O>[C:20]([S:22][C@@H:11]1[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C@H:9]([CH2:18][OH:19])[CH2:10]1)(=[O:23])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](OS(C)(=O)=O)C[C@@H]1CO
Reactant: CC([O-])=S
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)S[C@H]1C[C@@H](CO)N(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Yield: 86 %

Procedure:
A solution of (2R,4S)-1-t-butoxycarbonyl-4-methanesulfonyloxypyrrolidine-2-methanol (i.e., a substrate) (11.8 g: 40 mmole) and potassium thioacetate (5.94 g: 52 mmole) in dimethylformamide (120 ml) is stirred at 65° C. for 3.75 hours. The reaction mixture is mixed with ethyl acetate (330 ml), ice water (100 ml), and 1N-hydrochloric acid (20 ml) to adjust the aqueous layer at pH 4. The organic layer is taken, successively washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel chromatography (toluene-ethyl acetate=2:1) to give (2S,4S)-4-acetylthio-1-t-butoxycarbonylpyrrolidine-2-methanol (9.48 g). Yield: 86%. Pale orange colored oil. NMR δ(CDCl3) ppm: 1.47(s, 9H), 2.34(s, 3H), 2.4 to 3.2(m, 2H), 3.58 to 4.1(m, 6H). IR ν (CHCl3) cm-1 : 3380, 1690.
Reaction SMILES: [O:1]=[C:2]1[NH:11][CH:10]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=2[S:20][CH3:21])[C:9]2[C:8](=[O:22])[CH2:7][CH2:6][CH2:5][C:4]=2[N:3]1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=1.[CH:33]([N:36]([CH:39](C)C)CC)(C)C.C1C([N+]([O-])=[O:49])=CC=C([Cl-]C([O-])=O)C=1.CN.C(=O)(OC1C=CC([N+]([O-])=O)=CC=1)N>C(#N)C.CN(C)C1C=CN=CC=1>[CH3:33][NH:36][C:39]([N:11]1[CH:10]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=2[S:20][CH3:21])[C:9]2[C:8](=[O:22])[CH2:7][CH2:6][CH2:5][C:4]=2[N:3]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)[C:2]1=[O:1])=[O:49]
Reactant: CSc1cc(C#N)ccc1C1NC(=O)N(c2cccc(C(F)(F)F)c2)C2=C1C(=O)CCC2
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: CN(C)c1ccncc1
Agent: NC(=O)Oc1ccc([N+](=O)[O-])cc1
Solvent: CC#N
Product: CNC(=O)N1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CCC2)C1c1ccc(C#N)cc1SC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 4-[2,5-dioxo-1-(3-trifluoromethyl-phenyl)-1,2,3,4,5,6,7,8-octahydroquinazoline-4-yl]-3-methylsulfanyl-benzonitrile (INTERMEDIATE 6; 82 mg; 0.179 mmol) and diisopropylethylamine (100 μL; 0.588 mmol) in acetonitrile (1 mL) is added 4-nitrophenylchloroformate (170 mg; 0.843 mmol) and 4-dimethylaminopyridine (210 mg; 1.719 mmol) in little portions over 19 h at room temperature. Methylamine (1M in THF; 1 mL; 1.00 mmol) is added to the mixture containing the 4-nitro-phenyl carbamate intermediate and the mixture is stirred at room temperature for 30 min. The reaction mixture is purified by reversed phase HPLC (Sunfire, gradient of acetonitrile in water, 0.1% TFA). Yield: 63 mg. ESI mass spectrum: [M+H]+=515; Retention time HPLC: 1.11 min (Z018_S04).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=2)[N:10]=1.[F:27][C:28]1[CH:36]=[CH:35][C:31]([C@H:32]([OH:34])[CH3:33])=[CH:30][CH:29]=1>>[F:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=3)[N:10]=2)=[C:2]([O:34][C@@H:32]([C:31]2[CH:35]=[CH:36][C:28]([F:27])=[CH:29][CH:30]=2)[CH3:33])[CH:7]=1
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3F)n2)c1
Reactant: C[C@@H](O)c1ccc(F)cc1
Product: C[C@@H](Oc1cc(F)ccc1-c1ncnc(Nc2cccc(CS(C)(=O)=O)c2)n1)c1ccc(F)cc1

Procedure:
Starting with 4-(2,4-difluorophenyl)-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine (50 mg; 0.129 mmol), intermediate 42.1, and (R)-4-fluoro-α-methylbenzyl alcohol (74.4 mg; 0.515 mmol), example 67 was prepared analogously to the procedure for the preparation of example 42.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][O:7][CH2:6][CH2:5][N:4]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])#[N:2].[N-:16]=[N+:17]=[N-:18].[Na+].[Cl-].[NH4+]>CN(C=O)C.CCOC(C)=O>[N:16]1[CH:1]([CH:3]2[CH2:8][O:7][CH2:6][CH2:5][N:4]2[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[N:2]=[N:18][N:17]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCOCC1C#N
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCOCC1C1N=NN=N1
Temperature: 25 °C
Yield: 41 %

Procedure:
A mixture of tert-butyl 3-cyanomorpholine-4-carboxylate (5 g, 23.6 mmol, the compound was synthesized according to the procedure as described in J. Med. Chem. 2007, 50(20), 4953-4975), sodium azide (1.53 g, 23.6 mmol) and ammonium chloride (0.63 g, 11.8 mmol) in anhydrous DMF (30 mL) was stirred at 100° C. for 72 hours and cooled to 25° C. The reaction mixture was diluted with EtOAc (300 mL), then washed with brine (150 mL×6). The organic phase was concentrated in vacuo and the residue was purified by a silica gel column chromatography (PETROLEUM ETHER/EtOAc (V/V)=1/1) to give the title compound as a brownish solid (2.5 g, 41%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[C:6]([CH3:16])[N:5]=[C:4]([O:17][CH2:18][C:19]([N:21]([CH3:28])[CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[O:20])[N:3]=1.Br[CH2:30][C:31]1[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][CH:32]=1>>[C:35]([C:34]1[CH:37]=[CH:38][C:31]([CH2:30][N:25]2[CH2:24][CH2:23][CH:22]([N:21]([CH3:28])[C:19](=[O:20])[CH2:18][O:17][C:4]3[N:3]=[C:2]([CH3:1])[C:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:12])[CH3:13])=[C:6]([CH3:16])[N:5]=3)[CH2:27][CH2:26]2)=[CH:32][CH:33]=1)#[N:36]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: Cc1nc(OCC(=O)N(C)C2CCNCC2)nc(C)c1NC(=O)OC(C)(C)C
Product: Cc1nc(OCC(=O)N(C)C2CCN(Cc3ccc(C#N)cc3)CC2)nc(C)c1NC(=O)OC(C)(C)C

Procedure:
The title compound was synthesized from Compound 31 and 4-(bromomethyl)benzonitrile in the same manner as in Example 32.
Reaction SMILES: [C:1]12([CH2:11][CH2:12][O:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH2:22])=[CH:16][CH:15]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH2:23]([O:30][C:31]1[CH:36]=[CH:35][C:34]([C@@H:37]([O:40][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42])[CH2:38]Br)=[CH:33][C:32]=1[NH:48][CH:49]=[O:50])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[I-].[Na+].C(=O)([O-])O.[Na+]>CS(C)=O.O>[C:1]12([CH2:11][CH2:12][O:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][CH2:38][C@@H:37]([C:34]4[CH:35]=[CH:36][C:31]([O:30][CH2:23][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)=[C:32]([NH:48][CH:49]=[O:50])[CH:33]=4)[O:40][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:42])[CH3:43])=[CH:16][CH:15]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CBr)c1ccc(OCc2ccccc2)c(NC=O)c1
Reactant: NCCc1ccc(OCCC23CC4CC(CC(C4)C2)C3)cc1
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)O[C@@H](CNCCc1ccc(OCCC23CC4CC(CC(C4)C2)C3)cc1)c1ccc(OCc2ccccc2)c(NC=O)c1
Temperature: 130 °C

Procedure:
To a solution of Intermediate 22 (0.4 g, 1.34 mmol) and (R)—N-(2-(benzyloxy)-5-(2-bromo-1-(tert-butyldimethylsilyloxy)ethyl)phenyl)formamide (0.62 g, 0.82 mmol) in dimethyl sulfoxide (3 mL) was added sodium iodide (0.59 g, 3.99 mmol) and sodium hydrogen carbonate (0.67 g, 8.03 mmol). The reaction mixture was heated under argon at 130° C. for 1 hour. The mixture was poured into water and extracted with ether. The organic layer was washed with water and brine and the solvent was removed under reduced pressure. The title compound was obtained as yellow foam (0.84 g, 73%) and used in the next step without further purification. MS (M+): 684.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][NH:6][C:7]([N:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:14]1)=[C:8]([C:11]#[N:12])[C:9]#[N:10])[CH3:2].[Cl:28][C:29]1[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=1[CH2:31]Br.C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][N:6]([C:7]([N:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:14]1)=[C:8]([C:9]#[N:10])[C:11]#[N:12])[CH2:31][C:30]1[CH:33]=[CH:34][CH:35]=[CH:36][C:29]=1[Cl:28])[CH3:2]
Reactant: CCOC(=O)CNC(=C(C#N)C#N)N1CCC[C@@H](NC(=O)OC(C)(C)C)C1
Reactant: Clc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)CN(Cc1ccccc1Cl)C(=C(C#N)C#N)N1CCC[C@@H](NC(=O)OC(C)(C)C)C1

Procedure:
A solution of N-(1-{(3R)-3-[(tertbutoxycarbonyl)amino]piperidin-1-yl}-2,2-dicyanovinyl)glycine ethyl ester (300 mg), 2-chlorobenzyl bromide (0.15 ml) and potassium carbonate (330 mg) in acetone (4 ml) was stirred at 25° C. for 24 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with an aqueous sodium chloride solution, dried over sodium sulfate and then filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by a silica gel column chromatography (hexane/ethyl acetate=5/1 to 1/1) to obtain the title compound (340 mg) as a white amorphous substance.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:25])[C@H:5]([CH:22]([CH3:24])[CH3:23])[NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]#[N:21])=[CH:10][CH:9]=1.C(=O)(O)[O-].[Na+].[C:31](Cl)(=[O:36])[CH2:32][CH2:33][CH2:34][CH3:35]>O.C1(C)C=CC=CC=1>[CH3:2][O:3][C:4](=[O:25])[C@H:5]([CH:22]([CH3:23])[CH3:24])[N:6]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]#[N:21])=[CH:10][CH:9]=1)[C:31](=[O:36])[CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: CCCCC(=O)Cl
Reactant: COC(=O)[C@@H](NCc1ccc(-c2ccccc2C#N)cc1)C(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCC(=O)N(Cc1ccc(-c2ccccc2C#N)cc1)[C@H](C(=O)OC)C(C)C
Temperature: 28 °C
Reaction time: 0.42 h
Yield: 107.7 %

Procedure:
150 g N-[(2′-cyanobiphenyl-4-yl)methyl]-(L)-valine methyl ester hydrochloride was charged into a round bottomed flask containing a mixture of sodium bicarbonate (158.1 g), water (450 ml) and toluene (900 ml). The contents were stirred at 28° C. for 25 minutes and then cooled to 0° C. 110.9 g of valeryl chloride was added slowly to the reaction mass at 0-20° C. over about 55 minutes. The reaction mass was stirred at about 2-4° C. for about 2 hours. Reaction completion was confirmed by thin layer chromatography and the reaction mixture was allowed to attain 28° C. 450 ml of water was added to the reaction mass and stirred for about 20 minutes. The organic layer was separated, washed with a solution of sodium bicarbonate (30 g) in water (450 ml) twice, followed by washing with water (450 ml). The organic layer was concentrated under reduced pressure at 60-68° C. to obtain 183 g of the title compound.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1.Br[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].O>CS(C)=O>[N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([O:3][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]=1
Reactant: CCOC(=O)CBr
Reactant: Oc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)COc1cccnc1

Procedure:
Sodium hydride (7.15 g) was added portion-wise to a stirred solution of 3-hydroxypyridine (19 g) in dry dimethylsulphoxide (100 ml) during 1 hr. Ethyl bromoacetate (33.4. g) was added during 1 h. and water (250 ml) slowly added. The solution was extracted with chloroform (3×150 ml) and the combined extracts washed with 2 N sodium carbonate (75 ml) and dried (Na2SO4). Evaporation of the solvent gave a liquid which was distilled (120°-130°/0.1 mm) to yield the title compound (8.7 g).
Reaction SMILES: [C:1]([C:4]1[CH:20]=[CH:19][C:7]2[C:8](=[O:18])[C:9]3[CH:16]=[CH:15][CH:14]=[C:13](Br)[C:10]=3[CH2:11][CH2:12][C:6]=2[CH:5]=1)([OH:3])=[O:2].[ClH:21]>CN1CCCC1=O.O>[C:1]([C:4]1[CH:20]=[CH:19][C:7]2[C:8](=[O:18])[C:9]3[CH:16]=[CH:15][CH:14]=[C:13]([Cl:21])[C:10]=3[CH2:11][CH2:12][C:6]=2[CH:5]=1)([OH:3])=[O:2]
Reactant: O=C(O)c1ccc2c(c1)CCc1c(Br)cccc1C2=O
Reactant: Cl
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C(O)c1ccc2c(c1)CCc1c(Cl)cccc1C2=O

Procedure:
0.81 G. of 2-carboxy-9-bromo-10,11-dihydro-5-oxo-5H-dibenzo[a,d]cycloheptene and 0.32 g. of cuprous chloride were refluxed for 8 hours in 10 ml of N-methylpyrrolidinone. The solution was cooled and added to a solution of 4.4 g. of ferric chloride hexahydrate in 6 ml of water and 3 ml of concentrated hydrochloric acid. The mixture was heated to 90° for 1 hour, then was poured into water and filtered. The residue was recrystallized from aqueous dimethylformamide to afford 2-carboxy-9-chloro-10,11-dihydro-5-oxo-5H-dibenzo[a,d]cycloheptene, m.p. 258.5°-260°.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)(=O)=O)[C:5]([C:12]#[N:13])=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1.[CH2:20]([NH2:23])[CH2:21][CH3:22]>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]([C:12]#[N:13])=[C:6]([NH:23][CH2:20][CH2:21][CH3:22])[N:7]=1
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccccc2)c1C#N
Reactant: CCCN
Solvent: COCCOC
Product: CCCNc1nc(N)nc(-c2ccccc2)c1C#N

Procedure:
From 2-amino-4-methanesulfonyl-6-phenyl-pyrimidine-5-carbonitrile and propylamine in DME. ES-MS m/e (%): 254 (M+H+, 100).