Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]([O:14][CH3:15])=[O:13])=[CH:6][CH:5]=1)([O-])=O>CO.C1COCC1.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:8][CH:9]=1
Reactant: COC(=O)/C=C/c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)CCc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A solution of methyl (E)-3-(4-nitrophenyl)acrylate (S31, 4.10 g, 19.8 mmol) in MeOH (30 mL) and THF (30 mL) was treated with 10% Pd/C (400 mg). The reaction mixture was purged with H2 and was stirred at 25° C. for 10 h. The suspension was filtered through diatomaceous earth and concentrated to afford S32 (3.40 g, 19.0 mmol, 95%) as a yellow solid: 1H NMR (CDCl3, 500 MHz) 6.99 (d, 2H, J=8.2 Hz), 6.63 (d, 2H, J=8.4 Hz), 3.60 (s, 3H), 2.85 (t, 2H, J=7.7 Hz), 2.58 (t, 2H, J=7.7 Hz); 13C NMR (CDCl3, 125 MHz) 173.5, 144.6, 130.5, 129.1, 115.3, 51.5, 36.1, 30.1.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:21])[C:5]2[C:10]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[CH3:19])=[CH:9][N:8]([CH3:20])[C:6]=2[N:7]=1.[CH3:22]N(C)C=O.[H-].[Na+].CI>O>[NH2:1][C:2]1[N:3]([CH3:22])[C:4](=[O:21])[C:5]2[C:10]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[CH3:19])=[CH:9][N:8]([CH3:20])[C:6]=2[N:7]=1
Reactant: Cc1cc(C)c(-c2cn(C)c3nc(N)[nH]c(=O)c23)c(C)c1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: Cc1cc(C)c(-c2cn(C)c3nc(N)n(C)c(=O)c23)c(C)c1
Reaction time: 0.5 h
Yield: 62 %

Procedure:
To a solution of 2-amino-5-mesityl-7-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (847 mg, 3.00 mmol) and N,N-dimethylformamide (30 ml) was added sodium hydride (60% in oil, 120 mg, 3.00 mmol) at 0° C. and stirred for 0.5 hour. After stirring at room temperature for 0.5 hour, to the mixture was added a solution of MeI (426 mg, 3.0 mmol) and N,N-dimethylformamide (5 ml) at 0° C. and stirred for 0.5 hour. After stirring at room temperature for 1 hour, the mixture was diluted with water (20 ml) and extracted with ethyl acetate (50 ml×3). The extracts were combined, washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with hexane/ethyl acetate (3:1) to give 553 mg (62%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:17](=[O:25])[NH:18][C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1.[C:26]([O:30][C:31](=[O:36])[NH:32][CH2:33][CH2:34][NH2:35])([CH3:29])([CH3:28])[CH3:27]>>[C:26]([O:30][C:31](=[O:36])[NH:32][CH2:33][CH2:34][NH:35][C:12](=[O:13])[C:11]1[CH:15]=[CH:16][C:8]([C:5]2[CH:6]=[N:7][C:2]([NH2:1])=[C:3]([C:17](=[O:25])[NH:18][C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[CH:4]=2)=[CH:9][CH:10]=1)([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: Nc1ncc(-c2ccc(C(=O)O)cc2)cc1C(=O)Nc1ccncc1
Product: CC(C)(C)OC(=O)NCCNC(=O)c1ccc(-c2cnc(N)c(C(=O)Nc3ccncc3)c2)cc1

Procedure:
Reaction of 4-[6-amino-5-(pyridin-4-ylcarbamoyl)-pyridin-3-yl]-benzoic acid with (2-amino-ethyl)-carbamic acid tert-butyl ester gives “A96”; method 1: HPLC/MS: 1.47 min, [M+H]=477;
Reaction SMILES: [Na].[CH3:2][N:3]1[C:7]([SH:8])=[N:6][N:5]=[N:4]1.Br[CH2:10][Cl:11]>CN(C)C=O.O>[Cl:11][CH2:10][S:8][C:7]1[N:3]([CH3:2])[N:4]=[N:5][N:6]=1
Reactant: Cn1nnnc1S
Reactant: ClCBr
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1nnnc1SCCl
Reaction time: 1.5 h

Procedure:
To a solution of 1-methyltetrazole-5-thiol sodium salt (2.00 g : 14.5 mMol.) in dimethylformamide (20 ml) under ice cooling is added bromochloromethane (20 ml) in one portion, and the mixture is stirred for 1.5 hour. The reaction mixture is diluted with water and extracted with ethyl acetate. The extract is washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue is purified by silica gel column chromatography (toluene : ethyl acetate=20:1-10:1) to give 5-chloromethylthio-1-methyltetrazole as colorless crystals (1.73 g). Yield : 72%, m.p. 55° to 56° C.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[NH2:3].[C:12]([O:20][C@@H:21]1[C@H:25]([O:26][C:27](=[O:34])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C@@H:24]([CH2:35][O:36][C:37](=[O:44])[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[O:23][C@H:22]1[N:45]1[CH:53]=[N:52][C:51]2[C:46]1=[N:47][C:48]([Cl:55])=[N:49][C:50]=2Cl)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>O1CCOCC1>[C:12]([O:20][C@@H:21]1[C@H:25]([O:26][C:27](=[O:34])[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C@@H:24]([CH2:35][O:36][C:37](=[O:44])[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[O:23][C@H:22]1[N:45]1[C:46]2[N:47]=[C:48]([Cl:55])[N:49]=[C:50]([NH:3][N:2]([CH3:1])[CH2:4][CH2:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:51]=2[N:52]=[CH:53]1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Reactant: CN(N)CCc1ccccc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CN(CCc1ccccc1)Nc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 163.1 %

Procedure:
The above hydrochloride salt of 1-methyl-1-(2-phenylethyl)hydrazine (0.67 g, 1.05 mmol), 9-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine (1.90 g, 3 mmol) and triethylamine (1.24 ml, 9 mmol) were dissolved in 1,4 -dioxan (20 ml). The solution was stirred at ambient temperature for 20 h. The cooled reaction mixture was evaporated to a gum and purified by flash chromatography on silica gel. Bution with cyclohexane/ethyl acetate (4/1) initially and then with a 1/1 mixture of these solvents provided 2',3',5'-tri-O-benzoyl-2-chloro-N-(N-methyl-N-(2-phenylethyl)amino)adenosine (1.28 g, 60%) as a foam, 1H NMR (DMSO-d6)γ 2.63 (3H, s,--CH3), 4.66 (1H, dd, H-5'a), 4.77 (1H, dd, H-5'b), 4.86 (1H, q, H-4'), 6.23 (1H, t, H-3'), 6.36 (1H, t, H-2'), 6.54 (1H, d, H-1'), 7.11-7.98 (20H, m, Ar-H), 8.44 (1H, s, H-8), 9.40 (1H, br s, N-H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[C:6]([N+:8]([O-])=O)[CH:7]=1.ClCCl>C(OCC)(=O)C.C(O)(=O)C.[Pd]>[CH3:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:3]=1
Reactant: Cc1cc(-c2ccccc2)cc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cc1cc(N)cc(-c2ccccc2)c1
Reaction time: 3 h

Procedure:
Pd/C (10 wt %, 161 mg, 0.151 mmol) was added to a solution of 3-methyl-5-nitrobiphenyl (322 mg, 1.51 mmol) in ethyl acetate (10 mL) and acetic acid (1 mL). The reaction mixture was stirred under an atmosphere of H2 (balloon) for 3 hours and then dichloromethane (5 mL) was added. The reaction mixture was filtered through CELITE, washed with ethyl acetate and concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate/hexanes) provided 5-methylbiphenyl-3-amine as a brown oil. 1H NMR (400 MHz, CDCl3) δ 7.58 (d, J=7.6 Hz, 2H), 7.43 (t, J=7.6 Hz, 2H), 7.34 (t, J=7.3 Hz, 1H), 6.85 (s, 1H), 6.75 (s, 1H), 6.55 (s, 1H), 2.35 (s, 3H).
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[C:14]([F:15])=[CH:13][C:12]([F:16])=[CH:11][N:10]=2)=[N:6][CH:5]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[Cl:24])[C:4]=1[C:25]([O:27][CH2:28][CH3:29])=[O:26].[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH:31]1[C:36]([OH:38])=[O:37]>>[Cl:24][C:18]1[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:17]=1[CH:5]1[N:6]=[C:7]([C:9]2[C:14]([F:15])=[CH:13][C:12]([F:16])=[CH:11][N:10]=2)[NH:8][C:3]([CH2:2][N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH:31]2[C:36]([OH:38])=[O:37])=[C:4]1[C:25]([O:27][CH2:28][CH3:29])=[O:26]
Reactant: CCOC(=O)C1=C(CBr)NC(c2ncc(F)cc2F)=NC1c1ccc(F)cc1Cl
Reactant: O=C(O)C1COCCN1
Product: CCOC(=O)C1=C(CN2CCOCC2C(=O)O)NC(c2ncc(F)cc2F)=NC1c1ccc(F)cc1Cl
Yield: 65.5 %

Procedure:
Ethyl 6-(bromomethyl)-4-(2-chloro-4-fluorophenyl)-2-(3,5-difluoropyridin-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.75 g, 1.53 mmol) (The compound was synthesized according to the procedure as described in U.S. Pat. No. 7,074,784) was reacted with morpholine-3-carboxylic acid (0.2 g, 1.53 mmol) according to the procedure as described in Example 28 to give the title compound as a yellow solid (0.54 g, 65%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7](Cl)=[O:8])(=[O:3])[CH3:2].[CH:14]12[O:21][CH:18]([CH2:19][CH2:20]1)[CH2:17][NH:16][CH2:15]2.C(N(CC)CC)C>C1C=CC=CC=1>[C:1]([O:4][C:5]1[C:6](=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:7]([N:16]1[CH2:15][CH:14]2[O:21][CH:18]([CH2:19][CH2:20]2)[CH2:17]1)=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Reactant: C1CC2CNCC1O2
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CC(=O)Oc1ccccc1C(=O)N1CC2CCC(C1)O2
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
o-Acetoxybenzoyl chloride (0.1 mole, 19.85 grams) was slowly added to a mixture of 8-oxa-3-azabicyclo(3.2.1)octane (0.1 mole, 11.13 grams) and triethylamine (0.1 mole) in 60 ml of benzene at 20° C. The reaction mixture was stirred 2.5 hours at 25° C. The salt was filtered off and washed with benzene. After removal of benzene, the product was obtained as a viscous liquid which was purified by column chromatography (alumina). Impurities were eluted with ether and the product with methanol to yield the product represented by formula (IX).
Reaction SMILES: Br[CH:2]([CH2:14][CH3:15])[C:3]([NH:5][C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:13])=[O:4].C(O)C.[CH3:19][NH:20][CH3:21]>C(OCC)C.O>[CH3:19][N:20]([CH3:21])[CH:2]([CH2:14][CH3:15])[C:3]([NH:5][C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:13])=[O:4]
Reactant: CCC(Br)C(=O)Nc1c(C)cccc1C
Reactant: CNC
Solvent: CCOCC
Solvent: O
Solvent: CCO
Product: CCC(C(=O)Nc1c(C)cccc1C)N(C)C
Yield: 47.9 %

Procedure:
A mixture of 7.7 g (28.5 mmoles) of N-(2-bromo-butyryl)-2,6-dimethyl-aniline, 70 ml of ethanol and 20 ml of a 33% aqueous dimethyl amine solution is heated in a bomb at 100°-110° C. for 6 hours. The mixture is cooled, diluted with 150 ml of diethyl ether and 40 ml of water, the phases are separated, and the aqueous phase is extracted twice with 25 ml of diethyl ether, each. The etheral solutions are combined, washed thrice with 35 ml of 1 n aqueous hydrochloric acid, each, the aqueous acidic solutions are combined, rendered alkaline (pH=9) with concentrated aqueous ammonia, and extracted thrice with 40 ml of 1,2-dichloroethane, each. The dichloroethane solutions are combined, washed thrice with 20 ml of water, each, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. The oily residue, weighing 7.1 g, is triturated with diisopropyl ether to obtain 4.1 g of crude product, which is recrystallized then from ethyl acetate. 3.2 g (47.9%) of pure N-(2-dimethylamino-butyryl)-2,6-dimethyl-aniline are obtained; m.p.: 155°-157° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:17])[C:13]([NH:15][NH2:16])=[O:14])[CH3:2].[CH2:18]=O>CO>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:17])[C:13]([NH:15][N:16]=[CH2:18])=[O:14])[CH3:2]
Reactant: C=O
Reactant: CCc1cc(C)cc(CC)c1C(=O)C(=O)NN
Solvent: CO
Product: C=NNC(=O)C(=O)c1c(CC)cc(C)cc1CC
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a 100 mL volume three-necked flask, 10.0 g of 2-(2,6-diethyl-4-methylphenyl)-2-oxoacetohydrazide ((12-1)-(11)-39), 38 ml of methanol and 6.93 g of 37 wt % formalin aqueous solution were added and the mixture was stirred at room temperature for 5 hours. Methanol was added to the reaction mixture and cooled on ice-bath. The precipitated crystals were collected by filtration, washed with cool methanol, and dried under reduced pressure to give 1.22 g of 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-2-methylidenehydrazine ((40-a)-(14)-1).
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]([F:15])([F:14])[C:7]1[S:8][CH:9]=[C:10]([CH2:12]O)[N:11]=1>>[Cl:3][CH2:12][C:10]1[N:11]=[C:7]([C:6]([F:15])([F:14])[F:5])[S:8][CH:9]=1
Reactant: OCc1csc(C(F)(F)F)n1
Reactant: O=S(Cl)Cl
Product: FC(F)(F)c1nc(CCl)cs1
Reaction time: 3 h
Yield: 60.7 %

Procedure:
Thionyl chloride (4.89 g) was added to [2-(trifluoromethyl)thiazol-4-yl]methanol (512 mg) at room temperature, and the mixture was stirred for 3 hr. The reaction mixture was concentrated to give the title compound (342 mg).
Reaction SMILES: [NH2:1][C:2]1[C:13]([CH3:14])=[C:12]([CH3:15])[C:5]2[C:6](=[O:11])[C:7]([CH3:10])([CH3:9])[O:8][C:4]=2[C:3]=1[CH3:16].[CH:17](O)=[O:18]>>[CH3:10][C:7]1([CH3:9])[C:6](=[O:11])[C:5]2[C:12]([CH3:15])=[C:13]([CH3:14])[C:2]([NH:1][CH:17]=[O:18])=[C:3]([CH3:16])[C:4]=2[O:8]1
Reactant: O=CO
Reactant: Cc1c(C)c2c(c(C)c1N)OC(C)(C)C2=O
Product: Cc1c(C)c2c(c(C)c1NC=O)OC(C)(C)C2=O
Yield: 81 %

Procedure:
A mixture of formic acid (5 mL) with 6-amino-2,2,4,5,7-pentamethyl-1-benzofuran-3 (2H)-one (700 mg, 3.19 mmol) obtained in Reference Example 72, was heated under reflux for 5 hours. The solvent was distilled off under reduced pressure, water and ethyl acetate were added to the residue, and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water and a saturated sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The obtained residue was crystallized from hexane-ethyl acetate to obtain 640 mg (yield 81%) of the title compound. Melting point: 191-192° C.
Reaction SMILES: [C:1]([CH:4]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[C:5]([O:7]C)=O)(=O)[CH3:2].[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([NH2:23])=[N:15]1>C1(C)C=CC=CC=1>[OH:7][C:5]1[N:15]2[N:14]=[C:22]3[C:17]([CH:18]=[CH:19][CH:20]=[CH:21]3)=[C:16]2[N:23]=[C:1]([CH3:2])[C:4]=1[CH2:9][C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)CC(C(C)=O)C(=O)OC
Reactant: Nc1n[nH]c2ccccc12
Solvent: Cc1ccccc1
Product: COC(=O)Cc1c(C)nc2c3ccccc3nn2c1O
Yield: 65.9 %

Procedure:
A mixture of a dimethyl acetylsuccinate (1.55 g; 8.27 mmol) and 1H-indazol-3-amine (1 g; 7.5 mmol) in toluene (7.5 mL) was heated to reflux under a Dean Stark system for 48 h. The precipitate was filtered-off, washed with toluene and diethylether to afford 1.34 g (67%) of methyl 2-(4-hydroxy-2-methylpyrimido[1,2-b]indazol-3-yl)acetate, which was used for the next step without any further purification. ESI/APCI(+): 272 (M+H).
Reaction SMILES: I[C:2]1[C:3]([CH3:16])=[C:4]2[C:8]3=[C:9]([CH2:11][NH:12][CH2:13][C:14](=[O:15])[N:7]3[CH:6]=[CH:5]2)[CH:10]=1.[F:17][C:18]([F:29])([F:28])[C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1>>[F:17][C:18]([F:29])([F:28])[C:19]1[CH:24]=[C:23]([C:2]2[C:3]([CH3:16])=[C:4]3[C:8]4=[C:9]([CH2:11][NH:12][CH2:13][C:14](=[O:15])[N:7]4[CH:6]=[CH:5]3)[CH:10]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: Cc1c(I)cc2c3c1ccn3C(=O)CNC2
Product: Cc1c(-c2cccc(C(F)(F)F)c2)cc2c3c1ccn3C(=O)CNC2
Reaction time: 0.03 h
Yield: 81 %

Procedure:
Using the procedure described in Example 50(b), the title compound was synthesized from 6-iodo-7-methyl-3,4-dihydro-2H-[1,4]diazepino[6,7,1-hi]indol-1-one (Example 50(a)) and 3-trifluoromethylphenylboronic acid in 81% yield after purification by preparative HPLC. A gradient mobile phase, starting with 90% 0.1M NH4OAc, 10% CH3CN up to 2 min, then reaching 100% CH3CN after 22 min, was used. Rt=17.59 min. The title compound was obtained in the form of a white solid: 1H NMR (DMSO-d6) δ 2.25 (s, 3H), 3.44-3.48 (m, 2H), 4.13-4.16 (m, 2H), 7.19 (t, 1H, J=7.5 Hz), 7.77-7.88 (m, 6H), 8.32-8.36 (m, 1H). HRMS calcd. for C19H15N2OF3 (M+) 344.136, found 344.1136. Anal. HPLC Rt=14.9 min.
Reaction SMILES: [C:1]([C:4]1[N:5]=[CH:6][C:7]([NH:28][C@@H:29]2[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30]2)=[N:8][C:9]=1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:26][CH2:25][C:20]3([O:24][CH2:23][CH2:22][O:21]3)[CH2:19][CH2:18]2)=[C:13]([CH3:27])[CH:12]=1)(=[O:3])[NH2:2].[Cl:41]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[C:1]([C:4]1[N:5]=[C:6]([Cl:41])[C:7]([NH:28][C@@H:29]2[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30]2)=[N:8][C:9]=1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:26][CH2:25][C:20]3([O:21][CH2:22][CH2:23][O:24]3)[CH2:19][CH2:18]2)=[C:13]([CH3:27])[CH:12]=1)(=[O:3])[NH2:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1cc(Nc2nc(N[C@@H]3CCN(C(=O)OC(C)(C)C)C3)cnc2C(N)=O)ccc1N1CCC2(CC1)OCCO2
Solvent: ClC(Cl)Cl
Product: Cc1cc(Nc2nc(N[C@@H]3CCN(C(=O)OC(C)(C)C)C3)c(Cl)nc2C(N)=O)ccc1N1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 4 h
Yield: 69.1 %

Procedure:
To a mixture of tert-butyl (3R)-3-[(5-carbamoyl-6-{[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-3-methylphenyl]amino}pyrazin-2-yl)amino]pyrrolidine-1-carboxylate (1.16 g) and chloroform (35 mL) was added N-chlorosuccinimide (294 mg), followed by stirring at room temperature for 4 hours, and then N-chlorosuccinimide (84 mg) was added thereto, followed by stirring at room temperature for 1 hour. To the reactant was added silica gel, and then the solvent was evaporated under reduced pressure and then purified by silica gel column chromatography (eluent; chloroform) to obtain tert-butyl (3R)-3-[(5-carbamoyl-3-chloro-6-{[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-3-methylphenyl]amino}pyrazin-2-yl)amino]pyrrolidine-1-carboxylate (851 mg) as a yellow solid.
Reaction SMILES: F[C:2](F)(F)[C:3]([OH:5])=O.[F:8][CH2:9][CH:10]1[CH2:13][NH:12][CH2:11]1.BrCCO.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:8][CH2:9][CH:10]1[CH2:13][N:12]([CH2:2][CH2:3][OH:5])[CH2:11]1
Reactant: FCC1CNC1
Reactant: O=C(O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: OCCBr
Agent: [K+]
Solvent: CC#N
Product: OCCN1CC(CF)C1
Temperature: 80 °C
Yield: 78.1 %

Procedure:
A mixture of 3-(fluoromethyl)azetidine 2,2,2-trifluoroacetate (Intermediate 6, 100 mg, 0.5 mmol), 2-bromoethanol (60 mg, 0.5 mmol), and potassium carbonate (0.2 g, 1.5 mmol) in acetonitrile (5 mL) was heated to 80° C. overnight. After cooling, solids were filtered off and washed with acetonitrile. The filtrate was concentrated on a rotary evaporator to give a residue that was purified by silica gel chromatography eluting with 10:7 ethyl acetate/hexanes to 10:7:2:1 ethyl acetate/hexane/methanol/triethylamine to afford 52 mg of 2-(3-(fluoromethyl)azetidin-1-yl)ethanol as a pale yellow oil. 1H NMR (DMSO-d6): δ 5.13 (t, 1H), 4.62 (d, 1H), 4.50 (d, 1H), 4.06 (t, 2H), 3.84 (dd, 2H), 3.54 (q, 2H), 3.11 (t, 2H), 3.06-3.03 (m, 1H).
Reaction SMILES: [CH2:1]([C:3]1[N:7]([CH2:8][CH2:9][CH3:10])[N:6]=[C:5]([C:11]([NH2:13])=O)[CH:4]=1)[CH3:2]>P(Cl)(Cl)(Cl)=O>[CH2:1]([C:3]1[N:7]([CH2:8][CH2:9][CH3:10])[N:6]=[C:5]([C:11]#[N:13])[CH:4]=1)[CH3:2]
Reactant: CCCn1nc(C(N)=O)cc1CC
Solvent: O=P(Cl)(Cl)Cl
Product: CCCn1nc(C#N)cc1CC
Yield: 98.7 %

Procedure:
5-Ethyl-1-propyl-1H-pyrazole-3-carboxamide (5.50 g, 30.35 mmol) was treated with phosphorous oxychloride (20 mL) according to the procedure described in Part D of Examples 37-39 to yield 4.89 g of 5-ethyl-1-propyl-1H-pyrazole-3-carbonitrile as an oil.
Reaction SMILES: [CH3:1][S:2][CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[CH:9]2.[CH:13]1([C:16]([C:19]2[CH:29]=[CH:28][C:22]3[O:23][C:24]([F:27])([F:26])[O:25][C:21]=3[CH:20]=2)(O)[CH3:17])[CH2:15][CH2:14]1.C1(C(C2C3C(=C(CSC)C=CC=3)NC=2)(C2C=CC(OC)=C(F)C=2)C)CC1>>[CH:13]1([C:16]([C:9]2[C:8]3[C:12](=[C:4]([CH2:3][S:2][CH3:1])[CH:5]=[CH:6][CH:7]=3)[NH:11][CH:10]=2)([C:19]2[CH:29]=[CH:28][C:22]3[O:23][C:24]([F:26])([F:27])[O:25][C:21]=3[CH:20]=2)[CH3:17])[CH2:15][CH2:14]1
Reactant: CSCc1cccc2cc[nH]c12
Reactant: CC(O)(c1ccc2c(c1)OC(F)(F)O2)C1CC1
Agent: COc1ccc(C(C)(c2c[nH]c3c(CSC)cccc23)C2CC2)cc1F
Product: CSCc1cccc2c(C(C)(c3ccc4c(c3)OC(F)(F)O4)C3CC3)c[nH]c12

Procedure:
The title compound was prepared starting from 32 mg (0.18 mmol) of the compound from Example 8A and 43 mg (0.18 mmol) of the compound from Example 144A in analogy to the synthesis of the compound from Example 186. 38 mg (53% of theory) of the target compound were obtained.
Reaction SMILES: Br.[CH3:2][O:3][CH:4]([O:24][CH3:25])[CH2:5][NH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C.[CH2:33]([O:40][C:41](ON1C(=O)CCC1=O)=[O:42])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CC(C)=O>[CH2:33]([O:40][C:41]([N:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:5][CH:4]([O:3][CH3:2])[O:24][CH3:25])=[O:42])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: COC(CNCCCCCCOCCCCc1ccccc1)OC
Agent: Br
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: COC(CN(CCCCCCOCCCCc1ccccc1)C(=O)OCc1ccccc1)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.2 %

Procedure:
To a solution of 4.15 g (9.93 mmol) N-dimethoxyethyl-6-(4-phenylbutoxy)hexylamine hydrobromide in 40 ml acetone is added 1.4 ml triethylamine and 2.41 g (10.71 mmol) N-(benzyloxycarbonyloxy)succinimide. After allowing the mixture to stir for 2 hr at room temperature, acetone is evaporated of f and 40 ml Et2O is added thereto. The resulting mixture is washed three times with 40 ml H2O. Once separated, the ether phase is dried on anhydrous Na2SO4 and evaporated to dryness, to yield 4.46 g (95.3%) N-benzyloxycarbonyl-N-dimethoxyethyl-6-(4-phenylbutoxy)hexylamine as an oil.
Reaction SMILES: [CH3:1][CH:2]([CH3:5])[CH2:3][SH:4].O.CS([C@H:11]1[NH:14][C:13](=[O:15])[C@H:12]1[NH:16][C:17]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=O)=O>C1(C)C=CC=CC=1.C([O-])(=O)C.[Zn+2].C([O-])(=O)C>[CH2:3]([S:4][C@H:11]1[NH:14][C:13](=[O:15])[C@H:12]1[NH:16][C:17]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[CH:2]([CH3:5])[CH3:1]
Reactant: CS(=O)(=O)[C@H]1NC(=O)[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)CS
Agent: CC(=O)[O-]
Agent: [Zn+2]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)CS[C@H]1NC(=O)[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 90 °C

Procedure:
A solution of zinc acetate (0.7 g, 3 mmol) in toluene (15 mL) and 2-methyl-propanethiol (0.72 g, 8 mmol) was refluxed for 45 min in an apparatus equipped with a Dean-Stark trap to azeotrope water. (3R,4R)-4-(Methylsulfonyl)-3-(triphenylmethylamino)azetidin-2-one (1.5 g, 36 mmol) was added and the mixture was heated to 90° C. for 2 h. The mixture was concentrated and the residue was triturated with ethyl acetate and the insoluble material was removed by filtration. The filtrate was concentrated and the residue was chromatographed on silica gel eluted with 20% ethyl acetate:hexane. The fractions containing the product were combined, concentrated to give the title compound. MS(ES) m/e 417 [M+H]+.