Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH:4]([C:5]([O:7]CC)=[O:6])[CH2:3][CH2:2]1.Cl.ClCCN1CCOCC1.C(=O)(O)[O-].[Na+]>>[NH:1]1[CH2:11][CH2:10][CH:4]([C:5]([OH:7])=[O:6])[CH2:3][CH2:2]1
Reactant: CCOC(=O)C1CCNCC1
Agent: Cl
Agent: ClCCN1CCOCC1
Agent: O=C([O-])O
Product: O=C(O)C1CCNCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of ethyl isonipecotate (7.85 g, 0.05 mole, N-(2-chloroethyl)morpholine hydrochloride (9.30 g, 0.05 mole) and sodium bicarbonate (12.0 g, 0.14 mole) inEtOH (250 ml) was stirred at room temperature for two hours and at reflux temperature for three hours. The reaction mixture was filtered, concentrated and the residue extracted with Et2O. The Et2O layer was concentrated to give 13.4 g (quantitative yield) of 4-piperidinecarboxylic acid, 1-[2-(4-morpholinyl)-ethyl]-, ethyl ester, NMR (CDCl3) 4.0 (t, 2H), 3.6 (m, 4H), 3.0-2.3 (m, 13H), 2.2-1.5 (m, 4H), 1.4-1.0 (t, 3H).
Reaction SMILES: [Si]([O:18][C:19]1[CH:49]=[CH:48][C:22]([O:23][CH2:24][C@@H:25]([OH:47])[CH2:26][NH:27][CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([S:36][CH2:37][C:38]3[N:42]=[C:41]([C:43]([CH3:46])([CH3:45])[CH3:44])[O:40][N:39]=3)=[CH:32][CH:31]=2)=[CH:21][CH:20]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.[Cl-].[NH4+]>[C:43]([C:41]1[O:40][N:39]=[C:38]([CH2:37][S:36][C:33]2[CH:32]=[CH:31][C:30]([CH2:29][CH2:28][NH:27][CH2:26][C@H:25]([OH:47])[CH2:24][O:23][C:22]3[CH:48]=[CH:49][C:19]([OH:18])=[CH:20][CH:21]=3)=[CH:35][CH:34]=2)[N:42]=1)([CH3:46])([CH3:44])[CH3:45]
Reactant: CC(C)(C)c1nc(CSc2ccc(CCNC[C@H](O)COc3ccc(O[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)cc3)cc2)no1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)c1nc(CSc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)no1
Reaction time: 6 h
Yield: 100 %

Procedure:
To a solution of the amino alcohol of Example 31(0.140 g, 0.201 mmol) in THF (3 mL) was added a 1M solution of TBAF (0.10 mL, 0.10 mmol). The reaction mixture was stirred for 6 h. TLC showed the absence of starting material, therefore 2 drops of a saturated aqueous ammonium chloride solution was added. The reaction mixture was evaporated in vacuo to dryness and the residue was flash chromatographed (silica gel; dichloromethane/chloroform/methanol: 15/5/3) to afford 0.092 g of the title compound as a tan foam.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[CH2:22][CH2:21][CH2:20][CH2:19][C:18]=1[CH2:23]O.CS([Cl:29])(=O)=O.O>ClCCl>[Cl:29][CH2:23][C:18]1[CH2:19][CH2:20][CH2:21][CH2:22][C:17]=1[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[F:10]
Reactant: OCC1=C(c2ccccc2F)CCCC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Fc1ccccc1C1=C(CCl)CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N,N-Diisopropylethylamine (14.7 mL) was added to a solution of [2-(2-fluorophenyl)cyclohex-1-enyl]methanol obtained in Preparation Example 1-(3) (8.88 g) in dichloromethane (300 mL). Methanesulfonyl chloride (4.00 mL) was added dropwise to the reaction solution in an ice bath. The reaction solution was gradually warmed to room temperature and stirred overnight. Water was added to the reaction solution, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography to obtain the title compound (5.88 g).
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:48](=[O:49])[N:13]3[C:14]([C:32]([O:34]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:33])=[C:15]([CH2:18][O:19][C:20]([O:22][C:23]4[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=4)=[O:21])[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OC(C)C)(C)C>ClCCl.FC(F)(F)C(O)=O>[C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:48](=[O:49])[N:13]3[C:14]([C:32]([OH:34])=[O:33])=[C:15]([CH2:18][O:19][C:20]([O:22][C:23]4[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=4)=[O:21])[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(COC(=O)Oc3ccc([N+](=O)[O-])cc3)CS[C@H]12
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)OC(C)C
Solvent: ClCCl
Product: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)O)=C(COC(=O)Oc3ccc([N+](=O)[O-])cc3)CS[C@H]12
Reaction time: 0.83 h

Procedure:
To a solution of benzhydryl 7-phenylacetamido-3-p-nitrophenoxycarbonyloxymethyl-3-cephem-4-carboxylate (6.79 g, 0.01 mol) in dichloromethane (14 ml), trifluoroacetic acid (17 ml) was added dropwise under ice cooling, followed by stirring for 50 minutes. The reaction mixture was poured into diisopropyl ether. The precipitate thus obtained was collected by filtration, washed with diisopropyl ether and dried in air, whereby 7-phenylacetamido-3-p-nitrophenoxycarbonyloxymethyl-3-cephem-4-carboxylic acid was obtained (yield: 4.50 g; 87.7%).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].CC(C)([O-])C.[K+].[C:13]([O:17][C:18]([N:20]1[C:28]2[C:23](=[CH:24][C:25]([Br:31])=[C:26]([CH2:29]Br)[CH:27]=2)[C:22]([CH3:33])([CH3:32])[CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].[Cl-].[NH4+]>C1COCC1>[C:13]([O:17][C:18]([N:20]1[C:28]2[C:23](=[CH:24][C:25]([Br:31])=[C:26]([CH2:29][N:1]3[CH2:5][CH2:4][CH2:3][C:2]3=[O:6])[CH:27]=2)[C:22]([CH3:33])([CH3:32])[CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CC(C)(C)c2cc(Br)c(CBr)cc21
Reactant: O=C1CCCN1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(C)(C)c2cc(Br)c(CN3CCCC3=O)cc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 2-pyrrolidinone (0.8 g, 9.4 mmol) in THF (15.6 mL) was added potassium tert-butoxide (1.05 g, 9.4 mmol) and the mixture was stirred for 30 minutes at room temperature. 5-Bromo-6-bromomethyl-3,3-dimethyl-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester was added in one portion and the reaction stirred for 2 h at room temperature. Saturated aqueous ammonium chloride (15 mL) was added and the mixture extracted with EtOAc. The organic layer was washed with brine, dried with sodium sulfate, filtered and concentrated. Chromatography (silica gel, gradient elution, 0-100%, EtOAc in petrol 40-60) gave the title compound (0.17 g) MS: [M+H]+=424.
Reaction SMILES: [CH3:1][S:2]([O:5][CH2:6][CH:7]1[O:19][C:18]2[C:9](=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:20])[CH:12]=[CH:11]3)[CH2:8]1)(=[O:4])=[O:3].[H][H]>O1CCOCC1.[C].[Pd]>[CH3:1][S:2]([O:5][CH2:6][CH:7]1[O:19][C:18]2[C:9](=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:20])[CH2:12][CH2:11]3)[CH2:8]1)(=[O:3])=[O:4]
Reactant: [H][H]
Reactant: CS(=O)(=O)OCC1Cc2c(ccc3[nH]c(=O)ccc23)O1
Agent: [Pd]
Solvent: C1COCCO1
Product: CS(=O)(=O)OCC1Cc2c(ccc3c2CCC(=O)N3)O1
Yield: 84.8 %

Procedure:
The compound obtained in Example 157 (0.85 g, 2.88 mmol) dissolved in dioxane (50 ml) was combined with 10% palladium-carbon (1.55 g), then stirred in the stream of hydrogen at 60° for 16 hours. From the reaction mixture, palladium-carbon was filtered off. The filtrate was condensed under reduced pressure, and the reside was washed with ether. 0.726 g of the tile compound was obtained as pale brown crystals (84.8%). They were recrystallized from a solvent mixture of chloroform--methanol--ether to obtain colorless prisms of the title compound (mp.: 209°-210° C. (dec.)).
Reaction SMILES: Br[C:2]1[C:7]2[C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.C[Sn:15](C)C.C[Sn](C)C>>[CH3:11][C:9]1([CH3:12])[C:8](=[O:13])[C:7]2[C:2]([Sn:15])=[CH:3][CH:4]=[CH:5][C:6]=2[O:10]1
Reactant: CC1(C)Oc2cccc(Br)c2C1=O
Reactant: C[Sn](C)C
Product: CC1(C)Oc2cccc([Sn])c2C1=O

Procedure:
In a slight variation in the method to the 2,4-diamino-5,6-disubstituted-5-deazapteridines described above, using a method taught by A. Pidcock et al (J. Organometallic Chem. 1981, 215, 49-58), 4-bromo-2,3-dihydro-2,2-dimethyl-3-benzofuranone is reacted with hexamethylditin in the presence of tetrakis(triphenylphosphine)palladium(0)in toluene, yielding (2,3-dihydro -2,2-dimethyl-3-benzofuranon-4-yl)tin. The organometallic derivative is then reacted with 2-amino-3-cyano-5-iodo-4-methylpyridine, again in the presence of tetrakis(triphenylphosphine)palladium(0) in toluene, affording the corresponding 2-amino-3-cyano-5-(2,3-dihydro-2,2-dimethyl-3-benzofuranon-4-yl)-4-methylpyridine. This compound is then cyclized with guanidine in ethanol, as previously described, yielding the corresponding 2,4-diamino-5-methyl-6-(2,3-dihydro-2,2-dimethyl-3-benzofuranon-4-yl)-5-deazapteridine. Example 9 provides a detailed description of how this reaction is conducted.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[CH:13]1([C:19]2[C:20]3[CH:21]=[CH:22][C:23]([C:38](O)=[O:39])=[CH:24][C:25]=3[N:26]3[CH2:32][CH:31]([OH:33])[CH2:30][C:29]4[CH:34]=[CH:35][CH:36]=[CH:37][C:28]=4[C:27]=23)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[CH3:41][N:42]([CH3:47])[S:43]([NH2:46])(=[O:45])=[O:44]>CN(C1C=CN=CC=1)C.CN(C=O)C.C(Cl)Cl>[CH:13]1([C:19]2[C:20]3[CH:21]=[CH:22][C:23]([C:38]([NH:46][S:43]([N:42]([CH3:47])[CH3:41])(=[O:45])=[O:44])=[O:39])=[CH:24][C:25]=3[N:26]3[CH2:32][CH:31]([OH:33])[CH2:30][C:29]4[CH:34]=[CH:35][CH:36]=[CH:37][C:28]=4[C:27]=23)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: CN(C)S(N)(=O)=O
Reactant: O=C(O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(O)Cc1ccccc1-3
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN(C)S(=O)(=O)NC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(O)Cc1ccccc1-3
Temperature: 22 °C
Reaction time: 18 h

Procedure:
1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (11.5 mg, 0.06 mmol) was added to a solution of (±)13-cyclohexyl-6,7-dihydro-6-hydroxy-5H-indolo[2,1-a][2]benzazepine-10-carboxylic acid (7.5 mg, 0.02 mmol) and DMAP(7.4 mg, 0.06 mmol) in DMF (0.5 mL) and CH2Cl2 (0.5 mL) at 22° C. The vial was shaken for a minute at 22° C. N,N-Dimethylsulfamide (4.9 mg, 0.04 mmol) was then added. Stirring was continued for 18 hr. The solution was filtered and purified on the Shimadzu preparative liquid chromatograph. The product containing fraction was concentrated on a Speed Vac® to leave the titled compound as a white film (3.0 mg, 30%). ESI-MS m/z 482 (MH+); 1H NMR (500 MHz, MeOD) δ 1.26–1.34 (m, 1 H) 1.40–1.55 (m, 2 H) 1.63 (m, 1 H) 1.82 (m, 2 H) 1.96 (m, 1 H) 2.01–2.19 (m, 3 H) 2.36 (m, 1 H) 2.95–3.08 (m, 2 H) 3.03 (s, 6 H) 3.76 (dd, J=15.26, 3.36 Hz, 1 H) 4.41–4.69 (m, 2 H) 7.40–7.50 (m, 4 H) 7.60 (m, 1 H) 7.93 (m, 1 H) 8.11 (m, 1 H).
Reaction SMILES: [Br:1][CH:2]([C:4]1[N:5]=[C:6]2[S:13][CH:12]=[C:11]([CH3:14])[N:7]2[C:8](=[O:10])[CH:9]=1)[CH3:3].C(#N)C.[Br:18]N1C(=O)CCC1=O.S([O-])([O-])=O.[Na+].[Na+]>O>[Br:18][C:9]1[C:8](=[O:10])[N:7]2[C:11]([CH3:14])=[CH:12][S:13][C:6]2=[N:5][C:4]=1[CH:2]([Br:1])[CH3:3]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1csc2nc(C(C)Br)cc(=O)n12
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Cc1csc2nc(C(C)Br)c(Br)c(=O)n12
Reaction time: 0.33 h
Yield: 91.8 %

Procedure:
Under nitrogen, a suspension of 7-(1-bromoethyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (13.2 g, 48.3 mmol) in acetonitrile (100 mL, 2000 mmol) was stirred until a clear solution was obtained. N-Bromosuccinimide (9.891 g, 55.57 mmol) was then added and the reaction mixture was stirred at 50° C. After 20 min, HPLC indicated that the reaction was complete. A solution of sodium sulfite (3.046 g, 24.16 mmol) in water (50 mL) was added and the mixture was stirred at room temperature for 20 min. Water (200 mL) was added slowly and the mixture stirred at room temperature for 30 min. and then filtered. The solid was washed with water (100 mL×3) and dried to give 6-bromo-7-(1-bromoethyl)-3-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one as an off-white solid (15.61 g, 91%). LCMS calculated for C9H9Br2N2OS (M+H)+: m/z 352.87, 354.87. Found: 352.65, 354.60. 1H NMR (400 MHz, DMSO-d6) δ 7.15 (q, J=1.3 Hz, 1H), 5.51 (q, J=6.7 Hz, 1H), 2.66 (d, J=1.2 Hz, 3H), 1.90 (d, J=6.7 Hz, 3H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][NH:13][CH2:12][CH:11]([C:15]([O:17][CH3:18])=[O:16])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].[N:19]1([C:24](Cl)=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:14][N:13]([C:24]([N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:25])[CH2:12][CH:11]([C:15]([O:17][CH3:18])=[O:16])[CH2:10]2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: O=C(Cl)N1CCCC1
Reactant: CCc1ccc(C2CNCC(C(=O)OC)C2)cc1
Product: CCc1ccc(C2CC(C(=O)OC)CN(C(=O)N3CCCC3)C2)cc1

Procedure:
6.7 g (24.1 mmol) of methyl 5-(4-ethylphenyl)piperidine-3-carboxylate and 4.2 g (31.4 mmol, 1.3 eq.) of pyrrolidine-1-carbonyl chloride were reacted according to the General Method 3A. Yield: 7.6 g (91% of theory)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](O)([C:23]([F:26])([F:25])[F:24])[CH2:10][C:11]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[C:15]([CH3:22])[CH:14]=2)=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C1(C)C=CC=CC=1.C(OC(=O)C)(=O)C.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.Cl.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:23]([F:26])([F:24])[F:25])=[CH:10][C:11]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[C:15]([CH3:22])[CH:14]=2)=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Cc1cc(C(=O)CC(O)(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(N)=O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: Cc1cc(C(=O)C=C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(N)=O
Temperature: 30 °C
Reaction time: 2.5 h
Yield: 69.7 %

Procedure:
0.48 g of 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutanoyl)-2-methylbenzoic acid amide, 1.5 g of toluene, 0.23 g of acetic anhydride, 27 mg of 4-dimethylaminopyridine and 0.23 g of triethylamine were fed and the mixture was stirred for 2.5 hours at 30° C. 2 ml of iced water and 2 drops of concentrated hydrochloric acid were added to the reaction solution, and the deposited solid was collected by filtration. The solid was washed with a small amount of toluene and distilled water, and dried under reduced pressure. 0.32 g of 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-butenoyl)-2-methylbenzoic acid amide was obtained as a flesh color solid.
Reaction SMILES: [CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].[NH2:17]N1C=NN=C1.CC(C)([O-])C.[K+].O>CS(C)=O.C(O)(=O)C>[NH2:17][C:9]1[C:10]([N+:11]([O-:13])=[O:12])=[C:2]([CH3:1])[C:3]([N+:14]([O-:16])=[O:15])=[CH:4][C:5]=1[C:6]([NH2:8])=[O:7]
Reactant: Nn1cnnc1
Reactant: Cc1c([N+](=O)[O-])cc(C(N)=O)cc1[N+](=O)[O-]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CC(=O)O
Solvent: O
Product: Cc1c([N+](=O)[O-])cc(C(N)=O)c(N)c1[N+](=O)[O-]
Temperature: 20 °C
Reaction time: 1 h
Yield: 84.4 %

Procedure:
A solution of 4-methyl-3,5-dinitrobenzamide (6) (15.1 kg) in dimethyl sulfoxide (95.6 kg) is added to a solution of 4-amino-1,2,4-triazole (21.6 kg) and potassium tert-butoxide (21.7 kg) in dimethyl sulfoxide (144.5 kg) at a rate to maintain a temperature of about 20° C. The mixture is allowed to stir for about 30 minutes, whereupon additional amounts of 4-amino-1,2,4-triazole (5.5 kg) and potassium tert-butoxide (3.7 kg) are added. The mixture is allowed to stir for about 1 hour at about 20° C., and then the mixture is added, over a period of about 30 minutes, to a cold (about 5° C.) solution of water (347 kg) and acetic acid (15 kg), allowing the temperature to rise to about 25° C. The vessel containing the initial reaction mixture is then rinsed with water (87 kg) and the rinse solution is also added to the acetic acid solution. The resulting mixture is cooled to about 5° C. and held at this temperature for about 30 minutes, whereupon the mixture is filtered and the solids obtained are washed with water (82 kg). The solids are then dried in a vacuum tray dryer for about 19 hours, at a temperature of about 50° C. and a vacuum of about 15 torr, to provide 2-amino-4-methyl-3,5-dinitrobenzamide (7) (13.6 kg, 84% yield).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[C:15]([N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:25]=[C:26]([CH:28]=[CH:29][CH:30]=2)[NH2:27])[CH2:20][CH2:19]1)(=[O:17])[CH3:16].C(N(CC)CC)C>CN1C(=O)CCC1>[C:15]([N:18]1[CH2:19][CH2:20][N:21]([C:24]2[CH:25]=[C:26]([CH:28]=[CH:29][CH:30]=2)[NH:27][C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=2[N+:12]([O-:14])=[O:13])[CH2:22][CH2:23]1)(=[O:17])[CH3:16]
Reactant: CC(=O)N1CCN(c2cccc(N)c2)CC1
Reactant: COC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: COC(=O)c1ccc(Nc2cccc(N3CCN(C(C)=O)CC3)c2)c([N+](=O)[O-])c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 84.9 %

Procedure:
To a solution of methyl 4-chloro-3-nitrobenzoate (2.0 g, 9.28 mmol) in anhydrous NMP (5 ml) was added 2d (2.03 g, 9.28 mmol) and triethylamine (1.3 ml, 9.28 mmol). The mixture was heated with stirring to 80° C. overnight. The cooled solution was poured into ice-water (50 ml) and the resulting mixture was extracted with ethyl acetate (3×10 ml). The combined organic extracts were washed with water, dried over sodium sulfate and evaporated to dryness. The residue was triturated with petroleum ether to yield methyl 4-(3-(1-acetylpiperazin-4-yl)anilino)-3-nitrobenzoate (3.14 g, 85%) as red crystals.
Reaction SMILES: [CH:1]1([NH:7][C:8](=[O:25])[CH2:9][N:10]2[C:15](=[O:16])[C:14]3[C:17]([CH3:24])=[C:18]([C:20]([O:22]C)=[O:21])[S:19][C:13]=3[N:12]=[CH:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.O.[OH-].[Li+]>C1COCC1.CO>[CH:1]1([NH:7][C:8](=[O:25])[CH2:9][N:10]2[C:15](=[O:16])[C:14]3[C:17]([CH3:24])=[C:18]([C:20]([OH:22])=[O:21])[S:19][C:13]=3[N:12]=[CH:11]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1sc2ncn(CC(=O)NC3CCCCC3)c(=O)c2c1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1c(C(=O)O)sc2ncn(CC(=O)NC3CCCCC3)c(=O)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.7 %

Procedure:
To a solution of methyl 3-(2-(cyclohexylamino)-2-oxoethyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate (3.6 g, 10 mmol) in THF (30 mL), MeOH (10 mL), and H2O (10 mL) was added lithium hydroxide monohydrate (1.26 g, 30 mmol). The reaction mixture was then stirred at RT overnight. The reaction mixture was concentrated, diluted with H2O (30 mL) and washed with DCM (2×30 mL). The aqueous layer was acidified (pH˜2) with 1M HCl and the resultant precipitate was filtered and dried to give 1.7 g of 3-(2-(cyclohexylamino)-2-oxoethyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylic acid, (yield: 52%).
Reaction SMILES: [CH2:1]([N:3]([CH2:12][CH3:13])[C:4](=[O:11])[CH:5]=[CH:6][CH2:7][CH:8]([CH3:10])[CH3:9])[CH3:2].[C-:14]#[N:15].[K+].C(O)C.CCCCCC>C(O)(=O)C>[C:14]([CH:6]([CH2:7][CH:8]([CH3:9])[CH3:10])[CH2:5][C:4]([N:3]([CH2:1][CH3:2])[CH2:12][CH3:13])=[O:11])#[N:15]
Reactant: CCN(CC)C(=O)C=CCC(C)C
Reactant: [C-]#N
Agent: [K+]
Solvent: CCCCCC
Solvent: CC(=O)O
Solvent: CCO
Product: CCN(CC)C(=O)CC(C#N)CC(C)C
Temperature: 32.5 °C
Reaction time: 18 h

Procedure:
Added 3.46 grams of compound N,N-diethyl-5-methylhex-2-enamide (formula-4-a) to a mixture of 0.863 gram of potassium cyanide and 3.5 grams of ethanol. Stirred the reaction mixture for 18 hours at 25-40° C. Added 4.45 ml of hexane to the reaction mixture. Added 0.875 gram of glacial acetic acid to the reaction mixture at 35° C. Quenched the reaction mixture with water. Separated the organic and aqueous phases. Extracted the aqueous phase with hexane. Washed the organic layer with water. Distilled the organic phase under reduced pressure to get the title compound as a residue
Reaction SMILES: [C:1]1([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:16]([NH2:18])[CH3:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:20]1[N:28]=[C:27]([NH2:29])[N:26]=[C:25]2[C:21]=1[N:22]=[CH:23][NH:24]2.C(N(C(C)C)C(C)C)C>CCCCO>[C:1]1([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:16]([NH:18][C:20]2[N:28]=[C:27]([NH2:29])[N:26]=[C:25]3[C:21]=2[N:22]=[CH:23][NH:24]3)[CH3:17])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1nc(Cl)c2nc[nH]c2n1
Reactant: C[C@H](N)c1nc2ccccc2n1-c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: C[C@H](Nc1nc(N)nc2[nH]cnc12)c1nc2ccccc2n1-c1ccccc1
Temperature: 130 °C
Reaction time: 8 h
Yield: 44.5 %

Procedure:
Into a 25-mL round-bottom flask was placed a solution of (S)-1-(1-phenyl-1H-benzo[d]imidazol-2-yl)ethanamine from Example 4 (238 mg, 1.00 mmol, 1.00 equiv) in n-BuOH (8 mL), 6-chloro-9H-purin-2-amine (155 mg, 0.91 mmol, 0.91 equiv, 98%) and N-ethyl-N-isopropylpropan-2-amine (390 mg, 2.96 mmol, 2.95 equiv, 98%). The resulting solution was stirred overnight at 130° C. and concentrated under vacuum. The residue was eluted onto a C18 column (water/acetonitrile) to afford 0.150 g (40%) of 149 as a white solid. LC-MS (ES, m/z): 371 [M+H]+. H-NMR (300 MHz, CD3OD, ppm): δ 7.71 (d, 2H), 7.51 (s, 5H), 7.29 (m, 2H), 7.10 (d, 1H), 5.67 (s, 1H), 1.69 (d, 3H)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[C:5](Br)([CH3:7])[CH3:6])[CH3:2].[C:10]([C:12]1([C:18]2[N:23]=[CH:22][C:21]([NH:24][C:25]([C:27]3[CH:28]=[N:29][N:30]([C:33]4[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][N:34]=4)[C:31]=3[CH3:32])=[O:26])=[CH:20][CH:19]=2)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)#[N:11].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:9])[C:5]([N:15]1[CH2:14][CH2:13][C:12]([C:10]#[N:11])([C:18]2[CH:19]=[CH:20][C:21]([NH:24][C:25]([C:27]3[CH:28]=[N:29][N:30]([C:33]4[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][N:34]=4)[C:31]=3[CH3:32])=[O:26])=[CH:22][N:23]=2)[CH2:17][CH2:16]1)([CH3:7])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Cc1c(C(=O)Nc2ccc(C3(C#N)CCNCC3)nc2)cnn1-c1ccc(C(F)(F)F)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)N1CCC(C#N)(c2ccc(NC(=O)c3cnn(-c4ccc(C(F)(F)F)cn4)c3C)cn2)CC1
Temperature: 50 °C
Reaction time: 12 h

Procedure:
2-Bromo-2-methylpropanoic acid ethyl ester (193 μl) was added to a suspension of N-[6-(4-cyanopiperidin-4-yl)pyridin-3-yl]-5-methyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxamide (455 mg) described in Reference Example 169 and potassium carbonate (276 mg) in N,N-dimethylformamide (3.3 ml) and stirred at 50° C. for 12 hours. Then, 2-bromo-2-methylpropanoic acid ethyl ester (100 μl) and potassium carbonate (276 mg) were added and stirred at 50° C. for 5 hours and at 80° C. for 3 hours. Further, 2-bromo-2-methylpropanoic acid ethyl ester (100 μl) was added and stirred at 80° C. for 3 hours. Water was added to the reaction solution, the precipitated solid was purified with silica gel chromatography (chloroform/methanol) to give 2-{4-cyano-4-[5-({5-methyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carbonyl}amino)pyridin-2-yl]piperidin-1-yl}-2-methylpropanoic acid ethyl ester (320 mg) as a white solid. MS (ESI) m/z: 570 (M+H)+. (2) Lithium borohydride (25 mg) was added to a solution of 2-{4-cyano-4-[5-({5-methyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carbonyl}amino)pyridin-2-yl]piperidin-1-yl}-2-methylpropanoic acid ethyl ester (320 mg) in tetrahydrofuran (3.7 ml) and stirred at room temperature for 1.5 hours. Then, lithium borohydride (25 mg) was added and stirred at 80° C. for 2 hours. To the reaction solution, were added methanol (1.5 ml) and sodium borohydride (85 mg), and stirred at room temperature for an hour. A saturated aqueous solution of ammonium chloride was added to the reaction solution, extracted with dichloromethane, and the organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was purified with silica gel chromatography (chloroform/methanol) to give the titled compound (35 mg) as a white solid.