Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]([C:6]1[N:11]=[CH:10][C:9]([C:12]2[N:13]([C:33]([N:35]3[CH2:40][CH2:39][N:38]([CH2:41][C:42](O)=[O:43])[CH2:37][CH2:36]3)=[O:34])[C@@:14]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)([CH3:25])[C@@:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)([CH3:17])[N:16]=2)=[C:8]([O:45][CH2:46][CH3:47])[CH:7]=1)([CH3:5])([CH3:4])[CH3:3].[NH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][N:50]=1>>[C:2]([C:6]1[N:11]=[CH:10][C:9]([C:12]2[N:13]([C:33]([N:35]3[CH2:36][CH2:37][N:38]([CH2:41][C:42]([NH:48][C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][N:50]=4)=[O:43])[CH2:39][CH2:40]3)=[O:34])[C@@:14]([C:26]3[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=3)([CH3:25])[C@@:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)([CH3:17])[N:16]=2)=[C:8]([O:45][CH2:46][CH3:47])[CH:7]=1)([CH3:4])([CH3:3])[CH3:5]
Reactant: Nc1ccccn1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)O)CC1
Agent: Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)Nc2ccccn2)CC1

Procedure:
In a manner analogous to the method described in examples 99, {4-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-acetic acid hydrochloride (example 94) was coupled with 2-aminopyridine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C40H46Cl2N7O3 [(M+H)+] 742.3034, observed 742.3032.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:23]([O:25][C:26]([C:28]1[CH:29]=[N:30][C:31](Cl)=[C:32]([N+:35]([O-:37])=[O:36])[C:33]=1[NH2:34])=[O:27])[CH3:24]>C1(C)C=CC=CC=1>[CH2:23]([O:25][C:26]([C:28]1[CH:29]=[N:30][C:31]([N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:32]([N+:35]([O-:37])=[O:36])[C:33]=1[NH2:34])=[O:27])[CH3:24]
Reactant: CCOC(=O)c1cnc(Cl)c([N+](=O)[O-])c1N
Reactant: c1ccc(CNCc2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cnc(N(Cc2ccccc2)Cc2ccccc2)c([N+](=O)[O-])c1N
Temperature: 25 °C
Yield: 103.3 %

Procedure:
Dibenzylamine (1.95 mL, 10 mmol), triethylamine (1.37 mL, 10 mmol), 4-amino-6-chloro-5-nitro-pyridine-3-carboxylic acid ethyl ester (2.45 g, 10 mmol) and toluene (73 mL) were combined and heated at reflux over night. The reaction mixture was cooled to room temperature and filtered through a short column of silica gel (eluting first with dichloromethane then ethyl acetate). The organics were concentrated to provide 10 as a yellow oil (4.2 g). 1H NMR (400 MHz, d6-DMSO) δ: 1.28 (t, J=7.1 Hz, 3H), 4.25 (q, J=7.1 Hz, 2H), 4.60 (s, 4H), 7.14-7.31 (m, 10H), 8.35 (s, br, 2H), 8.54 (s, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[O:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[C:26](=[O:27])[NH:25][C:24]3[C:19]2=[N:20][CH:21]=[N:22][CH:23]=3)=[CH:14][CH:13]=1.I[CH2:29][CH3:30].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH2:29]([N:25]1[C:24]2[C:19](=[N:20][CH:21]=[N:22][CH:23]=2)[N:18]([C:15]2[CH:16]=[CH:17][C:12]([O:11][C:3]3[N:2]([CH3:1])[C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=4[N:4]=3)=[CH:13][CH:14]=2)[C:26]1=[O:27])[CH3:30]
Reactant: CCI
Reactant: Cn1c(Oc2ccc(-n3c(=O)[nH]c4cncnc43)cc2)nc2ccccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1c(=O)n(-c2ccc(Oc3nc4ccccc4n3C)cc2)c2ncncc21
Temperature: 50 °C
Reaction time: 4 h

Procedure:
A mixture of 9-{4-[(1-methyl-1H-benzimidazol-2-yl)oxy]phenyl}-7,9-dihydro-8H-purin-8-one (56 mg), iodoethane (20 μL) and cesium carbonate (120 mg) in DMF (3 mL) was stirred at 50° C. for 4 h. The mixture was poured into water, and the mixture was extracted with AcOEt. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residual crystals were recrystallized from AcOEt to give 7-ethyl-9-{4-[(1-methyl-1H-benzimidazol-2-yl)oxy]phenyl}-7,9-dihydro-8H-purin-8-one (40 mg) as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=[CH:9]2)=[CH:5][CH:4]=1.C([Li])CCC.CN([CH:29]=[O:30])C.[NH4+].[Cl-]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=[C:9]2[CH:29]=[O:30])=[CH:19][CH:20]=1
Reactant: CN(C)C=O
Reactant: COc1ccc(Cn2cnc(-c3ccccc3)c2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(Cn2cc(-c3ccccc3)nc2C=O)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 79 %

Procedure:
To a solution of 1-(4-methoxybenzyl)-4-phenylimidazole (2.00 g, 7.56 mmol) in THF (20 mL) cooled to −78° C. under nitrogen add dropwise a solution of n-butyl lithium (1.6 M hexane, 5.60 mL, 8.96 mmol). Stir the mixture at this temperature for 10 minutes then add DMF (1.43 mL, 18.5 mmol) dropwise, and continue stirring for 30 minutes. Add a saturated aqueous solution of NH4Cl (50 mL), raise the temperature to room temperature, and extract the aqueous layer with CH2Cl2 (150 mL), dry (Na2SO4), and concentrate in vacuo. Purify the residue by flash chromatography (SiO2, hexane/EtOAc 9:1) to provide 1.75 g (79% yield). MS(ES+): m/z=293 (M+H)+
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1[S:8][C:7]2[CH:9]=[C:10]3[C:15](=[C:16]([C:17]4[CH:22]=[CH:21][C:20]([O:23][C:24](=[O:26])[CH3:25])=[CH:19][CH:18]=4)[C:6]=2[C:5]=1[CH3:27])[CH:14]=[CH:13][CH:12]=[CH:11]3.S(=O)(O)[O-].[Na+]>ClCCl.[Fe](Cl)(Cl)Cl>[Br:1][C:9]1[C:7]2[S:8][C:4]([CH3:3])=[C:5]([CH3:27])[C:6]=2[C:16]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24](=[O:26])[CH3:25])=[CH:19][CH:18]=2)=[C:15]2[C:10]=1[CH:11]=[CH:12][CH:13]=[CH:14]2
Reactant: BrBr
Reactant: CC(=O)Oc1ccc(-c2c3ccccc3cc3sc(C)c(C)c23)cc1
Agent: Cl[Fe](Cl)Cl
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)Oc1ccc(-c2c3ccccc3c(Br)c3sc(C)c(C)c23)cc1
Reaction time: 0.17 h
Yield: 90.8 %

Procedure:
A solution of bromine (0.326 mL, 6.15 mmol) in dichloromethane (9 mL) was added dropwise over a 15 minute period to a solution that was stirred in the absence of light of acetic acid 4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenyl ester (1.87 g, 5.41 mmol) and iron (III) chloride (50 mg, 0.31 mmol) in dichloromethane (47 mL) at −78° C. under a dry nitrogen atmosphere. After 10 minutes, a dilute aqueous sodium bisulfite solution was added and the reaction mixture was partitioned between water and ether. The ether phase was washed with brine and concentrated to provide the title compound as a white solid (2.09 g, 91%): mp: 190-191° C.; NMR (DMSO-d6); δ8.20 (d, J=8 Hz, 1H), 7.65 (ddd, J=8, 7, 1, 1H), 7.49 (ddd, J=8, 7, 1 Hz, 1H), 7.43-7.38 (m, 1H), 7.40 (d, J=9 Hz, 2H), 7.30 (d, J=9 Hz, 2H), 2.43 (d, J=1 Hz, 3H), 2.33 (s, 3H), 1.55 (d, J=1 Hz, 3H); MS (EI): 1 bromine isotope pattern 424 (95%, MI), 426 (100%); Anal. Calc. for C22H17BrO2S: C, 62.12; H, 4.03; N, 0.00. Found: C, 62.46; H, 4.05; N, 0.09.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:12]3=[C:13]([C:15](=[O:25])[C:16]([CH2:18][C:19]4[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=4)=[CH:17][N:11]3[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]2=3)[CH:14]=1.[NH3:26]>[Cu].[Cu](I)I>[NH2:26][C:2]1[CH:3]=[C:4]2[C:12]3=[C:13]([C:15](=[O:25])[C:16]([CH2:18][C:19]4[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=4)=[CH:17][N:11]3[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]2=3)[CH:14]=1
Reactant: O=c1c(Cc2cccnc2)cn2c3ccccc3c3cc(Br)cc1c32
Reactant: N
Agent: I[Cu]I
Agent: [Cu]
Product: Nc1cc2c(=O)c(Cc3cccnc3)cn3c4ccccc4c(c1)c23
Temperature: 185 °C
Reaction time: 8 h
Yield: 26 %

Procedure:
2-bromo-5-(3-pyridylmethyl)-4H-pyrido[3,2,1-jk]carbazole-4-one (555 mg) produced in Example 178, copper (20 mg), and copper iodide (10 mg) were suspended in aqueous ammonia (28%, 30 ml) in a pressure-resistant microbomb, and the suspension was heated to 180 to 190° C. in an oil bath and stirred for 8 hours. The reaction mixture was then allowed to cool and brought back to normal pressure, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluent: ethyl acetate), and the crude purification product was recrystallized from ethanol to obtain the title compound (120 mg; 26%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([C:16]([NH:18][CH3:19])=[O:17])[CH:11]=2)[C:5]([C:20]#[N:21])=[C:4]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[C:3]=1[C:29]#[N:30].Cl.[NH:32]1[CH2:35][CH:34]([OH:36])[CH2:33]1.C(N(CC)CC)C>CN(C=O)C>[C:20]([C:5]1[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([C:16]([NH:18][CH3:19])=[O:17])[CH:11]=2)=[N:7][C:2]([N:32]2[CH2:35][CH:34]([OH:36])[CH2:33]2)=[C:3]([C:29]#[N:30])[C:4]=1[C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)#[N:21]
Reactant: OC1CNC1
Reactant: CNC(=O)c1cc(COc2nc(Cl)c(C#N)c(-c3ccc(F)cc3)c2C#N)ccn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)c1cc(COc2nc(N3CC(O)C3)c(C#N)c(-c3ccc(F)cc3)c2C#N)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
50 mg (0.12 mmol) of 4-({[6-chloro-3,5-dicyano-4-(4-fluorophenyl)pyridin-2-yl]oxy}methyl)-N-methylpyridine-2-carboxamide Example 81A were initially charged in 1.5 ml of DMF. After addition of 26 mg (0.24 mmol) of azetidin-3-ol hydrochloride and 24 mg (0.24 mmol) of triethylamine, the mixture was stirred at RT overnight. The reaction mixture was purified by preparative HPLC (Chromasil, water/acetonitrile).
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH2:7][CH2:8][C:9]#[N:10].[Br:11]Br.O>C(O)(=O)C>[Br:11][C:4]1[S:3][C:2]([CH3:1])=[C:6]([CH2:7][CH2:8][C:9]#[N:10])[CH:5]=1
Reactant: Cc1sccc1CCC#N
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: Cc1sc(Br)cc1CCC#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.3 %

Procedure:
A solution of 3-(2-methylthiophen-3-yl)-propionitrile 60 (320 mg, 2.1 mmol) in acetic acid (5 mL) was treated with bromine (0.12 mL, 2.3 mmol) and the mixture stirred at rt for 1 hour. Water was added and the mixture was extracted with EtOAc (2×20 mL). The combined organics were washed with water and dried over MgSO4. Removal of the solvent followed with silica gel column chromatography (eluent: DCM/hexane, 1/1) gave 61 as a colorless liquid (330 mg).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([NH2:22])[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]>CN(C=O)C>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([NH:22][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Clc1ccnc(Cl)n1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccnc(Cl)n2)CC1

Procedure:
A mixture of 2,4-dichloro-pyrimidine (4.0 g, 26.85 mmol, 1.0 equiv; commercially available) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (6.45 g, 32.22 mmol, 1.2 equiv) in anhydrous DMF (100 mL) was stirred at rt for 18 h. The organic phase was concentrated under reduced pressure and the crude reaction mixture purified with silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane/ethyl acetate providing 3.2 g (38%) of the title compound. 1H NMR (400 MHz, CDCl3): δ1.35-1.45 (m, 2H), 1.47 (s, 9H), 1.99-2.03 (m, 2H), 2.91-2.97 (m, 2H), 3.81-3.90 (m, 1H), 4.04-4.07 (br d, 2H), 5.33 (d, J=8.0 Hz, 1H), 6.25 (d, J=4.0 Hz, 1H), 7.98 (d, J=4.0 Hz, 1H). 13C NMR (75 MHz, DMSO): δ 28.05, 30.94, 42.04, 46.69, 78.64, 105.13, 153.86, 155.57, 159.81, 162.72. MS (ISP): 313.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([C:13]1[O:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[CH:17]=1)=O.[C:22]([O:29][CH3:30])(=[O:28])[CH2:23][CH2:24][C:25]([CH3:27])=O.Cl[Si](C)(C)C>CN(C=O)C>[CH3:30][O:29][C:22](=[O:28])[CH2:23][C:24]1[C:11]([C:13]2[O:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=2)=[C:3]2[C:4]3[CH2:10][CH2:9][CH2:8][CH2:7][C:5]=3[S:6][C:2]2=[N:1][C:25]=1[CH3:27]
Reactant: Nc1sc2c(c1C(=O)c1cc3ccccc3o1)CCCC2
Reactant: COC(=O)CCC(C)=O
Agent: C[Si](C)(C)Cl
Solvent: CN(C)C=O
Product: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1cc2ccccc2o1)CCCC3
Yield: 85.6 %

Procedure:
This compound was prepared according to the procedure B from (2-amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)(benzofuran-2-yl)methanone (0.297 g; 1 mmol), methyl levulinate (0.141 mL; 1.1 mmol), chlorotrimethylsilane (0.511 mL; 4 mmol) in DMF (4 mL) for 48 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-50%) in heptane furnished 0.335 g (85%) of the title compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:29])[C:7]=1[CH2:8][C:9]1[C:18]2[C:13](=[C:14](OS(C(F)(F)F)(=O)=O)[C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[CH:12]=[N:11][N:10]=1.[CH2:30]([N:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1)[C:31]#[CH:32]>C(NCC)C>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:29])[C:7]=1[CH2:8][C:9]1[C:18]2[C:13](=[C:14]([C:32]#[C:31][CH2:30][N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[CH:12]=[N:11][N:10]=1
Reactant: C#CCN1CCOCC1
Reactant: COc1ccc2c(Cc3c(Cl)cncc3Cl)nncc2c1OS(=O)(=O)C(F)(F)F
Solvent: CCNCC
Product: COc1ccc2c(Cc3c(Cl)cncc3Cl)nncc2c1C#CCN1CCOCC1
Yield: 38.5 %

Procedure:
Operating analogously to what described in example 74 starting from trifluoro-methanesulfonic acid 1-(3,5-dichloro-pyridin-4-ylmethyl)-6-methoxy-phthalazin-5-yl ester (2 g, 4.27 mmoles), prepared as described in example 73, 4-prop-2-ynyl-morpholine (640 mg, 5.12 mmoles), prepared as described in example 137, diethylamine (40 ml), bis(triphenylphosphine)PdCl2 (60 mg, 0.0854 mmole) and Cul (16 mg, 0.0854 mmole), 728 mg of the title compound were obtained (yield: 38.6%).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[NH:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[C:16]1(=O)[CH2:19][CH2:18][CH2:17]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(O)(=O)C>[CH:16]1([N:7]2[CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3][C:2]2([CH3:15])[CH3:1])[CH2:19][CH2:18][CH2:17]1
Reactant: O=C1CCC1
Reactant: CC1(C)CN(C(=O)OC(C)(C)C)CCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCN(C2CCC2)C(C)(C)C1
Temperature: 40 °C
Reaction time: 5 h

Procedure:
Tert-butyl 3,3-dimethylpiperazine-1-carboxylate (413 mg, 1.65 mmol) was dissolved in DCE (15 mL). TEA (1.148 mL, 8.23 mmol) was added, followed by cyclobutanone (231 mg, 3.29 mmol) and sodium triacetoxyborohydride (524 mg, 2.47 mmol). The reaction mixture was stirred for 5 h and a few drops of acetic acid were added. The reaction mixture was heated at 40° C. for 4 days, cooled to rt, washed with sat NaHCO3, dried over MgSO4, filtered and concentrated under reduced pressure to give a dark yellow oil. The crude title compound was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.[F:18][C:19]([F:30])([F:29])[O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH2:26])=[CH:23][CH:22]=1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([NH:26][CH2:25][C:24]2[CH:27]=[CH:28][C:21]([O:20][C:19]([F:18])([F:29])[F:30])=[CH:22][CH:23]=2)[N:3]=1
Reactant: NCc1ccc(OC(F)(F)F)cc1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Solvent: COCCOC
Product: N#Cc1c(NCc2ccc(OC(F)(F)F)cc2)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile and 4-(trifluoromethoxy)benzylamine in DME. ES-MS m/e (%): 376 (M+H+, 100).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2([CH2:14][OH:15])[CH2:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.[H-].[Na+].[CH3:18]I>C1COCC1>[CH3:18][O:15][CH2:14][C:10]1([C:7]2[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)[CH2:13][CH2:12][CH2:11]1
Reactant: O=[N+]([O-])c1ccc(C2(CO)CCC2)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCC1(c2ccc(N)cc2)CCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of [(4-nitrophenyl)cyclobutyl]methane-1-ol (500 mg) and NaH (60% in mineral oil, 1.2 eq) and MeI (1.2 eq) in THF was stirred at RT overnight then quenched with H2O. The solution was extracted with EtOAc and washed with H2O followed by brine, dried over Na2SO4 and evaporated. The residue was mixed with Pd—C (10%, 100 mg) in EtOH (50 ml) and hydrogenated under H2 atmosphere for 30 min. The reaction was filtered through Celite and evaporated to give 4-[(methoxymethyl)cyclobutyl]phenylamine which used for next step without further purification.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN1CCOCC1.COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.Cl.[NH:44]1[C@H:48]([C:49]([OH:51])=[O:50])[CH2:47][CH:46]=[N:45]1>C(#N)C>[CH:1]1([CH2:6][C@H:7]([CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:8]([N:44]2[C@H:48]([C:49]([OH:51])=[O:50])[CH2:47][CH:46]=[N:45]2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(C)OC(=O)C[C@@H](CC1CCCC1)C(=O)O
Reactant: O=C(O)[C@@H]1CC=NN1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)C[C@@H](CC1CCCC1)C(=O)N1N=CC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
To a 1000 ml round bottom flask under N2 was added (2R)-2-(cyclopentylmethyl)-4-[(1,1-dimethylethyl)oxy]-4-oxobutanoic acid (Tetrahedron, 2001, 57(36), 7675-7683) (38.1 g, 149 mmol) in acetonitrile (650 mL) at 0° C., followed by N-methylmorpholine (82 mL, 744 mmol) and 4-[4,6-bis(methyloxy)-1,3,5-triazin-2-yl]-4-methylmorpholin-4-ium (53.7 g, 164 mmol). The solution was stirred at the same temperature for 2 hours and then (5S)-4,5-dihydro-1H-pyrazole-5-carboxylic acid, hydrochloride (22.4 g, 149 mmol) was added. The solution was allowed to warm up to room temperature and stirring continued overnight. LCMS showed that the reaction was complete. The acetonitrile was removed under reduced pressure, and the residue was taken up in DCM (500 mL) and neutralized by the addition of 2 N HCl. The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by Combiflash automated silica gel chromatography (0-5% methanol containing 1% formic acid/DCM) to provide (5S)-1-{(2R)-2-(cyclopentylmethyl)-4-[(1,1-dimethylethyl)oxy]-4-oxobutanoyl}-4,5-dihydro-1H-pyrazole-5-carboxylic acid (27.7 g, 79 mmol, 53% yield) as a clear oil. LCMS: [M+H]+: 353.4.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[CH3:12][N:13]1[CH:17]=[CH:16][N:15]=[C:14]1[CH:18]=[O:19].[N:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:21]>ClCCl>[OH:21][N:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:18]([C:14]1[N:13]([CH3:12])[CH:17]=[CH:16][N:15]=1)=[O:19]
Reactant: Cn1ccnc1C=O
Reactant: O=Nc1ccccc1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: Cn1ccnc1C(=O)N(O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
DBU (3.8 mg, 0.025 mmol) was added under argon to a solution of 1-methyl-1H-imidazole-2-carbaldehyde (110 mg, 1 mmol), nitrosobenzene (107 mg, 1 mmol) and catalyst (1.82 mg, 0.005 mmol) in dichloromethane (5 mL). The reaction mixture was stirred at room temperature for 10 min. The solvent was removed under vacuum, and the residue was purified by flash silica gel column chromatography using hexane and ethyl acetate as the eluents.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:10][N:9]=[N:8][N:7]=1)=[O:5])[CH3:2].[Na].[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Br)=[CH:16][CH:15]=1.C(N(CC)CC)C>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[N:8][N:9]([CH2:18][C:17]2[CH:20]=[CH:21][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)[N:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nnn[nH]1
Reactant: COc1ccc(CBr)cc1
Agent: [Na]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)c1nnn(Cc2ccc(OC)cc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of sodium tetrazole-5-carboxylic acid ethyl ester (2 g, 12.19 mmol) in DMF (8 mL) is added 4-methoxybenzyl bromide (3.68 g, 18.28 mmol) followed by the addition of triethylamine (5.10 mL). The resulting mixture is stirred at room temperature overnight then ice/water is added. The mixture is extracted with EtOAc and the combined organic phases were washed with water and brine, dried over MgSO4, filtered and concentrated. The residue is purified by column chromatography to afford 2-(4-methoxy-benzyl)-2H-tetrazole-5-carboxylic acid ethyl ester; HPLC Retention time 1.37 minutes (condition C): MS 263.2 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([OH:11])[N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:7]=1)=[O:5])[CH3:2].Br[CH2:19][C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([O:11][CH2:19][C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(O)n(-c2ccccc2)n1
Reactant: O=C(CBr)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(OCC(=O)OCc2ccccc2)n(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 10.0 g 5-hydroxy-1-phenyl-1H-pyrazole-3-carboxylic acid ethyl ester in 100 ml DMF were added 7.1 ml benzyl bromoacetate and 24.0 g cesium carbonate. After stirring for 16 h at RT the suspension was filtered, washed with DMF and concentrated. The residue was taken up with ethyl acetate and extracted with aqueous LiCl (4%). Evaporation of the solvent yielded the crude product which was used in the subsequent debenzylation. Yield: 15.5 g yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:13]([C:14]([OH:16])=[O:15])[CH2:12][C@@H:11]2[C@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[C@H:13]([C:14]([O:16][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:15])[CH2:12][C@@H:11]2[C@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1C(=O)O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1R,3S,5R)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-tert-butyl ester (2.5 g, 11.0 mmol) and Cs2CO3 (3.94 g, 12.1 mmol) in DMF (50 mL) at 0° C. benzylbromide (2.26 g, 13.2 mmol) was added dropwise. The reaction mixture was stirred overnight at RT. DMF was evaporated. The residue was dissolved in EtOAc and washed with a saturated aqueous solution of NaHCO3, the layers were separated and the aqueous phase was extracted with EtOAc (×2). The combined organic extracts were dried over Na2SO4, filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane/EtOAc 100:0 to 0:100) to give the desired material as a colorless oil. MS (LCMS): 318.2 [M+H]+; tR (HPLC conditions f): 2.23 min.