Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14](Br)[N:15]=2)[N:10]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(C1CN(C(=O)[C@H](NC(C2C3C(=NC=C([C:47]4[C:51]5=[N:52][CH:53]=[CH:54][CH:55]=[C:50]5[N:49]([CH3:56])[N:48]=4)N=3)NC=2)=O)C)C1)#N>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:47]3[C:51]4=[N:52][CH:53]=[CH:54][CH:55]=[C:50]4[N:49]([CH3:56])[N:48]=3)[N:15]=2)[N:10]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Reactant: C[C@@H](NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cccnc34)nc12)C(=O)N1CC(C#N)C1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cn1nc(-c2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)c2ncccc21
Temperature: 80 °C
Reaction time: 8 h
Yield: 40.9 %

Procedure:
In a round-bottomed flask, 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide (110 mg, 0.26 mmol) and 1-methyl-3-tributylstannyl-1H-pyrazolo[4,3-b]pyridine (see Example 98, 340 mg, 0.40 mmol) were dissolved in DMF (2.4 ml). The reaction mixture was evacuated and backfilled with argon then tetrakis(triphenylphosphine)palladium (0) (15 mg, 0.013 mmol) and copper (I) iodide (10 mg, 0.053 mmol) were added. The reaction mixture was stirred at 80° C. overnight then cooled to room temperature, quenched with water and extracted with diethyl ether (2×). The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated. The residue was chromatographed over 12 g silica gel with EtOAc/hexanes (gradient: 0-70% EtOAc) to afford 51 mg (41%) of 2-(1-methyl-1H-pyrazolo[4,3-b]pyridin-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide as a light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:12]([Br:13])=[C:11]([F:14])[CH:10]=[CH:9][C:3]=1[C:4]([NH:6][CH2:7][CH3:8])=[O:5].Cl[C:16](Cl)([O:18]C(=O)OC(Cl)(Cl)Cl)Cl.O>C1(C)C=CC=CC=1>[Br:13][C:12]1[C:11]([F:14])=[CH:10][CH:9]=[C:3]2[C:2]=1[NH:1][C:16](=[O:18])[N:6]([CH2:7][CH3:8])[C:4]2=[O:5]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCNC(=O)c1ccc(F)c(Br)c1N
Solvent: O
Solvent: Cc1ccccc1
Product: CCn1c(=O)[nH]c2c(Br)c(F)ccc2c1=O
Temperature: 25 °C
Yield: 291 %

Procedure:
A solution of 2-amino-3-bromo-N-ethyl-4-fluorobenzamide (512a, 2.00 g, 7.66 mmol) and triphosgene (Aldrich; 0.796 g, 2.68 mmol) in toluene (80 mL) was heated at 110° C. for 18 h (water-cooled reflux condenser attached to flask). The reaction mixture was then cooled to RT and concentrated in vacuo to give 8-bromo-3-ethyl-7-fluoroquinazoline-2,4(1H,3H)-dione (2.238 g, 7.80 mmol) as a light-yellow solid: m/z (ESI, +ve) 286.9/288.8 (M+H)+. This material was used directly in the subsequent transformation.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]=[O:17])[CH:11]=2)[C:5]([CH3:9])=[CH:6][C:7]=1[OH:8].N1C=CN=C1.[C:24]([Si:28]([CH3:31])([CH3:30])Cl)([CH3:27])([CH3:26])[CH3:25].O>CN(C)C=O>[Si:28]([O:8][C:7]1[CH:6]=[C:5]([CH3:9])[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]=[O:17])[CH:11]=2)=[C:3]([CH3:18])[C:2]=1[Cl:1])([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:31])[CH3:30]
Reactant: Cc1cc(O)c(Cl)c(C)c1-c1cccc(C=O)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(O[Si](C)(C)C(C)(C)C)c(Cl)c(C)c1-c1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 87.7 %

Procedure:
To a solution of 3′-chloro-4′-hydroxy-2′,6′-dimethylbiphenyl-3-carbaldehyde (1.41 g, 5.41 mmol) and imidazole (1.10 g, 16.2 mmol) in N,N-dimethylformamide (10 mL), was added tert-butyldimethylchlorosilane (1.22 g, 8.09 mmol) at room temperature, and the mixture was stirred at room temperature for 24 hr under nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=0:100-20:80) to give the title compound (1.78 g, yield 88%) as a colorless oil.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[C@@H:3]1[CH3:18].CCN(C(C)C)C(C)C.[CH3:28][N:29]([CH3:33])[C:30](Cl)=[O:31]>CC#N>[CH3:28][N:29]([CH3:33])[C:30](=[O:31])[NH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[C@@H:3]1[CH3:18]
Reactant: C[C@@H]1[C@H](N)CCCN1C(=O)OCc1ccccc1
Reactant: CN(C)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C[C@@H]1[C@H](NC(=O)N(C)C)CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
Commercial (2R,3R)-benzyl 3-amino-2-methylpiperidine-1-carboxylate (323, CAS: 104461-49-7) (900 mg, 3.63 mmol) was dissolved in 30 mL MeCN and stirred at RT. To it were added DIEA (1.89 mL, 10.89 mmol) and then drop-wise dimethylcarbamoyl chloride (1.00 mL, 10.89 mmol). The mixture was stirred for overnight, concentrated on rotavap, diluted with EtOAc, washed with water ×2, dried over MgSO4, concentrated on rotavap, subjected to silica flash column using 0 to 4% MeOH in DCM to give (2R,3R)-benzyl 3-(3,3-dimethylureido)-2-methylpiperidine-1-carboxylate (324). It was dissolved in 100 mL iPrOH, and subjected to hydrogenation at 35 psi on Parr shaker with 10% Pd/C (1.0 g) for overnight. The mixture was filtered through celite, and the filtrate was concentrated in vacuo to afford 1,1-dimethyl-3-((2R,3R)-2-methylpiperidin-3-yl)urea (325) as a thick oil. It was dissolved in 30 mL dry DMF. To it were added 3,5-dichloropyrazine-2-carbonitrile (630 mg, 3.6 mmol) and then DIEA (1.25 mL, 7.2 mmol). The mixture was stirred at RT for overnight. It was diluted with 300 mL EtOAc, washed with water ×3, dried over MgSO4, concentrated on rotavap, and subjected to silica flash column with 0 to 4% MeOH in DCM to isolate 3-((2R,3R)-1-(6-chloro-5-cyanopyrazin-2-yl)-2-methylpiperidin-3-yl)-1,1-dimethylurea (326) (850 mg, 73% overall yield for three steps).
Reaction SMILES: P(=O)(O)(O)O.[C:6]1([CH:12]2[CH2:16][CH2:15][NH:14][CH2:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.N.CO.[CH:20]([C:22]1[CH:37]=[CH:36][C:25]([O:26][C:27]2[CH:35]=[CH:34][C:30]([C:31]([NH2:33])=[O:32])=[CH:29][N:28]=2)=[CH:24][CH:23]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl.CO>[C:6]1([CH:12]2[CH2:16][CH2:15][N:14]([CH2:20][C:22]3[CH:37]=[CH:36][C:25]([O:26][C:27]4[CH:35]=[CH:34][C:30]([C:31]([NH2:33])=[O:32])=[CH:29][N:28]=4)=[CH:24][CH:23]=3)[CH2:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: c1ccc(C2CCNC2)cc1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: N
Agent: O=P(O)(O)O
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: CO
Product: NC(=O)c1ccc(Oc2ccc(CN3CCC(c4ccccc4)C3)cc2)nc1
Reaction time: 24 h
Yield: 88.4 %

Procedure:
Convert 3-phenyl-pyrrolidine phosphoric acid salt (0.152 g, 1.03 mmol) to the free base by ion exchange chromatography (SCX resin, methanol→2 M ammonia/methanol) and then concentrate. Combine free base with 6-(4-formyl-phenoxy)-nicotinamide (compound of example 332, step 1) (0.150 g, 0.618 mmol), sodium triacetoxyborohydride (0.201 g, 0.948 mmol), and acetic acid (0.053 mL, 0.891 mmol) in 1,2-dichloroethane (9.5 mL) and stir at ambient temperature. After 1 d, purify the reaction mixture by ion exchange chromatography (SCX resin, methanol→2 M ammonia in methanol) and concentrate to provide 0.204 g (88%) of the title compound as a white solid: high resolution mass spectrum (electrospray): m/z calc for C23H24N3O2 374.1869, found 374.1887; 1H NMR (methanol-d4): 8.67 (dd, 1H, J=1.0, 2.4 Hz), 8.29 (dd, 1H, J=2.4, 8.8 Hz), 7.52-7.47 (m, 2H), 7.34-7.28 (m, 4H), 7.25-7.14 (m, 3H), 7.03 (dd, 1H, J=1.0, 8.8 Hz), 3.80 (d, 1H, J=13.2 Hz), 3.77 (d, 1H, J=12.7 Hz), 3.48-3.38 (m, 1H), 3.16 (dd, 1H, J=7.8, 9.3 Hz), 3.00-2.93 (m, 1H), 2.85-2.77 (m, 1H), 2.58 (t, 1H, J=8.8 Hz), 2.44-2.32 (m, 1H), 2.02-1.91 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]([CH2:11][C@H:12]([CH3:15])[CH2:13]I)[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.[CH2:18]([O:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[CH2:19][CH3:20]>CCCCCCC.CCOC(C)=O>[F:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]([CH2:11][C@H:12]([CH3:15])[CH2:13][N:25]3[CH2:26][CH2:27][CH:22]([O:21][CH2:18][CH2:19][CH3:20])[CH2:23][CH2:24]3)[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: CCCOC1CCNCC1
Reactant: C[C@H](CI)CN1C(=O)COc2cc(F)ccc21
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CCCOC1CCN(C[C@@H](C)CN2C(=O)COc3cc(F)ccc32)CC1
Yield: 72 %

Procedure:
The compound (S)-7-Fluoro-4-(3-iodo-2-methylpropyl)-4H-benzo[1,4]oxazin-3-one (111MF20) (0.501 g, 1.43 mmol) and 4-propyloxypiperidine (0.205 g, 1.43 mmol) were mixed according to GP16. CC (SiO2; Heptane/EtOAc 4:1-4) gave the title compound (111MF28) (0.375 g, 71%). 1H NMR (CDCl3) d 7.12-7.08 (m, 1H), 6.74-6.69 (m, 2H), 4.59 (q, J=15.0 Hz, J=31.0 Hz, 2H), 4.01-3.88 (m, 2H), 3.39 (t, J=6.8 Hz, 2H), 3.29-3.22 (m, 1H), 2.77 (t, J=6.3 Hz, 1H), 2.63 (t, J=5.6 Hz, 1H), 2-26-2.12 (m, 3H), 2.04-1.96 (m, 2H), 1.88-1.84 (m, 2H), 1.62-1.50 (m, 4H), 0.93-0.87 (m, 6H); 13C NMR (CDCl3) d 164.2, 158.9 (d, J=241.9 Hz), 146.5 (d, J=12.1 Hz), 125.2 (d, J=3.0 Hz), 116.1 (d, J=9.6 Hz), 109.0 (d, J=22.3 Hz), 105.2 (d, J=25.8 Hz), 75.2, 69.8, 67.8, 63.5, 52.8, 51.8, 45.5, 31.9, 31.8, 29.4, 23.5, 17.0, 10.8.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[CH:10]1[O:14][C:13](=[O:15])[NH:12][C:11]1=[O:16].[Na].Cl[C:19]([O:21][CH2:22][CH3:23])=[O:20]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[CH:10]1[O:14][C:13](=[O:15])[N:12]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:11]1=[O:16]
Reactant: COc1cccc(Cl)c1C1OC(=O)NC1=O
Reactant: CCOC(=O)Cl
Agent: [Na]
Solvent: Cc1ccccc1
Product: CCOC(=O)N1C(=O)OC(c2c(Cl)cccc2OC)C1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Anhydrous sodium 5-(2-chloro-6-methoxyphenyl)-oxazolidine-2,4-dione (542 mg., 2.06 moles) from Example 119 and ethyl chloroformate (291 mg., 268 mmoles) were combined with 20 ml. of toluene and the mixture refluxed for 3 hours, cooled to room temperature, stirred for a further 16 hours, and evaporated to solids (415 mg.). The solids were recrystallized from toluene to yield purified 5-(2-chloro-6-methoxyphenyl)-3-ethoxycarbonyloxazolidine-2,4-dione. (212 mg., m.p. 196°-200° C.).
Reaction SMILES: [I-:1].C[O:3][C:4]1[CH:5]=[C:6]([C@@H:10]([N+:12]([CH3:22])([CH3:21])[C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:14])[CH3:11])[CH:7]=[CH:8][CH:9]=1.COS([O-])(=O)=O.COC1C=C([C@@H]([N+](C)(C)[C@H](C2C=CC=CC=2)C)C)C=CC=1.Br>CC(C)=O>[I-:1].[OH:3][C:4]1[CH:5]=[C:6]([C@@H:10]([N+:12]([CH3:22])([CH3:21])[C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:14])[CH3:11])[CH:7]=[CH:8][CH:9]=1
Reactant: COc1cccc([C@H](C)[N+](C)(C)[C@@H](C)c2ccccc2)c1
Agent: Br
Agent: COS(=O)(=O)[O-]
Agent: [I-]
Solvent: CC(C)=O
Product: C[C@@H](c1ccccc1)[N+](C)(C)[C@@H](C)c1cccc(O)c1
Temperature: 25 °C
Yield: 80 %

Procedure:
Mix 8.2 g (0.02 mol) of (S)-1-(3-methoxyphenyl)-N,N-dimethyl-N—((S)-1-phenylethyl)ethanaminium iodide (formula VI) with 15 ml (content greater than 40% by mass) hydrobromic acid, heat and reflux the mixture for 10 hours. Let it cool to room temperature, and add 120 ml of acetone. A pale yellow solid is produced. Filter and dry it to receive 6.4 g pale yellow solid with a yield of 80%.
Reaction SMILES: [O:1]=[S:2]1(=[O:12])[CH2:7][CH2:6][N:5]([S:8](Cl)(=[O:10])=[O:9])[CH2:4][CH2:3]1.[C@H:13]1([NH:22][C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[C:28]([NH2:33])[CH:29]=3)[N:24]=2)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14]1>>[C@H:13]1([NH:22][C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[C:28]([NH:33][S:8]([N:5]4[CH2:6][CH2:7][S:2](=[O:12])(=[O:1])[CH2:3][CH2:4]4)(=[O:10])=[O:9])[CH:29]=3)[N:24]=2)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14]1
Reactant: Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Reactant: O=S1(=O)CCN(S(=O)(=O)Cl)CC1
Product: O=S1(=O)CCN(S(=O)(=O)Nc2ccc3nc(N[C@@H]4CCc5ccccc54)ccc3c2)CC1

Procedure:
The title compound was prepared in accordance with the general method described in example 66 from 1,1-dioxo-thiomorpholine-4-sulfonyl chloride and (R)—N2-indan-1-yl-quinoline-2,6-diamine; MS: m/e=473.7 (M+H+).
Reaction SMILES: [CH:1]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:2]=1[C:3](=[O:18])[N:4]1[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[NH:11][C:5]1=[N:6]2.[CH2:19](Br)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>>[CH2:19]([N:11]1[C:5]2=[N:6][C:7]3[C:2]([C:3](=[O:18])[N:4]2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]1=2)=[CH:1][CH:10]=[CH:9][CH:8]=3)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: O=c1c2ccccc2nc2[nH]c3ccccc3n12
Reactant: CCCCCCCCBr
Product: CCCCCCCCn1c2ccccc2n2c(=O)c3ccccc3nc12

Procedure:
6-(n-Octyl)benzimidazo[2,1-b]quinazolin-12(6H)one is prepared with benzimidazo[2,1-b]quinazolin-12(6H)one and n-octyl bromide.
Reaction SMILES: [O:1]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([NH2:19])=O)=[C:11]([C:20](=[O:34])[NH:21][CH:22]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[CH2:23][CH:24]([CH3:26])[CH3:25])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.O>O1CCOCC1>[CH3:25][CH:24]([CH3:26])[CH2:23][CH:22]([NH:21][C:20](=[O:34])[C:11]1[CH:10]=[C:9]([CH2:8][O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:14]=[CH:13][C:12]=1[CH2:15][CH2:16][C:17]#[N:19])[C:27]1[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=1
Reactant: CC(C)CC(NC(=O)c1cc(COc2ccccc2)ccc1CCC(N)=O)c1ccc(F)cc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: C1COCCO1
Solvent: O
Product: CC(C)CC(NC(=O)c1cc(COc2ccccc2)ccc1CCC#N)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 82.2 %

Procedure:
To a suspension of the compound prepared in Example 15 (119 mg) in dioxane (2 ml) were added pyridine (0.1 ml) and trifluoromethanesulfonic acid anhydride (54 μl) at 0° C. under an atmosphere of argon. The mixture was stirred at room temperature for 10 minutes. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride subsequently, dried over anhydrous magnesium sulfate and concentrated. The residue was washed with n-hexane:ethyl acetate to give the title compound (94 mg) having the following physical data.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[CH2:7]([NH:14][C:15](=O)[C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:25])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[N:27]([Si](C)(C)C)=[N+:28]=[N-:29].C(=O)(O)[O-].[Na+]>C(Cl)Cl.O>[CH2:7]([N:14]1[C:15]([C:16]2[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:25])=[N:29][N:28]=[N:27]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: Cc1cccc([N+](=O)[O-])c1C(=O)NCc1ccccc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cc1cccc([N+](=O)[O-])c1-c1nnnn1Cc1ccccc1
Reaction time: 0.5 h
Yield: 71.2 %

Procedure:
Phosphorous pentachloride (0.42 g, 2 mmol) was added to a solution of N-benzyl-2-methyl-6-nitrobenzamide (Intermediate 19, 0.54 g) in DCM (10 mL). The mixture was stirred under nitrogen for 30 minutes and then azidotrimethylsilane (0.48 g) was added and the mixture was stirred for a further 72 hours. The mixture was diluted with DCM (50 mL) and water (50 mL). Solid sodium bicarbonate was then added to the mixture until there was no further gaseous evolution. The organic solution was washed with saturated aqueous sodium bicarbonate, then with 1N hydrochloric acid, dried with magnesium sulfate and filtered. The solvent was evaporated to give an orange solid which was recrystallised from ethyl acetate to give the title compound as a white solid (0.42 g).
Reaction SMILES: [CH2:1]([N:5]1[C:10]2=[C:11]([CH3:14])[NH:12][CH:13]=[C:9]2[C:8](=[O:15])[N:7]([CH3:16])[C:6]1=[O:17])[CH:2]([CH3:4])[CH3:3].Cl[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[CH2:1]([N:5]1[C:10]2=[C:11]([CH3:14])[N:12]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[CH:13]=[C:9]2[C:8](=[O:15])[N:7]([CH3:16])[C:6]1=[O:17])[CH:2]([CH3:4])[CH3:3]
Reactant: COc1ccc(CCl)cc1
Reactant: Cc1[nH]cc2c(=O)n(C)c(=O)n(CC(C)C)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Cn2cc3c(=O)n(C)c(=O)n(CC(C)C)c3c2C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.8 %

Procedure:
A suspension of 1-isobutyl-3,7-dimethyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (78 mg, 0.33 mmol), 1-(chloromethyl)-4-methoxybenzene (88 μL, 0.63 mmol) and cesium carbonate (344 mg, 1.06 mmol) in anhydrous DMF is stirred at room temperature overnight. The mixture is diluted with 30 mL of water, and then extracted with CH2Cl2 three times. The combined organic phase is washed with brine, and then dried with anhydrous Na2SO4. After filtration, the filtrate is concentrated under vacuum. The residue is purified by basic alumina column chromatography to give 110 mg of product (yield: 93%). MS (ESI) m/z 356.2 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18](CC#N)=[C:17]([O:24][C:25]([F:28])([F:27])[F:26])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(OC(OC(C)(C)C)=O)=O)(C)(C)C.CCN(C(C)C)C(C)C.[C:53]([OH:56])(=[O:55])[CH3:54]>Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:54][C:53]([OH:56])=[O:55])=[C:17]([O:24][C:25]([F:28])([F:26])[F:27])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(CC#N)c(OC(F)(F)F)c2)CC1
Reactant: CC(=O)O
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(CC(=O)O)c(OC(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 0.1 h

Procedure:
4-(N-tert-butyloxycarbonyl-4-piperidinyloxy)-2-(trifluoromethoxy)phenylacetonitrile (1.9 g, 4.3 mmol) from Step 8 above dissolved in a 2:1 mixture of acetic acid and concentrated aqueous HCl (25 mL). Loss of the Boc group occurred within the first 5 minutes to give an intermediate which had an HPLC retention time of 6.3 min (method A). The solution was then refluxed for 2 h, during which time the 6.3 min peak disappeared and a new peak at 5.9 min appeared. The solvents were removed under reduced pressure. The residue was dissolved in degassed DMF (100 mL) and the solvent was removed under reduced pressure to minimize the amount of residual acetic acid and water in the sample. The crude product, 4-(4-piperidinyloxy)-2-(trifluoromethoxy)phenylacetic acid, was dissolved in DMF (50 mL) and di-tert-butyldicarbonate (1.0 g, 4.6 mmol) and DIEA (2.3 mL, 13 mmol) were added. The solution was stirred at ambient temperature for 30 min. The solvent was removed under reduced pressure and the residue was partitioned between EtOAc (100 mL) and 0.25 M aqueous citric acid (50 mL). The organic phase was separated, washed with water (2×25 mL), dried (MgSO4), filtered, and the solvent was removed under reduced pressure to give 4-(N-tert-butyloxycarbonyl-4-piperidinyloxy)-2-(trifluoromethoxy)phenylacetic acid as a gum (HPLC retention time=10.2 min (method A)).
Reaction SMILES: [NH:1]([C:23]([O:25][CH:26]1[CH2:31][C:30]([CH3:33])([CH3:32])[N:29]([O:34][CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)[C:28]([CH3:42])([CH3:41])[CH2:27]1)=[O:24])[NH:2][C:3]([O:5][CH:6]1[CH2:11][C:10]([CH3:13])([CH3:12])[N:9]([O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]([CH3:22])([CH3:21])[CH2:7]1)=[O:4].C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>>[N:2]([C:3]([O:5][CH:6]1[CH2:7][C:8]([CH3:22])([CH3:21])[N:9]([O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[C:10]([CH3:13])([CH3:12])[CH2:11]1)=[O:4])=[N:1][C:23]([O:25][CH:26]1[CH2:27][C:28]([CH3:41])([CH3:42])[N:29]([O:34][CH:35]2[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]2)[C:30]([CH3:32])([CH3:33])[CH2:31]1)=[O:24]
Reactant: CC1(C)CC(OC(=O)NNC(=O)OC2CC(C)(C)N(OC3CCCCC3)C(C)(C)C2)CC(C)(C)N1OC1CCCCC1
Solvent: Ic1ccccc1
Solvent: CC(=O)O
Product: CC1(C)CC(OC(=O)N=NC(=O)OC2CC(C)(C)N(OC3CCCCC3)C(C)(C)C2)CC(C)(C)N1OC1CCCCC1
Yield: 84.7 %

Procedure:
The procedure of Example 4 is repeated using 12.2 g of bis(1-cyclohexyloxy-2,2,6,6-tetramethylpiperidin-4-yl) hydrazine-1,2-dicarboxylate and 7.2 g of iodobenzene diacetate to afford 10.3 g of the title compound; mp 189°-19 1° C.
Reaction SMILES: [NH2:1][CH:2]([C:4]1[CH:5]=[C:6]2[CH:12]=[CH:11][N:10](C(OC(C)(C)C)=O)[C:7]2=[CH:8][N:9]=1)[CH3:3].Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[CH:32]=[C:31]([C@H:33]3[CH2:35][C@H:34]3[F:36])[NH:30][N:29]=2)[CH:24]=[CH:23][N:22]=1.ClC1N=C(NC2C=C(C3CC3)NN=2)C=CN=1>>[NH:10]1[C:7]2[C:8](=[N:9][C:4]([C@@H:2]([NH:1][C:21]3[N:26]=[C:25]([NH:27][C:28]4[CH:32]=[C:31]([C@H:33]5[CH2:35][C@H:34]5[F:36])[NH:30][N:29]=4)[CH:24]=[CH:23][N:22]=3)[CH3:3])=[CH:5][CH:6]=2)[CH:12]=[CH:11]1
Reactant: F[C@@H]1C[C@@H]1c1cc(Nc2ccnc(Cl)n2)n[nH]1
Reactant: CC(N)c1cc2ccn(C(=O)OC(C)(C)C)c2cn1
Agent: Clc1nccc(Nc2cc(C3CC3)[nH]n2)n1
Product: C[C@H](Nc1nccc(Nc2cc([C@H]3C[C@H]3F)[nH]n2)n1)c1ccc2[nH]ccc2n1

Procedure:
The title compound was prepared following the procedure according to Example 9, using (S)-1-(1H-pyrrolo[3,2-b]pyridin-5-yl)ethanamine hydrochloride (referential example 17) and 2-chloro-N-(5-((1R,2R)-2-fluorocyclopropyl)-1H-pyrazol-3-yl)pyrimidin-4-amine (referential example 4) in place of (1H-pyrrolo[3,2-b]pyridin-5-yl)methanamine and 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (referential example 1), respectively, as starting materials. 1H NMR (400 MHz, DMSO-d6) δ 11.98 (br s, 1H), 11.18 (s, 1H), 9.33 (br s, 1H), 7.79 (d, J=5.6 Hz, 1H), 7.70 (d, J=8.4 Hz, 1H), 7.57 (s, 1H), 7.16 (d, J=8.3 Hz, 1H), 6.93 (br s, 1H), 6.53 (s, 1H), 6.40 (br s, 1H), 6.10 (br s, 1H), 5.21 (s, 1H), 4.90 (d, J=65.8 Hz, 1H), 2.10-1.99 (m, 1H), 1.49 (d, J=6.9 Hz, 3H), 1.33 (s, 1H), 1.24 (s, 1H); MS (ESI) m/k: 379.2 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[O:6][C:5]([C:7]2[C:8]([CH:16]3[CH2:19][CH2:18][CH2:17]3)=[CH:9][C:10]([CH3:15])=[C:11]([CH:14]=2)[C:12]#[N:13])=[N:4][N:3]=1.[OH-].[K+].Cl.[CH3:23][CH2:24]O>>[CH:16]1([C:8]2[C:7]([C:5]3[NH:1][C:2]([O:6][CH2:23][CH3:24])=[N:3][N:4]=3)=[CH:14][C:11]([C:12]#[N:13])=[C:10]([CH3:15])[CH:9]=2)[CH2:19][CH2:18][CH2:17]1
Reactant: CCO
Reactant: Cc1cc(C2CCC2)c(-c2nnc(N)o2)cc1C#N
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: CCOc1nnc(-c2cc(C#N)c(C)cc2C2CCC2)[nH]1
Temperature: 85 °C

Procedure:
To a solution of 5-(5-amino-1,3,4-oxadiazol-2-yl)-4-cyclobutyl-2-methylbenzonitrile (219.6, 0.5 g, 2.0 mmol) in EtOH (40 ml) was added KOH (1.11 g, 20.0 mmol). The mixture was heated at 85° C. overnight. After cooling to ambient temperature, the mixture was neutralized to pH 7 with 1N HCl at 0° C. and then extracted with EtOAc (×2). The combined organic layers were dried (Na2SO4) and concentrated. The residue was purified using column (silica gel) chromatography (hexanes:EtOAc 1:1 to EtOAc). Yield: 0.2 g, white solid, 34%. m/z (ES+) 283 (M+H)+. 1H NMR (400 MHz, Chloroform-d) δ 7.84 (s, 1H), 7.35 (s, 1H), 4.48 (t, 2H), 4.19-4.10 (m, 1H), 2.58 (s, 3H), 2.30-2.19 (m, 2H), 2.11-1.95 (m, 3H), 1.85-1.76 (m, 1H), 1.45 (t, 3H).