Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]2(O)[CH2:14][CH2:13][S:12][CH2:11][CH2:10]2)=[C:4]([F:16])[CH:3]=1.Cl.O.N>C(O)(=O)C>[NH2:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]2[CH2:14][CH2:13][S:12][CH2:11][CH:10]=2)=[C:4]([F:16])[CH:3]=1
Reactant: Nc1cc(F)c(C2(O)CCSCC2)c(F)c1
Agent: Cl
Agent: N
Solvent: CC(=O)O
Solvent: O
Product: Nc1cc(F)c(C2=CCSCC2)c(F)c1
Temperature: 0 °C
Reaction time: 18 h
Yield: 98.2 %

Procedure:
4-(4-Amino-2,6-difluoro-phenyl)-tetrahydro-thiopyran-4-o1 (16.7 g, 68 mM) was suspended in a mixture of concentrated hydrochloric acid (200 ml), water (50 ml) and acetic acid (200 ml), BHT (50 mg) added, and the whole stirred under nitrogen at 800 for 18 hours. After cooling, the mixture was made basic by cautious addition of concentrated ammonia, and ice-water. The mixture was then extracted with diethyl ether (2×300 ml), the extracts washed with water (100 ml), brine (200 ml) and dried (magnesium sulfate). Evaporation gave the desired product as a cream solid (15.2 g).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Br:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH2:11]Br>CN(C)C=O>[Br:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH2:11][N:5]1[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]1
Reactant: OC1CCNCC1
Reactant: BrCc1ccccc1Br
Solvent: CN(C)C=O
Product: OC1CCN(Cc2ccccc2Br)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.2 %

Procedure:
0.202 g (0.002 mol) of 4-hydroxypiperidine and 0.55 g (0.0022 mol) of 2-bromobenzyl bromide were dissolved in 5 ml of dimethylformamide and stirred at room temperature for 2 hrs. The solvent was distilled off and the residue was taken up in dichloromethane and washed with sat. bicarbonate solution and sodium chloride solution. The organic phase was dried over sodium sulfate and concentrated. 0.52 g (96%) of 1-(2-bromo-benzyl)-piperidin-4-ol was obtained as a brown oil. MS: me/e (% basic peak)=271, 269 (C12H16BrNO+, 53, 56), 270, 268 (66, 60), 171, 169 (86, 88), 114 (100), 100 (77).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][NH:9][C:10](=O)OC(C)(C)C)=[C:6]([CH3:17])[CH:5]=[C:4]([CH3:18])[N:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1.C(OCC)(=O)C>[CH3:17][C:6]1[CH:5]=[C:4]([CH3:18])[N:3]=[C:2]([OH:1])[C:7]=1[CH2:8][NH:9][CH3:10]
Reactant: Cc1cc(C)c(CNC(=O)OC(C)(C)C)c(O)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNCc1c(C)cc(C)nc1O
Temperature: 70 °C
Yield: 86.6 %

Procedure:
To a solution of tert-butyl (2-hydroxy-4,6-dimethylpyridin-3-yl)methylcarbamate (700 mg, 2.78 mmol) in tetrahydrofuran (25 mL), lithium aluminum hydride (1 g, 26.3 mmol) was added in portions at room temperature. Then the mixture was heated at 70° C. for 15 hours with stirring. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (20 mL). And then water (20 mL) was added to the reaction mixture dropwise. The organic phase was separated and concentrated to provide 4,6-dimethyl-3-((methylamino)methyl)pyridin-2-ol as a pale yellow solid (0.4 g, 87%). LRMS (M+H+) m/z: calcd 166.1. found 166.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N+:12]=2[O-])=[CH:5][CH:4]=1.COS(OC)(=O)=O.[C-:25]#[N:26].[Na+]>C(O)(C)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]2[N:12]=[C:13]([C:25]#[N:26])[CH:14]=[CH:15][CH:16]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C=Cc2cccc[n+]2[O-])cc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CC(C)O
Solvent: COS(=O)(=O)OC
Product: COc1ccc(C=Cc2cccc(C#N)n2)cc1

Procedure:
Following the general method described in example 2b, 2-[2-(4-methoxy-phenyl)-vinyl]-pyridine 1-oxide was reacted first with dimethylsulfate and then with NaCN. After extraction and crystallization the title compound was obtained as a yellow crystalline material. Mp. 121-122° C. (isopropanol), MS: m/e=236 (M+)
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[CH:9]([CH2:20][O:21][CH:22]([F:24])[F:23])[C:10]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])C1C=CC=CC=1>C(O)C.[OH-].[OH-].[Pd+2]>[NH2:8][CH:9]([CH2:20][O:21][CH:22]([F:23])[F:24])[C:10]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11]
Reactant: O=C(NCc1ccccc1)C(COC(F)F)N(Cc1ccccc1)Cc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: NC(COC(F)F)C(=O)NCc1ccccc1
Yield: 92.5 %

Procedure:
2-(Dibenzylamino)-3-(difluoromethoxy)-N-benzylpropanamide (362 mg, 0.863 mmol) was stirred with 10% Pd(OH)2 (200 mg) in ethanol under H2 overnight. The reaction mixture was filtered and concentrated to give 2-amino-N-benzyl-3-(difluoromethoxy)propanamide (195 mg, 93.6%) as a colorless oil. 1H NMR (300 MHz, CDCl3): δ(ppm) 7.83 (t, 1H), 7.25-7.40 (m, 5H), 6.27 (wt, 1H), 4.49 (d, 2H), 4.19 (d, 2H) and 3.68 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:20]2[C@@H:19]3[C@@H:10]([C@H:11]4[C@@:15]([CH2:17][CH2:18]3)([CH3:16])[C@@H:14]([O:21]C(=O)C)[CH2:13][CH2:12]4)[CH2:9][CH2:8][C:7]=2[CH:6]=[C:5]([O:25][CH3:26])[CH:4]=1.CO.C([O-])([O-])=O.[K+].[K+]>C(O)(=O)C>[CH3:1][O:2][C:3]1[C:20]2[C@@H:19]3[C@@H:10]([C@H:11]4[C@@:15]([CH2:17][CH2:18]3)([CH3:16])[C@@H:14]([OH:21])[CH2:13][CH2:12]4)[CH2:9][CH2:8][C:7]=2[CH:6]=[C:5]([O:25][CH3:26])[CH:4]=1
Reactant: COc1cc2c(c(OC)c1)[C@H]1CC[C@]3(C)[C@@H](OC(C)=O)CC[C@H]3[C@H]1CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1cc2c(c(OC)c1)[C@H]1CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]1CC2

Procedure:
4.5 g. of rac.-1,3-dimethoxy-17β-acetoxy-8α-estra-1,3,5(10)-triene is saponified under N2 in 100 ml. of methanol with 13 ml. of aqueous potash solution (10%) by heating for 1.5 hours under reflux. After cooling, the mixture is gently neutralized with glacial acetic acid, concentrated to half its volume, precipitated into ice water/NaCl, and worked up, thus obtaining 4.1 g. of crude product. By recrystallization of 500 mg. from methanol, 330 mg. of final product is obtained, m.p. 153/153.5°-154°C.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][N:11]=1)[C:6]([OH:8])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]2[C:51]3[O:50][C:49]([NH2:52])=[N:48][C:47]=3[C:46]([O:53][CH3:54])=[CH:45][CH:44]=2)=[CH:39][CH:38]=1>C1COCC1.O1CCOCC1.CN(C=O)C>[Cl:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][N:11]=1)[C:6]([NH:52][C:49]1[O:50][C:51]2[C:43]([C:40]3[CH:41]=[CH:42][C:37]([F:36])=[CH:38][CH:39]=3)=[CH:44][CH:45]=[C:46]([O:53][CH3:54])[C:47]=2[N:48]=1)=[O:8]
Reactant: O=C(O)c1ccnc(CCl)c1
Reactant: COc1ccc(-c2ccc(F)cc2)c2oc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: COc1ccc(-c2ccc(F)cc2)c2oc(NC(=O)c3ccnc(CCl)c3)nc12

Procedure:
From 2-chloromethyl-isonicotinic acid, HATU and N-diethylisopropylamine in THF, then treatment with 7-(4-fluoro-phenyl)-4-methoxy-benzooxazol-2-yl-amine in dioxane and DMF. ES-MS m/e (%): 414 (M{37Cl}+H+, 30), 412 (M{35Cl}+H+, 100).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]1[NH:13][C:14]3[CH:19]=[C:18]([CH3:20])[C:17]([CH3:21])=[CH:16][C:15]=3[N:7]1[C:6]2=[O:22])[CH3:2].[CH3:23]Br>>[CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]1[N:13]([CH3:23])[C:14]3[CH:19]=[C:18]([CH3:20])[C:17]([CH3:21])=[CH:16][C:15]=3[N:7]1[C:6]2=[O:22])[CH3:2]
Reactant: CBr
Reactant: CCc1ccc2nc3[nH]c4cc(C)c(C)cc4n3c(=O)c2c1
Product: CCc1ccc2nc3n(C)c4cc(C)c(C)cc4n3c(=O)c2c1

Procedure:
2-Ethyl-6,8,9-Trimethylbenzimidazo[2,1-b]quinazoline-12(6H)one is prepared with 2-ethyl-8,9-dimethylbenzimidazo[2,1-b]-quinazolin-12(6H)one and methyl bromide.
Reaction SMILES: [CH2:1]1[CH2:37][O:36][C:3]([CH2:24][O:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)(/[CH:4]=[CH:5]/[C@H:6]2[C@H:13]([O:14]C(=O)C3C=CC=CC=3)[CH2:12][C@H:11]3[C@@H:7]2[CH2:8][C:9](=[O:23])[O:10]3)[O:2]1.C(=O)([O-])[O-].[K+].[K+].CO.Cl>[Cl-].[Na+].O>[CH2:1]1[CH2:37][O:36][C:3]([CH2:24][O:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)(/[CH:4]=[CH:5]/[C@H:6]2[C@H:13]([OH:14])[CH2:12][C@H:11]3[C@@H:7]2[CH2:8][C:9](=[O:23])[O:10]3)[O:2]1
Reactant: O=C1C[C@@H]2[C@@H](/C=C/C3(COc4ccc5ccccc5c4)OCCO3)[C@H](OC(=O)c3ccccc3)C[C@@H]2O1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: CO
Product: O=C1C[C@@H]2[C@@H](/C=C/C3(COc4ccc5ccccc5c4)OCCO3)[C@H](O)C[C@@H]2O1

Procedure:
A mixture of 500 mg. of (1S,5R,6R,7R)-6-[(E)-3,3-ethylenedioxy-4-(2-naphthyloxy)-1-butenyl]-7-benzoyloxy-2-oxabicyclo[3,3,0]octan-3-one (prepared according to Example 1[a]), 138 mg. of anhydrous potassium carbonate, and 20 ml. of methanol was stirred for 2 hours at room temperature under an argon atmosphere. The mixture was then diluted with 20 ml. of 0.1N hydrochloric acid, agitated for 10 minutes, diluted with brine, and extracted with methylene chloride. The organic phase was washed with brine, dried over magnesium sulfate, and evaporated under vacuum. The residue was recrystallized from diisopropyl ether/methylene chloride, thus obtaining 290 mg. of the title compound as colorless crystals, m.p. 159°. IR: 3600, 1770, 1630, 1600, 1510, 977 cm-1.
Reaction SMILES: [C:1]([CH:4]([CH2:9][C:10]([N:12]1[CH2:17][CH2:16][C@H:15]([NH:18][C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[C@H:14]([O:29][CH3:30])[CH2:13]1)=O)[C:5]([O:7][CH3:8])=[O:6])(=O)[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:40])=CC=1>C1(C)C=CC=CC=1>[CH2:22]([O:21][C:19]([NH:18][C@H:15]1[CH2:16][CH2:17][N:12]([C:10]2[S:40][C:1]([CH3:2])=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:9]=2)[CH2:13][C@H:14]1[O:29][CH3:30])=[O:20])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COC(=O)C(CC(=O)N1CC[C@H](NC(=O)OCc2ccccc2)[C@H](OC)C1)C(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(N2CC[C@H](NC(=O)OCc3ccccc3)[C@H](OC)C2)sc1C
Temperature: 110 °C
Reaction time: 2 h
Yield: 7.3 %

Procedure:
Methyl cis(±)-2-acetyl-4-(4-{[benzyloxy)carbonyl]amino}-3-methoxypiperidin-1-yl)-4-oxobutanoate obtained in Example (188b) (1.1 g) was dissolved in toluene. Lawesson's reagent (660 mg) was added, and the mixture was stirred at 110° C. for two hours. Further, Lawesson's reagent (330 mg) was added, and the mixture was stirred at 110° C. for two hours. The reaction solution was concentrated under reduced pressure, and then the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane=1/10) and recrystallized from methylene chloride/hexane, to obtain 50 mg of the title compound as crystals.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][CH2:19][C:20]3[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=3)[C:23]([OH:25])=[O:24])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:29]O>>[CH3:29][O:24][C:23](=[O:25])[C:22]1[CH:26]=[CH:27][CH:28]=[C:20]([CH2:19][NH:18][C:16]([O:15][CH2:14][CH:12]2[C:13]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[C:6]3[C:11]2=[CH:10][CH:9]=[CH:8][CH:7]=3)=[O:17])[CH:21]=1
Reactant: O=C(NCc1cccc(C(=O)O)c1)OCC1c2ccccc2-c2ccccc21
Reactant: CO
Product: COC(=O)c1cccc(CNC(=O)OCC2c3ccccc3-c3ccccc32)c1

Procedure:
3-[(9H-Fluoren-9-ylmethoxycarbonylamino)-methyl]-benzoic acid (200 mg, 0.54 mmol) was esterified with MeOH using Method B to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[C:11]4[CH2:19][CH2:18][O:17][C:16](=[O:20])[C:12]4=[N:13][CH:14]=3)[CH:9]=[CH:8]2)=[CH:4][CH:3]=1.[OH-:23].[Na+].Cl>CO.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3=[CH:14][N:13]=[C:12]([C:16]([OH:17])=[O:20])[C:11]([CH2:19][CH2:18][OH:23])=[C:10]3[CH:9]=[CH:8]2)=[CH:21][CH:22]=1
Reactant: [OH-]
Reactant: O=C1OCCc2c1ncc1c2ccn1Cc1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C(O)c1ncc2c(ccn2Cc2ccc(F)cc2)c1CCO
Temperature: 60 °C
Yield: 94.6 %

Procedure:
To 7-(4-fluorobenzyl)-1,7-dihydropyrano[3,4-b]pyrrolo[3,2-d]pyridin-4(2H)-one (0.11 g, 0.37 mmol) in methanol (10 mL) was added sodium hydroxide (0.066 g, 1.65 mmol) in water (2.0 mL). The reaction was heated to 60° C. for 3 hours. After cooling down, the reaction mixture was neutralized with 4N hydrochloric acid (0.42 mL, 1.65 mmol). It was concentrated and dried in vacuo to provide the crude title compound as a white powder (0.11 g, 94%). 1H NMR (DMSO-d6) δ; 8.93 (d, 1H, J=1.9 Hz), 8.06 (s, 1H), 7.36 (m, 2H), 7.16 (t, 2H, J=6.6 Hz), 6.96 (s, 1H), 5.63 (s, 2H), 3.66 (t, 2H, J=6.8 Hz), 3.44 (t, 2H, J=6.8 Hz). LCMS (APCl, M+H+): 315.1.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([C:19]2[CH:24]=[CH:23][C:22](Br)=[C:21]([CH2:26][C:27]3[S:28][C:29]([C:32]4[O:33][CH:34]=[CH:35][CH:36]=4)=[CH:30][N:31]=3)[CH:20]=2)[O:7][C@@H:6]1[CH2:37][O:38][C:39](=[O:41])[CH3:40])(=[O:3])[CH3:2].[Cu][C:43]#[N:44]>CN1C(=O)CCC1>[C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([C:43]#[N:44])=[C:21]([CH2:26][C:27]3[S:28][C:29]([C:32]4[O:33][CH:34]=[CH:35][CH:36]=4)=[CH:30][N:31]=3)[CH:20]=2)[O:7][C@@H:6]1[CH2:37][O:38][C:39](=[O:41])[CH3:40])(=[O:3])[CH3:2]
Reactant: N#C[Cu]
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(Br)c(Cc3ncc(-c4ccco4)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: CN1CCCC1=O
Product: CC(=O)OC[C@H]1O[C@@H](c2ccc(C#N)c(Cc3ncc(-c4ccco4)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Yield: 75.8 %

Procedure:
The bromide 58 (300 mg, 0.46 mmol) was added to a microwave reaction tube containing copper(I) cyanide (124 mg, 1.38 mmol) in NMP. The capped reaction tube was placed in a microwave reactor and the mixture irradiated at 230° C. for 30 min. After dilution with EtOAc, the organic layer was washed with 15% NH4OH solution prior to drying over anhydrous MgSO4. After filtration and concentration under reduced pressure, the residue was purified by silica column chromatography to provide the cyanide 59 (208 mg, 76%) as a white solid. MH+597.
Reaction SMILES: [K].[O-]CCCC.Cl[C:8]1[N:16]=[C:15]2[C:11]([N:12]=[CH:13][N:14]2[CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)=[C:10]([NH2:23])[N:9]=1.[CH3:24][O:25][CH2:26][CH:27]([OH:29])[CH3:28]>>[CH3:28][CH:27]([O:29][C:8]1[N:16]=[C:15]2[C:11]([N:12]=[CH:13][N:14]2[CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)=[C:10]([NH2:23])[N:9]=1)[CH2:26][O:25][CH3:24]
Reactant: Nc1nc(Cl)nc2c1ncn2C1CCCCO1
Reactant: COCC(C)O
Agent: CCCC[O-]
Agent: [K]
Product: COCC(C)Oc1nc(N)c2ncn(C3CCCCO3)c2n1
Temperature: 85 °C
Yield: 84.7 %

Procedure:
To a stirred solution of potassium t.butoxide (9.3 g, 82.8 mmol) in 1-methoxy-2-propanol (70 ml) was added 2-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (7 g, 27.6 mmol). The mixture was heated to 80-90° C. for 4 h. Then most of the solvent was removed by evaporation under reduced pressure. The residue was partitioned between water and dichloromethane. The dichloromethane layer was separated, concentrated to give a brown oil (7.2 g, 84.7%).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH3:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[C:12]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]>>[CH3:11][C:4]1[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([N:22]2[CH2:21][CH2:20][N:19]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:24][CH2:23]2)[CH:3]=1
Reactant: Cc1ccc([N+](=O)[O-])c(F)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: Cc1ccc([N+](=O)[O-])c(N2CCN(C(=O)OC(C)(C)C)CC2)c1
Yield: 97 %

Procedure:
Method 1 was followed using 3-fluoro-4-nitrotoluene (1.0 eq), 1-Boc-piperazine (1.2 eq), and TEA (2.0 eq) at 55° C. for 48 hours yielding tert-butyl 4-(5-methyl-2-nitrophenyl)piperazine-1-carboxylate (97%). LCMS (m/z): 322.1 (MH+); LC Rt=3.43 min.
Reaction SMILES: CC1(C)C(C)(C)OB(/[CH:9]=[CH:10]/[CH2:11][CH2:12][O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)O1.[NH2:21][C:22]1[CH:29]=[CH:28][CH:27]=[C:26](Br)[C:23]=1[C:24]#[N:25]>>[NH2:21][C:22]1[CH:29]=[CH:28][CH:27]=[C:26](/[CH:9]=[CH:10]/[CH2:11][CH2:12][O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[C:23]=1[C:24]#[N:25]
Reactant: CC1(C)OB(/C=C/CCOC2CCCCO2)OC1(C)C
Reactant: N#Cc1c(N)cccc1Br
Product: N#Cc1c(N)cccc1/C=C/CCOC1CCCCO1
Yield: 47 %

Procedure:
Prepared as in Example 270a from (E)-4,4,5,5-tetramethyl-2-(4-(tetrahydro-2H-pyran-2-yloxy)but-1-enyl)-1,3,2-dioxaborolane (Example 273b) and 2-amino-6-bromobenzonitrile in 47% yield as a yellow gum. 1H NMR (400 MHz, CDCl3) δ 1.570 (m, 4H), 1.727 (m, 2H), 1.837 (m, 2H), 2.565 (q, J=6 Hz, 2H), 3.541 (m, 2H), 3.879 (m, 2H), 4.387 (br. s, 2H), 4.635 (m, 1H), 6.423 (d of t, J=7 Hz, 16 Hz, 1H), 6.586 (d, J=8 Hz, 1H), 6.710 (d, J=16 Hz, 1H), 6.905 (d, J=8 Hz, 1H), 7.237 (t, J=8 Hz, 1H).
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH:11]1[CH2:17][CH2:16][CH2:15][NH:14][CH2:13][C:12]1=[O:18]>>[CH3:7][N:6]1[C:2]([N:14]2[CH2:15][CH2:16][CH2:17][NH:11][C:12](=[O:18])[CH2:13]2)=[C:3]([N+:8]([O-:10])=[O:9])[CH:4]=[N:5]1
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Reactant: O=C1CNCCCN1
Product: Cn1ncc([N+](=O)[O-])c1N1CCCNC(=O)C1
Yield: 92 %

Procedure:
Reaction of 5-chloro-1-methyl-4-nitro-1H-pyrazole and 1,4-diazepan-2-one gave 4-(1-methyl-4-nitro-1H-pyrazol-5-yl)-1,4-diazepan-2-one as an off-white solid (0.27 g, 92%). 1H NMR (400 MHz, CDCl3) δ 8.02 (s, 1H), 6.10 (s, 1H), 3.95-3.86 (m, 2H), 3.80 (s, 3H), 3.51-3.44 (m, 2H), 3.43-3.37 (m, 2H), 2.04-1.97 (m, 2H)
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[N:14]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[CH:15]=[C:16]([C:18]#[N:19])[N:17]=2)=[O:12])=[C:6]([C:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH:29]=2)[CH:5]=1)(=[O:3])[CH3:2].[CH:34](O)([OH:36])[CH3:35].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1.CCOC(C)=O>[C:28]1([C:6]2[CH:5]=[C:4]([C:1]3([CH3:2])[O:36][CH2:34][CH2:35][O:3]3)[CH:9]=[CH:8][C:7]=2[NH:10][C:11]([C:13]2[N:14]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:26])([CH3:27])[CH3:25])[CH:15]=[C:16]([C:18]#[N:19])[N:17]=2)=[O:12])[CH2:33][CH2:32][CH2:31][CH2:30][CH:29]=1
Reactant: CC(=O)c1ccc(NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)c(C2=CCCCC2)c1
Reactant: CC(O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: CC1(c2ccc(NC(=O)c3nc(C#N)cn3COCC[Si](C)(C)C)c(C3=CCCCC3)c2)OCCO1
Yield: 68 %

Procedure:
A solution of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid (4-acetyl-2-cyclohex-1-enyl-phenyl)-amide (as prepared in the previous step, 135 mg, 0.290 mmol), ethanediol (363 mg, 5.80 mmol) and catalytic p-toluenesulfonic acid (PTSA) in 21 mL of benzene were heated at reflux under Dean-Stark conditions for 4 h. The reaction was diluted with EtOAc (25 mL), washed with water (3×20 mL), dried (Na2SO4), and concentrated in vacuo. Purification of the residue using preparative TLC (10% MeOH—CHCl3) afforded 100 mg (68%) of the title compound as a white solid. Mass spectrum (ESI, m/z): Calcd. for C27H36N4O4Si, 509.2 (M+H). found 509.0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:16][O:17][CH2:18][CH2:19]Br.O>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([O:9][CH2:19][CH2:18][O:17][CH3:16])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Oc1ccc(F)c(F)c1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCOc1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.1 %

Procedure:
To a suspension of 3,4-difluorophenol (2 g) and cesium carbonate (7.51 g) in N,N-dimethylformamide (15 mL) was added 2-methoxyethyl bromide (2.14 g), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The extract was washed with water twice and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=5/1) to give 3,4-difluoro-1-(2-methoxyethoxy)-benzene (2.49 g). To the solution of the obtained 3,4-difluoro-1-(2-methoxyethoxy)benzene (1.47 g) in tetrahydrofuran (39 mL) was added n-butyllithium (2.64 mol/L n-hexane solution, 3.25 mL) at −78° C., and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture was added dry ice (10 g), and the mixture was stirred at the same temperature for 30 minutes, and then stirred at room temperature for 30 minutes. To the reaction mixture was added 2 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give the title compound (1.48 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:7][CH:6]([NH:8][C:9]2[C:14]([C:15]#[N:16])=[CH:13][N:12]=[C:11](Cl)[N:10]=2)[CH2:5][C:4]([CH3:19])([CH3:18])[NH:3]1.[CH:21]1([C:24]2[CH:25]=[C:26]([NH2:36])[CH:27]=[C:28]([N:31]3[CH:35]=[N:34][N:33]=[N:32]3)[C:29]=2[F:30])[CH2:23][CH2:22]1>CC(O)C>[CH3:1][C:2]1([CH3:20])[CH2:7][CH:6]([NH:8][C:9]2[C:14]([C:15]#[N:16])=[CH:13][N:12]=[C:11]([NH:36][C:26]3[CH:27]=[C:28]([N:31]4[CH:35]=[N:34][N:33]=[N:32]4)[C:29]([F:30])=[C:24]([CH:21]4[CH2:23][CH2:22]4)[CH:25]=3)[N:10]=2)[CH2:5][C:4]([CH3:19])([CH3:18])[NH:3]1
Reactant: Nc1cc(C2CC2)c(F)c(-n2cnnn2)c1
Reactant: CC1(C)CC(Nc2nc(Cl)ncc2C#N)CC(C)(C)N1
Solvent: CC(C)O
Product: CC1(C)CC(Nc2nc(Nc3cc(C4CC4)c(F)c(-n4cnnn4)c3)ncc2C#N)CC(C)(C)N1
Temperature: 60 °C
Yield: 34.8 %

Procedure:
A mixture of 4-(2,2,6,6-tetramethylpiperidin-4-ylamino)-2-chloropyrimidine-5-carbonitrile (112 mg, 0.380 mmol, 1 equiv), 3-cyclopropyl-4-fluoro-5-(1H-tetrazol-1-yl)benzenamine (100 mg, 0.456 mmol, 1.2 equiv), and PTSA monohydrate (58 mg, 0.304 mmol, 0.8 equiv) in IPA (4 mL) were heated to 60° C. for 5 days. After cooling to ambient temperature, the crude mixture was concentrated to dryness. The residue was taken in ice-cold water and EtOAc then adjusted to ca. pH 12-14 with 1N NaOH. The aqueous and organic layers were partitioned, and the aqueous layer was extracted with EtOAc (1×150 mL). The combined organic extracts were dried (Na2SO4), filtered, and the solvent removed under vacuum. The crude product was submitted to the analytical department for purification by reverse-phase HPLC using 0.1% formic acid as a modifier in water and acetonitrile (compound unstable in TFA). The product as the formate salt was taken in ice-cold water and EtOAc then adjusted to ca. pH 12-14 with 1N NaOH. The aqueous and organic layers were partitioned, and the aqueous layer was extracted with EtOAc (2×150 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated to give desired compound (63 mg, 35%) as a solid.