Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:22][CH:21]=2)([C:13]2[N:14](C=C)[CH:15]=[CH:16][N:17]=2)[OH:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Mn]([O-])(=O)(=O)=O.[K+]>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:22][CH:21]=2)([C:13]2[NH:14][CH:15]=[CH:16][N:17]=2)[OH:12])=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C=Cn1ccnc1C(O)(c1ccc(C(C)(C)C)cc1)c1ccc(C(C)(C)C)cc1
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Product: CC(C)(C)c1ccc(C(O)(c2ccc(C(C)(C)C)cc2)c2ncc[nH]2)cc1

Procedure:
This compound was prepared by the procedure indicated in Example XXII B using 8 g. (0.02 mol) of α,α-bis(p-tert.-butylphenyl)-1-vinylimidazole-2-methanol, 250 ml. of 4% potassium permanganate solution and 3.3 g. of solid potassium permanganate (total permanganate 0.08 mol). After removal of manganese dioxide and excess permanganate, the organic solvents were distilled off and the remaining liquid was poured into water. A precipitate was formed, which was filtered off and crystallised from a mixture of isopropyl alcohol and petroleum ether (boiling range 28°-40° C.). Melting point 215°-216° C.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[C:12]([CH3:13])=[N:11][NH:10][C:9]=2[OH:14])[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH:22]([CH3:33])[C:23]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=1[Cl:32])=[O:24]>CN(C=O)C>[Cl:32][C:26]1[CH:27]=[C:28]([Cl:31])[CH:29]=[CH:30][C:25]=1[C:23](=[O:24])[CH:22]([O:14][C:9]1[NH:10][N:11]=[C:12]([CH3:13])[C:8]=1[N:4]1[C:5]([CH3:7])=[N:6][C:2]([CH3:1])=[N:3]1)[CH3:33]
Reactant: Cc1nc(C)n(-c2c(C)n[nH]c2O)n1
Reactant: CC(Br)C(=O)c1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1nc(C)n(-c2c(C)n[nH]c2OC(C)C(=O)c2ccc(Cl)cc2Cl)n1
Temperature: 50 °C
Reaction time: 1.5 h

Procedure:
To a stirring solution of 4-(3,5-dimethyl-[1,2,4]triazol-1-yl)-5-methyl-2H-pyrazol-3-ol (Intermediate KF) (97 mg, 0.502 mmol) and cesium carbonate (164 mg, 0.502 mmol) in DMF (1.158 ml) at 50° C. is added 2-bromo-1-(2,4-dichloro-phenyl)-propan-1-one (Intermediate AA) (142 mg, 0.502 mmol) in DMF (0.772 ml). The reaction mixture is stirred under N2 at 50° C. for 1.5 hours and then left to stand @ RT overnight. The resulting suspension is filtered and the filtrate is concentrated in vacuo. Purification by trituration from EtOAc affords the title product; MS: m/z 394.0 [M+H]+
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[Cl:19][C:20]1[CH:21]=[C:22]([C:26]2[S:30][CH:29]=[N:28][C:27]=2[C:31](O)=[O:32])[CH:23]=[CH:24][CH:25]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:31]([C:27]3[N:28]=[CH:29][S:30][C:26]=3[C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([Cl:19])[CH:21]=3)=[O:32])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)c1ncsc1-c1cccc(Cl)c1
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2cc(NC(=O)c3ncsc3-c3cccc(Cl)c3)cn2)o1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and 5-(3-chloro-phenyl)-thiazole-4-carboxylic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][C:10]2[C:11](=[O:20])[N:12]=[C:13]([NH:16][N+:17]([O-:19])=[O:18])[NH:14][CH:15]=2)=[CH:5][N:4]=1.[CH3:21]I>C(Cl)(Cl)Cl>[CH3:21][N:14]1[CH:15]=[C:10]([CH2:9][C:6]2[CH:7]=[N:8][C:3]([O:2][CH3:1])=[N:4][CH:5]=2)[C:11](=[O:20])[N:12]=[C:13]1[NH:16][N+:17]([O-:19])=[O:18]
Reactant: CI
Reactant: COc1ncc(Cc2c[nH]c(N[N+](=O)[O-])nc2=O)cn1
Solvent: ClC(Cl)Cl
Product: COc1ncc(Cc2cn(C)c(N[N+](=O)[O-])nc2=O)cn1
Temperature: 23 °C
Reaction time: 8 h
Yield: 16.7 %

Procedure:
A solution of 5-{[2-(methyloxy)-5-pyrimidinyl]methyl}-2-(nitroamino)-4(1H)-pyrimidinone (200 mg, 0.719 mmol) in chloroform (5 mL) was mixed with methyl iodide (0.054 mL, 0.863 mmol). The reaction mixture was stirred at 23° C. overnight. Purification via a reverse phase Biotage then provided the title compound (35 mg, 16.66% yield). LCMS: rt=1.62 min, [M+H+]=293.1
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:26]=[CH:25][C:17]([NH:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:16][CH:15]=3)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[C:28]1[CH:29]=[C:30]([CH3:34])[CH:31]=[CH:32][CH:33]=1.C(=O)([O-])[O-].[K+].[K+]>[Cu].[N+](C1C=CC=CC=1)([O-])=O>[C:19]1([N:18]([C:33]2([N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[CH:29]=3)[CH:32]=[CH:31][C:30]([C:34]3[CH:10]=[CH:9][CH:8]=[CH:13][CH:12]=3)=[CH:29][CH2:28]2)[C:17]2[CH:25]=[CH:26][C:14]([C:11]3[CH:12]=[CH:13][C:8]([NH:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[CH:9][CH:10]=3)=[CH:15][CH:16]=2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: c1ccc(Nc2ccc(-c3ccc(Nc4ccccc4)cc3)cc2)cc1
Reactant: Cc1cccc(I)c1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=[N+]([O-])c1ccccc1
Product: Cc1cccc(N(c2ccccc2)C2(N(c3ccccc3)c3ccc(-c4ccc(Nc5ccccc5)cc4)cc3)C=CC(c3ccccc3)=CC2)c1
Yield: 83.6 %

Procedure:
A 500-ml reactor was charged with 33.6 g (0.10 mol) of N,N'-diphenylbenzidine, 25.0 g (0.11 mol) of m-iodotoluene, 27.6 g (0.2 mol) of potassium carbonate, 2.6 g of copper powder, and 200 ml of nitrobenzene. In an argon stream, the contents were heated under reflux for 24 hours. At the end of reaction, the insoluble was removed by filtration and the solvent was distilled off from the filtrate. The still residue was purified twice through a silica gel column with a 1/2mixture of n-hexane and toluene, obtaining 28.10 g of N,N'-diphenyl-N-[4-(N-phenyl-N-3-methylphenylamino)-biphenyl-4-yl]benzidine (yield 42%).
Reaction SMILES: [NH2:1][C:2]1=[C:3]([C:9]#[N:10])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1.[C:11]([N:19]=[C:20]=[O:21])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:9]([C:3]1=[C:2]([NH:1][C:20]([NH:19][C:11](=[O:18])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:21])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)#[N:10]
Reactant: N#CC1=C(N)CCCCC1
Reactant: O=C=NC(=O)c1ccccc1
Product: N#CC1=C(NC(=O)NC(=O)c2ccccc2)CCCCC1

Procedure:
Prepared as in Example 75a from (Z)-2-aminocyclohept-1-enecarbonitrile and benzoyl isocyanate as a white solid. MS 284 (MH+).
Reaction SMILES: [OH-].[Na+].O.NN.[C:6]([C:9]1[CH:10]=[N:11][CH:12]=[C:13]([Br:15])[CH:14]=1)(=O)[CH3:7]>C(O)COCCO>[Br:15][C:13]1[CH:12]=[N:11][CH:10]=[C:9]([CH2:6][CH3:7])[CH:14]=1
Reactant: CC(=O)c1cncc(Br)c1
Agent: NN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCO
Product: CCc1cncc(Br)c1
Temperature: 140 °C
Yield: 64.5 %

Procedure:
Sodium hydroxide (10 g, 0.25 mol) and hydrazine monohydrate (10 mL) were added to a solution of 3-acetyl-5-bromopyridine (5 g, 25 mmol) dissolved in diethylene glycol (18 mL). The reaction mixture was heated to 140° C. for 6 hours and then partitioned between H2O and Ether. The organic layers were washed with brine, dried over MgSO4 and concentrated. The residue was purified by flash silica gel chromatography (0% to 40% EtOAc in hexanes) to give the title compound (3 g, 65%). 1H NMR (400 MHz, CDCl3): δ 1.26 (t, J=7.6 Hz, 3H), 2.65 (q, J=7.6 Hz, 2H), 7.67 (s, 1H), 8.37 (s, 1H), 8.51 (s, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([C:13]([OH:15])=O)[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[NH2:37][N:38]1[CH2:43][CH2:42][N:41]([S:44]([C:47]2[CH:56]=[CH:55][C:54]3[C:49](=[CH:50][CH:51]=[C:52]([Cl:57])[CH:53]=3)[CH:48]=2)(=[O:46])=[O:45])[CH2:40][C:39]1=[O:58]>CN(C=O)C>[Cl:57][C:52]1[CH:53]=[C:54]2[C:49](=[CH:50][CH:51]=1)[CH:48]=[C:47]([S:44]([N:41]1[CH2:42][CH2:43][N:38]([NH:37][C:13]([CH:10]3[CH2:9][CH2:8][N:7]([C:4]4[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=4)[CH2:12][CH2:11]3)=[O:15])[C:39](=[O:58])[CH2:40]1)(=[O:45])=[O:46])[CH:56]=[CH:55]2
Reactant: O=C(O)C1CCN(c2ccncc2)CC1
Reactant: NN1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1=O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(NN1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1=O)C1CCN(c2ccncc2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 44 %

Procedure:
A solution of 1-(4-pyridinyl)-4-piperidinecarboxylic acid (102 mg) and HOBt (153 mg) in DMF (25 ml) was combined with WSC (192 mg) at 0° C. and stirred at 0° C. for 1 hour. The reaction mixture was combined with 1-amino-4-(6-chloronaphthalene-2-sulfonyl)-2-piperazinone (170 mg) obtained in Example 3 and stirred at room temperature for 2 days. The reaction mixture was concentrated and the residue obtained was partitioned between dichloromethane and aqueous sodium bicarbonate, and the organic phase was washed with saturated aqueous sodium bicarbonate, dried and concentrated to obtain a residue, which was purified by a column chromatography on a basic silica gel (dichloromethane to dichloromethane: methanol=20:1) and crystallized from ethyl acetate/methanol to obtain the title compound (115 mg) as a white powder.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1.[Si]([O:41][CH2:42][C:43]1[CH:48]=[CH:47][C:46]([CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])=[CH:45][C:44]=1[Cl:54])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.O>O1CCCC1>[Cl:54][C:44]1[CH:45]=[C:46]([CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[CH:47]=[CH:48][C:43]=1[CH2:42][OH:41]
Reactant: CCCCCc1ccc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c(Cl)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCc1ccc(CO)c(Cl)c1
Reaction time: 2 h
Yield: 82.2 %

Procedure:
A solution (1.0 M, 2.4 ml) of tetrabutylammonium fluoride/tetrahydrofuran was added to a solution of 1-((tert-butyldiphenylsilyloxy)methyl)-2-chloro-4-(n-pentyl)benzene (890 mg) in tetrahydrofuran (4.5 ml) under ice-cooling, and the mixture was stirred for 2 hr. Water was added to the reaction mixture and the resulting product was extracted three times with ethyl acetate. The organic layers were combined and washed successively with diluted hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=7/1) to give the objective compound (345 mg) as a colorless oil.
Reaction SMILES: [OH-].[Na+].Cl.[NH2:4]O.[C:6]([CH2:14][C:15]([O:17]CC)=O)(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl>O.C(O)C>[C:7]1([C:6]2[O:13][N:4]=[C:15]([OH:17])[CH:14]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Oc1cc(-c2ccccc2)on1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
40 g of sodium hydroxide was dissolved in 200 ml of water and 300 ml of ethanol. 69.5 g of hydroxylamine hydrochloride was added to the solution. A mixed solution of 2N sodium hydroxide and a 3:2 mixture of ethanol and water was added to the solution so that the pH thereof was adjusted to 10.0. 192 g of ethyl benzoylacetate and a mixed solution of 2N sodium hydroxide and a 3:2 mixture of ethanol and water were added dropwise to the solution at the same time under cooling with ice in such a manner that the pH thereof was 10±0.3. After the dropwise addition was finished, the solution was stirred at room temperature for 3 hours. The reaction mixture was then poured into a mixture of 500 g of conc. hydrochloric acid and 500 g of ice. 2.5 l of ethanol was added to the reaction mixture. The reaction mixture was heated under reflux for 3 hours. 2 l of water was added to cool the solution. The resulting crystals were filtered off, washed with water, and dried. (Yield: 98 g (61%); m.p.: 150°-151° C.)
Reaction SMILES: C[O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10]Br)=[CH:6][C:5]=1[Br:12].[CH3:14][N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([CH:24]=[N:25][OH:26])=[C:16]1[CH3:27]>>[Br:12][C:5]1[CH:6]=[C:7]([CH2:10][O:26]/[N:25]=[CH:24]/[C:17]2[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:15]([CH3:14])[C:16]=2[CH3:27])[CH:8]=[CH:9][C:4]=1[C:3]([OH:2])=[O:13]
Reactant: COC(=O)c1ccc(CBr)cc1Br
Reactant: Cc1c(C=NO)c2ccccc2n1C
Product: Cc1c(/C=N/OCc2ccc(C(=O)O)c(Br)c2)c2ccccc2n1C
Yield: 43.8 %

Procedure:
This compound was produced using similar methods as that used in Step 4, example 6, starting with 2-bromo-4-bromomethyl-benzoic acid methyl ester (0.28 g, 0.91 mmol) and 1,2-dimethyl-1H-indole-3-carbaldehyde oxime (0.18 g, 0.96 mmol). The crude material was purified by flash chromatography through silica gel using ethyl acetate/hexanes (50/50 with 1% formic acid) followed by HPLC (65% acetonitrile in 0.1% trifluoroacetic acid solution) and one final recrystallization from ethyl acetate/hexanes to give 2-bromo-4-[({[(1E)-(1,2-dimethyl-1H-indol-3-yl)methylidene]amino}oxy)methyl]benzoic acid (0.16 g, 45%) as a white solid. mp=165-166° C. 1H NMR (400 MHz, DMSO-d6); δ 13.34 (bs, 1H), 8.53 (s, 1H), 7.88 (d, 1H), 7.78 (s, 1H), 7.75 (d, 1H), 7.51 (d, 1H), 7.44 (d, 1H), 7.16 (t, 1H), 7.08 (t, 1H), 5.17 (s, 2H), 3.67 (s, 3H), 2.47 (s, 3H). Mass spec; (ES+) m/z 401.1, (ES−) m/z 399.0. Elemental analysis; Calculated for C19H17BrN2O3: C, 56.87; H, 4.27; N, 6.98. Found: C, 56.84; H, 4.3; N, 6.92.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:22][CH3:23])=[C:4]([N:10]2[C:15](=[O:16])[CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[NH:12][C:11]2=[O:21])[C:5]([F:9])=[CH:6][C:7]=1[Cl:8].[C:24](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[NH2:1][C:2]1[C:3]([O:22][CH3:23])=[C:4]([N:10]2[C:15](=[O:16])[CH:14]=[C:13]([C:17]([F:19])([F:18])[F:20])[N:12]([CH3:24])[C:11]2=[O:21])[C:5]([F:9])=[CH:6][C:7]=1[Cl:8]
Reactant: COc1c(N)c(Cl)cc(F)c1-n1c(=O)cc(C(F)(F)F)[nH]c1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1c(N)c(Cl)cc(F)c1-n1c(=O)cc(C(F)(F)F)n(C)c1=O
Yield: 129.5 %

Procedure:
A solution of 7.5 grams (0.021 mole) of 3-(3-amino-4-chloro-6-fluoro-2-methoxyphenyl)-6-trifluoromethyl-2,4-(1H,3H)-pyrimidinedione, 3.4 grams (0.025 mole) of potassium carbonate, and 3.5 grams (0.025 mole) of methyl iodide in 200 mL of acetone was stirred at ambient temperature for about 18 hours. The reaction mixture was then concentrated under reduced pressure, and the residue was taken up in 200 mL of water. The mixture was extracted with two 100 mL portions of ethyl acetate. The combined extracts were washed with two 50 mL portions of an aqueous saturated sodium chloride solution. The organic layer was dried with magnesium sulfate, filtered, and concentrated under reduced pressure, yielding 6.9 grams of crude product. The dark oil was combined with 7.0 grams of crude product prepared by a similar route to yield a total of 13.9 grams of crude product. The crude product was purified by column chromatography on silica gel, yielding 10.0 grams of title compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:24])[N:19]([CH2:25][CH:26]3[CH2:28][CH2:27]3)[CH:18]=[C:17]4[CH:29]=O)[CH:7]=2)[CH2:3][CH2:2]1.[CH3:32][NH:33][C@@H:34]1[CH2:38][CH2:37][NH:36][CH2:35]1>>[CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:24])[N:19]([CH2:25][CH:26]3[CH2:28][CH2:27]3)[CH:18]=[C:17]4[CH2:29][N:36]3[CH2:37][CH2:38][C@@H:34]([NH:33][CH3:32])[CH2:35]3)[CH:7]=2)[CH2:3][CH2:2]1
Reactant: CN[C@@H]1CCNC1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(C=O)c2c1
Product: CN[C@@H]1CCN(Cc2cn(CC3CC3)c(=O)c3ccc(-c4cc(C(=O)NC5CC5)cc(F)c4C)cc23)C1

Procedure:
The title compound was prepared as a solid by the method of Example 75 step ii) using the product of Example 75 step i) and (R)—N-methylpyrrolidin-3-amine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5](O)=[O:6]>O1CCCC1>[NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[CH2:5][OH:6]
Reactant: Nc1cc(C(=O)O)ccc1F
Solvent: C1CCOC1
Product: Nc1cc(CO)ccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.1 %

Procedure:
3-Amino-4-fluorobenzoic acid (15 g, 97 mmol) in tetrahydrofuran at 0° C. was treated with 1.0M borane-tetrahydrofuran complex (50 mL), stirred overnight at ambient temperature, treated with an additional 130 mL of 1.0M borane-tetrahydrofuran complex, stirred 10 hours, quenched by the addition of methanol, stirred 3 hours at ambient temperature, concentrated and partitioned between aqueous sodium bicarbonate/methylene chloride. The methylene chloride layer was separated, dried (sodium sulfate), filtered, and concentrated. The residue was purified by flash chromatography over silica gel (ethyl acetate:hexanes 1:1) to provide 7.0 g of the title compound.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:26][C:12]3[N:13]=[CH:14][N:15]=[C:16]([NH:17][C@@H:18]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH3:19])[C:11]=3[CH:10]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[Cl:34][CH2:35][C:36](Cl)=[O:37]>C1COCC1>[Cl:34][CH2:35][C:36]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:26][C:12]3[N:13]=[CH:14][N:15]=[C:16]([NH:17][C@@H:18]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH3:19])[C:11]=3[CH:10]=2)=[CH:5][CH:4]=1)=[O:37]
Reactant: O=C(Cl)CCl
Reactant: C[C@@H](Nc1ncnc2[nH]c(-c3ccc(CN)cc3)cc12)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@@H](Nc1ncnc2[nH]c(-c3ccc(CNC(=O)CCl)cc3)cc12)c1ccccc1
Reaction time: 0.5 h

Procedure:
A mixture of 0.21 g (0.6 mmol) [6-(4-aminomethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-((R)-1-phenyl-ethyl)-amine and 94 μl (0.67 mmol) triethylamine in 5 ml dry THF is treated dropwise with a solution of chloro-acetyl chloride (51 μl, 0.64 mmol) in 0.5 ml of dry THF at RT. After stirring for 30 min small amounts of insoluble material is removed by filtration and the filtrate is evaporated. The residue is purified by flash chromatography using ethyl acetate/methanol 100:2 to 100:4 as eluent. The title compound is obtained as light brown solid; HPLC tR=9.36 min; MS-ES+: (M+H)+=420.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:7][CH3:8])[CH2:4][NH:5][CH3:6].C1C=CC=CC=1.[CH3:15][S:16][C:17]([C:20]1[S:24][C:23]([N:25]=[C:26]=[O:27])=[N:22][N:21]=1)([CH3:19])[CH3:18]>CCCCCC>[CH3:15][S:16][C:17]([C:20]1[S:24][C:23]([NH:25][C:26](=[O:27])[N:5]([CH3:6])[CH2:4][CH:3]([O:7][CH3:8])[O:2][CH3:1])=[N:22][N:21]=1)([CH3:19])[CH3:18]
Reactant: CSC(C)(C)c1nnc(N=C=O)s1
Reactant: CNCC(OC)OC
Solvent: c1ccccc1
Solvent: CCCCCC
Product: COC(CN(C)C(=O)Nc1nnc(C(C)(C)SC)s1)OC

Procedure:
At ambient temperatures, 4.2 grams (0.035 mole) of methylaminoacetaldehyde dimethylacetal was added to 50 milliliters of benzene containing 7.1 grams (0.033 equivalents) of the 5-[1-methylthio-1-methylethyl]-1,3,4-thiadiazol-2-yl isocyanate dimer (prepared above). The resulting pink solution was heated to reflux, 100 milliliters of hexane was added, and the solution was cooled, filtered and topped on a roto-vac at 70° C. to yield 11.4 grams of a pale pink viscous oil of 3-[5-(1-methylthio-1-methylethyl)-1,3,4-thiadiazol-2-yl]-1-methyl-1-(2,2-dimethoxy-ethyl)urea.
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[N:3]1[CH:11]1[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]1.[ClH:24].O1CCOCC1>CO>[ClH:24].[ClH:24].[NH:14]1[CH2:13][CH2:12][CH:11]([N:3]2[C:4]3[C:5](=[N:6][CH:7]=[CH:8][CH:9]=3)[NH:10][C:2]2=[O:1])[CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: O=c1[nH]c2ncccc2n1C1CCNCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 87 %

Procedure:
tert-Butyl 4-(2-oxo-2,3-dihydroimidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate (5.97 g, 18.75 mmol) was dissolved in methanol (180 ml). 4M Hydrogen chloride in 1,4-dioxane (50 ml, 200 mmol) was added to the mixture. Reaction stirred at room temperature for 18 hours. Solids were filtered off and washed with methanol. Solids were collected and dried in vacuo. Title compound was obtained as white solid in 87% yield. MS (M+H)+=219.1.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH:9]([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=2[F:26])[S:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([CH3:18])[CH:12]=2)=[CH:4][N:3]=1.C([Li])CCC.CN(C)[CH:34]=[O:35].O>C1(C)C=CC=CC=1>[F:26][C:20]1[CH:21]=[CH:22][C:23]([F:25])=[CH:24][C:19]=1[CH:9]([S:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]([CH3:18])[CH:12]=1)[C:5]1[C:6]([CH3:8])=[CH:7][C:2]([CH:34]=[O:35])=[N:3][CH:4]=1
Reactant: Cc1cc(SC(c2cnc(Br)cc2C)c2cc(F)ccc2F)ccc1F
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc(SC(c2cnc(C=O)cc2C)c2cc(F)ccc2F)ccc1F
Temperature: -40 °C
Reaction time: 0.17 h
Yield: 60.9 %

Procedure:
A solution of 2-bromo-5-[(2,5-difluorophenyl)[(4-fluoro-3-methylphenyl)thio]methyl]-4-methylpyridine (2.0 g, 4.6 mmol) in toluene (50 ml) was cooled to −78° C., and in an argon atmosphere, n-butyllithium (1.54 M hexane solution, 3.6 ml, 5.5 mmol) was added thereto. After stirring for 10 minutes at the same temperature, the mixture was allowed to warm to −40° C., stirred for 30 minutes, and cooled again to −78° C., and then N,N-dimethylformamide (424 μl, 5.5 mmol) was added. After stirring for 30 minutes at the same temperature, water was added thereto, and the mixture was extracted twice with ethyl acetate. The combined organic layer was washed with saturated brine, subsequently dried over anhydrous sodium sulfate, and filtered, and then the filtrate was concentrated under reduced pressure. The resulting residue was subjected to flash silica gel column chromatography. The fraction obtained from an elution with hexane:ethyl acetate=95:5 was concentrated under reduced pressure to obtain the title compound (1.1 g, 2.8 mmol, 63%) as a colorless oily substance.
Reaction SMILES: O[Li].O.[CH2:4]([O:11][N:12]([C@H:25]1[CH2:30][N:29]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C@H:28]([C:38]([O:40]CC)=[O:39])[CH2:27][CH2:26]1)[S:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N+:22]([O-:24])=[O:23])(=[O:15])=[O:14])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl>C1COCC1.O>[CH2:4]([O:11][N:12]([C@H:25]1[CH2:30][N:29]([C:31]([O:33][C:34]([CH3:36])([CH3:37])[CH3:35])=[O:32])[C@H:28]([C:38]([OH:40])=[O:39])[CH2:27][CH2:26]1)[S:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N+:22]([O-:24])=[O:23])(=[O:14])=[O:15])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CCOC(=O)[C@@H]1CC[C@@H](N(OCc2ccccc2)S(=O)(=O)c2ccccc2[N+](=O)[O-])CN1C(=O)OC(C)(C)C
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@H](N(OCc2ccccc2)S(=O)(=O)c2ccccc2[N+](=O)[O-])CC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 36 h
Yield: 95.7 %

Procedure:
LiOH.H2O (2.7 g, 64 mmol) was added to a solution of (2S,5R)-1-tert-butyl 2-ethyl 5-(N-(benzyloxy)-2-nitrophenylsulfonamido)piperidine-1,2-dicarboxylate (9.0 g, 16 mmol) in THF (60 mL) and H2O (60 mL) at rt. The mixture was stirred at rt for 36 hrs., then the reaction mixture was adjusted to pH 4 with 1N HCl, and extracted with EtOAc (3×). The combined organic layer was washed with saturated sodium chloride, dried over Na2SO4 and concentrated to give (2S,5R)-5-(N-(benzyloxy)-2-nitrophenylsulfonamido)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (8.2 g, 95%) as a yellow solid. ESI-MS (EI+, m/z): 558 [M+Na]+.