Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:21]1[CH2:26][CH2:25][CH:24]([C:27]([NH:29][NH2:30])=[O:28])[CH2:23][CH2:22]1>>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:30][NH:29][C:27]([CH:24]1[CH2:25][CH2:26][O:21][CH2:22][CH2:23]1)=[O:28])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NNC(=O)C1CCOCC1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Product: O=C(NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1)C1CCOCC1
Yield: 54.6 %

Procedure:
Following a procedure analogous to Example 27, from the carboxylic acid (6b, 390 mg, 1.41 mmol) of Example 9 or 16 and tetrahydro-2H-pyran-4-carbohydrazide (952 mg) described in Reference Example 2, 309.8 mg of the title compound was afforded (yield 54.5%).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:19]([CH3:21])[CH3:20])[C:7]([N:9]1[C@H:14]([C:15](O)=[O:16])[CH:13]2[CH2:18][CH:10]1[CH2:11][CH2:12]2)=[O:8])=[O:4].C([N:25](C(C)C)CC)(C)C.[OH-].[NH4+]>C(#N)C.O>[C:15]([C@@H:14]1[CH:13]2[CH2:18][CH:10]([CH2:11][CH2:12]2)[N:9]1[C:7](=[O:8])[C@@H:6]([NH:5][C:3](=[O:4])[O:2][CH3:1])[CH:19]([CH3:21])[CH3:20])(=[O:16])[NH2:25]
Reactant: CCN(C(C)C)C(C)C
Reactant: COC(=O)N[C@H](C(=O)N1C2CCC(C2)[C@H]1C(=O)O)C(C)C
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: COC(=O)N[C@H](C(=O)N1C2CCC(C2)[C@H]1C(N)=O)C(C)C
Reaction time: 1 h

Procedure:
(3S)-2-((S)-2-(Methoxycarbonylamino)-3-methylbutanoyl)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid (1.78 g, 5.97 mmol), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (2.49 g, 5.56 mmol), and diisopropylethylamine (2.61 mL, 14.92 mmol) were dissolved in acetonitrile (30 mL) at ambient temperature and treated by dropwise addition with 28% ammonium hydroxide solution (2.49 g, 17.98 mmol). The resulting mixture was stirred for 1 hour and then diluted with water and extracted into dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated to give methyl (2S)-1-((3S)-3-carbamoyl-2-azabicyclo[2.2.1]heptan-2-yl)-3-methyl-1-oxobutan-2-ylcarbamate as a white waxy solid.
Reaction SMILES: [I:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.Br[CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[C:24]([O:23][C:21]([CH2:20][N:8]1[C:4]2[CH:3]=[C:2]([I:1])[CH:18]=[CH:17][C:5]=2[N:6]([C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[C:7]1=[O:9])=[O:22])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(C)(C)OC(=O)n1c(=O)[nH]c2cc(I)ccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)Cn1c(=O)n(C(=O)OC(C)(C)C)c2ccc(I)cc21

Procedure:
A mixture of 1.90 g (5.27 mmol) of tert-butyl 5-iodo-2-oxo-2,3-dihydro-benzimidazole-1-carboxylate (VIb), 1.13 g (5.80 mmol) of tert-butyl bromoacetate and 2.23 g (6.86 mmol) of cesium carbonate in acetonitrile (60 ml) was heated under reflux for 3 h. The solvent was removed in vacuo, water was added to the residue, and the aqueous mixture was extracted four times with ethyl acetate. The combined organic phases were washed with saturated NaCl solution and dried over magnesium sulfate, and the solvent was removed in vacuo. The residue was purified by chromatography on silica gel (mobile phase gradient 15-40% ethyl acetate in heptane). Yield: 2.26 g (90%) of white solid.
Reaction SMILES: [NH:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[CH:6]=[CH:5][N:4]=1)[NH2:2].[F:15][C:16]([F:21])([F:20])[C:17](O)=O>>[F:15][C:16]([F:21])([F:20])[C:17]1[N:4]2[CH:5]=[CH:6][C:7]3[C:12]([C:3]2=[N:1][N:2]=1)=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=3
Reactant: COc1ccc2ccnc(NN)c2c1
Reactant: O=C(O)C(F)(F)F
Product: COc1ccc2ccn3c(C(F)(F)F)nnc3c2c1
Yield: 70 %

Procedure:
A solution of 1-hydrazino-7-methoxyisoquinoline in excess trifluoroacetic acid was allowed to reflux for 2 hours. Excess acid was removed in vacuo and the residue was slurried in water and treated with sodium bicarbonate solution. The solid was removed by filtration and recrystallized from cyclohexane to give the product in a yield of 70%; m.p. 152°-154°C.
Reaction SMILES: [NH2:1][C:2]1[N:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:6][C:3]=1[CH:4]=O.[NH2:18][C:19]1[CH:20]=[C:21]([S:26]([NH2:29])(=[O:28])=[O:27])[CH:22]=[CH:23][C:24]=1[NH2:25].OS([O-])=O.[Na+].CCOC(C)=O>CC(N(C)C)=O>[NH2:1][C:2]1[C:3]([C:4]2[NH:18][C:19]3[CH:20]=[C:21]([S:26]([NH2:29])(=[O:27])=[O:28])[CH:22]=[CH:23][C:24]=3[N:25]=2)=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:8][N:9]=1
Reactant: Nc1ccc(S(N)(=O)=O)cc1N
Reactant: COc1ccc(-c2cnc(N)c(C=O)c2)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: COc1ccc(-c2cnc(N)c(-c3nc4ccc(S(N)(=O)=O)cc4[nH]3)c2)cc1
Temperature: 200 °C
Reaction time: 1 h
Yield: 15 %

Procedure:
2-amino-5-(4-methoxyphenyl)nicotinaldehyde (61.6 mg, 0.27 mmol), 3,4-diaminobenzene-1-sulphonamide (59.7 mg, 0.32 mmol), and NaHSO3 (29.2 mg, 0.4 mmol) were suspended in 3 ml dimethylacetamide. The reaction mixture was heated to 200° C. for 10 min in the SmithSynthesizer™ microwave instrument. Upon cooling, 5 ml of 4:1H2O/EtOAc was added to afford a slurry which was stirred for 1 h. The solids were collected via vacuum filtration, washed with water and then diethyl ether, and dried under vacuum for 15 hours to yield 2-[2-amino-5-(4-methoxyphenyl)pyridin-3-yl]-1H-benzimidazole-6-sulfonamide (16 mg).
Reaction SMILES: C[O:2][C:3](=[O:41])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][O:14]/[N:15]=[CH:16]/[C:17]2[CH:22]=[CH:21][C:20]([C:23](F)(F)F)=[CH:19][CH:18]=2)=[CH:6][C:5]=1[NH:27][C:28](=[O:40])[C:29]1[CH:34]=[CH:33][C:32]([O:35][C:36]([F:39])([F:38])[F:37])=[CH:31][CH:30]=1.CO.[OH-].[Li+]>O1CCCC1>[C:20]1([C:23]2[CH:8]=[CH:9][CH:4]=[CH:5][CH:6]=2)[CH:21]=[CH:22][C:17](/[CH:16]=[N:15]/[O:14][CH2:13][CH2:12][CH2:11][O:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:2])=[O:41])=[C:5]([NH:27][C:28](=[O:40])[C:29]3[CH:30]=[CH:31][C:32]([O:35][C:36]([F:37])([F:38])[F:39])=[CH:33][CH:34]=3)[CH:6]=2)=[CH:18][CH:19]=1
Reactant: COC(=O)c1ccc(OCCCO/N=C/c2ccc(C(F)(F)F)cc2)cc1NC(=O)c1ccc(OC(F)(F)F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(Nc1cc(OCCCO/N=C/c2ccc(-c3ccccc3)cc2)ccc1C(=O)O)c1ccc(OC(F)(F)F)cc1
Reaction time: 2 h
Yield: 192.8 %

Procedure:
This compound was produced using similar methods as those used in Step 6, example 28, starting with 2-{[4-(trifluoromethoxy)benzoyl]amino}-4-{3-[({(1E)-[4-(trifluoromethyl)phenyl]methylidene}amino)oxy]propoxy}benzoic acid methyl ester (0.31 g, 0.52 mmol), 1:1 methanol:tetrahydrofuran (10 mL) and 4N aqueous lithium hydroxide solution (0.39 mL). The crude material was crystallized from hot chloroform (10 mL) by the addition of room temperature hexanes (100 mL), and allowing the mixture to sit for 2 hours. The product was isolated and then triturated with hexanes to give 4-[3-({[(1E)-1,1′-biphenyl-4-ylmethylidene]amino}oxy)propoxy]-2-{[4-(trifluoromethoxy)benzoyl]amino}benzoic acid (0.29 g, 97%) as a white solid. mp=187.5-188.5° C. 1H NMR (500 MHz, DMSO-d6); δ 13.47 (bs, 1H), 12.45 (s, 1H), 8.38 (s,2H), 8.04 (d, 2H), 7.99 (d, 1H), 7.81-7.72 (AA′BB′, 4H), 7.58 (d, 2H), 6.80 (d, 1H), 4.34 (t, 2H), 4.20 (t, 2H), 2.18 (m, 2H). Mass spec (MW 570.44); (ES−) m/z 569.39. Elemental analysis; Calculated for C26H20F6N2O6: C, 54.74; H, 3.53; N, 4.91. Found: C, 54.05; H, 3.13; N, 4.80.
Reaction SMILES: O.[OH-].[Li+].[F:4][C:5]([F:32])([F:31])[C:6]1[N:10]2[N:11]=[C:12]([N:15]3[CH2:20][CH2:19][CH:18]([C:21]4[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=[O:26])=[CH:23][CH:22]=4)[CH2:17][CH2:16]3)[CH:13]=[CH:14][C:9]2=[N:8][N:7]=1>CO.O>[F:32][C:5]([F:4])([F:31])[C:6]1[N:10]2[N:11]=[C:12]([N:15]3[CH2:20][CH2:19][CH:18]([C:21]4[CH:30]=[CH:29][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=4)[CH2:17][CH2:16]3)[CH:13]=[CH:14][C:9]2=[N:8][N:7]=1
Reactant: COC(=O)c1ccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Temperature: 50 °C
Reaction time: 16 h
Yield: 96.7 %

Procedure:
Lithium hydroxide monohydrate (0.154 g, 3.66 mmol) was added to methyl 4-[1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]benzoate (1.35 g, 3.33 mmol) in a mixture of methanol (30 mL) and water (15 mL). The resulting suspension was stirred at 50° C. for 16 hours. The mixture was cooled to room temperature, the methanol evaporated and the aqueous residue treated with 1M citric acid until precipitation ceased. The precipitate was collected by filtration, washed with water and dried to give 4-[1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]benzoic acid (1.26 g, 97%) as a solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[O:5][C:6]2[CH:12]=[CH:11][C:10]([C:13]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=3)=[CH:9][C:7]=2[CH:8]=1.C(N(CC)CC)C.[C:28]1([CH3:38])[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1>C(#N)C.CN(C)C1C=CN=CC=1>[CH3:38][C:28]1[CH:33]=[CH:32][C:31]([S:34]([O:1][CH2:2][CH2:3][C:4]2[O:5][C:6]3[CH:12]=[CH:11][C:10]([C:13]4[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=4)=[CH:9][C:7]=3[CH:8]=2)(=[O:36])=[O:35])=[CH:30][CH:29]=1
Reactant: N#Cc1ccc(-c2ccc3oc(CCO)cc3c2)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)OCCc2cc3cc(-c4ccc(C#N)cc4)ccc3o2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 80.5 %

Procedure:
The product from Example 1B (2.03 kg, 7.71 mol) in acetonitrile (31.8 kg) was treated in succession with triethylamine (1.86 kg, 18.34 mol), 4-(dimethylamino)pyridine 0.10 kg, 0.87 mol), and p-toluenesulfonyl chloride (3.50 kg, 17.99 mol). After stirring at room temperature for about 5 hours, the reaction mixture was distilled to a minimum volume and treated with isopropyl alcohol (24.1 kg). The suspension was heated at about 30° C. for 1 hour, then cooled to about 5° C., filtered, and the filter cake was washed with isopropyl alcohol (5.20 kg). The solid was dried at 50° C. to provide 2.59 kg (80% yield) of the title compound. MS-DCI (M+NH4)+ m/z at 435; 1H NMR (CDCl3 at 400 MHz) δ 2.38 (s, 3H), 3.15 (t, 2H), 4.38 (t, 2H), 6.50 (s, 1H) 7.18-7.24 (m, 2H), 7.37-7.46 (m, 2H), 7.67-7.74 (m, 7H); 13C NMR (CDCl3 at 100 MHz) δ 21.9, 28.9, 67.2, 104.4, 110.3, 111.2, 118.7, 119.2, 123.0,127.5, 127.6, 129.0, 129.4, 132.2, 132.4, 133.9, 144.4, 145.7, 154.1, 154.5.
Reaction SMILES: [OH:1]O.S(=O)(=O)(O)O.[Cl:8][C:9]1[CH:30]=[CH:29][C:12]2[C:13]3[C:14](=[CH:25][NH:26][C:27]=3[CH3:28])[CH2:15][N:16]=[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:11]=2[CH:10]=1>C(O)(=O)C.C(Cl)Cl.[OH-].[NH4+]>[Cl:8][C:9]1[CH:30]=[CH:29][C:12]2[C:13]3[CH:27]([CH3:28])[NH:26][C:25](=[O:1])[C:14]=3[CH2:15][N:16]=[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:11]=2[CH:10]=1
Reactant: Cc1[nH]cc2c1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Reactant: OO
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC1NC(=O)C2=C1c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Reaction time: 1 h

Procedure:
In one portion, 1 ml of 30% hydrogen peroxide was added to 40 ml of a 1% solution of concentrated sulfuric acid in acetic acid. After stirring for 1 hour, 2.0 g (5.8 mmol) of 8-chloro-6-(2-chlorophenyl)-1-methyl-2H,4H-pyrrolo[3,4-d][2]benzazepine were added, and the resulting mixture was stirred at room temperature for 30 minutes. The mixture was diluted with methylene chloride and neutralized with concentrated ammonium hydroxide solution. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated at reduced pressure to a dark residue. Crystallization from ethyl acetate gave 8-chloro-6-(2-chlorophenyl)-1,4-dihydro-1-methylpyrrolo[3,4-d][2]benzazepin-3(2H)-one as pale yellow prisms, mp 239°-241° C.
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:30][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:36]3[CH:37]=[CH:38][C:33]([O:32][CH3:31])=[CH:34][CH:35]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:22][CH2:23][N:24]([CH:27]([CH3:28])[CH3:29])[CH2:25][CH2:26]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Reactant: COc1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(-n2c(C(=O)N3CCC(F)(F)CC3)cc3cc(C(=O)N4CCN(C(C)C)CC4)ccc32)cc1
Yield: 41 %

Procedure:
The title compound was synthesized in analogy to example 66, from (4,4-difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone (example 32), 4-methoxyphenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a colorless foam (41%).
Reaction SMILES: C(O[C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[C:15]([CH:17]([CH3:19])[CH3:18])[C:14]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:13][C:12]=2[O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:8][N:7]=1)=[O:5])C.[CH2:36]([NH2:38])[CH3:37]>CO>[CH2:36]([NH:38][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[C:15]([CH:17]([CH3:18])[CH3:19])[C:14]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:13][C:12]=2[O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:8][N:7]=1)=[O:5])[CH3:37]
Reactant: CCN
Reactant: CCOC(=O)c1cc(-c2cc(C(C)C)c(OCc3ccccc3)cc2OCc2ccccc2)on1
Solvent: CO
Product: CCNC(=O)c1cc(-c2cc(C(C)C)c(OCc3ccccc3)cc2OCc2ccccc2)on1
Temperature: 120 °C

Procedure:
5-(2,4-Bis-benzyloxy-5-isopropyl-phenyl)-isoxazole-3-carboxylic acid ethyl ester was dissolved in excess 2M ethylamine in methanol and heated in the Smith Synthesiser microwave at 120° C. for 600 seconds. The solution was concentrated in vacuo to give a solid which was purified by hexane trituration, to give 5-(2,4-Bis-benzyloxy-5-isopropyl-phenyl)isoxazole-3-carboxylic acid ethylamide.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7])=[O:2].[F:11][C:12]([Si](C)(C)C)([F:14])[F:13].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[F:11][C:12]([F:14])([F:13])[CH:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7])[OH:2]
Reactant: N#Cc1cccc(C=O)c1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: N#Cc1cccc(C(O)C(F)(F)F)c1
Yield: 92 %

Procedure:
According to Reference Example 8-12, by use of 3-formylbenzonitrile (500 mg, 3.81 mmol), (trifluoromethyl)trimethylsilane (678 μL, 4.58 mmol), tetrabutylammonium fluoride (a 1.0 mol/L solution in tetrahydrofuran, 381 μL, 0.381 mmol) and tetrahydrofuran (10 mL), the mixture was stirred and reacted at room temperature for 3 hours. Then, purification by silica gel column chromatography (hexane/ethyl acetate=7/3) was performed to give 3-(2,2,2-trifluoro-1-hydroxyethyl)benzonitrile (Compound CZ) (705 mg, yield: 92%).
Reaction SMILES: [CH3:1][C:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]([NH2:11])[CH:3]=1.[CH3:12][C:13]1[C:18]([C:19](O)=[O:20])=[CH:17][N:16]=[C:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[N:14]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][C:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]([NH:11][C:19]([C:18]2[C:13]([CH3:12])=[N:14][C:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)=[N:16][CH:17]=2)=[O:20])[CH:3]=1
Reactant: Cc1nc(-c2ccccn2)ncc1C(=O)O
Reactant: Cc1cn(N)c2cccnc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccccn2)ncc1C(=O)Nn1cc(C)c2ncccc21
Temperature: 150 °C
Reaction time: 1 h

Procedure:
A mixture of 3-methyl-pyrrolo[3,2-b]pyridin-1-yl amine (839 mg, <5.71 mmol), 4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid (1.32 g, 6.13 mmol), HATU (2.6 g, 6.85 mmol), DIPEA (2.21 g 17.1 mmol) in DMF (17 mL) is stirred at 150° C. for 1 h. The reaction is quenched with water and ether. The water layer is concentrated in vacuo. The residue is chromatographed through silica gel eluting with a mixture of DCM, MeOH and triethylamine (9.5:0.5:0.05) to afford 4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid (3-methyl-pyrrolo[3,2-b]pyridin-1-yl)-amide (134 mg). MS: 345 345 (M+H); 1H NMR (300 MHz, CD3OD): δ 9.22 (s, 1H), 8.79 (d, 1H), 8.64 (d, 1H), 8.40(d, 1H), 8.05 (t, 1H), 7.87 (d, 1H), 7.60 (t, 1H), 7.49 (s, 1H) 7.30 (dd, 1H), 2.87 (s, 3H), 2.42 (s, 3H).
Reaction SMILES: [Na+].[I-].[F:3][C:4]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[C:5]=1[CH2:6][NH:7][C:8]([NH2:10])=[O:9].[CH2:19]=[C:20]1O[C:22](=[O:23])[CH2:21]1.C[Si](Cl)(C)C>C(#N)C.O>[F:3][C:4]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:16])([F:17])[F:18])[C:5]=1[CH2:6][N:7]1[C:20]([CH3:19])=[CH:21][C:22](=[O:23])[NH:10][C:8]1=[O:9]
Reactant: NC(=O)NCc1c(F)cccc1C(F)(F)F
Reactant: C=C1CC(=O)O1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Cc1cc(=O)[nH]c(=O)n1Cc1c(F)cccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 20 h
Yield: 81.6 %

Procedure:
NaI (43.9 g, 293 mmol) was added to N-[2-fluoro-6-(trifluoromethyl)benzyl]urea 1b (46.2 g, 19.6 mmol) in 365 mL of acetonitrile. The resulting mixture was cooled in an ice-water bath. Diketene (22.5 mL, 293 mmol) was added slowly via dropping funnel followed by addition of TMSCl (37.2 mL, 293 mmol) in the same manner. The resulting yellow suspension was allowed to warm to room temperature slowly and was stirred for 20 hours. LC-MS showed the disappearance of starting material. To the yellow mixture 525 mL of water was added and stirred overnight. After another 20 hours stirring, the precipitate was filtered via Buchnner funnel and the yellow solid was washed with water and EtOAc to give 1c as a white solid (48.5 g, 16 mmol). 1H NMR (CDCl3) δ 2.152 (s, 3H), 5.365 (s, 2H), 5.593 (s, 1H), 7.226–7.560 (m, 3H), 9.015 (s, 1H); MS (CI) m/z 303.0 (MH+).
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[F:11][C:12]1[C:20]([OH:21])=[C:19]([F:22])[C:18]([F:23])=[CH:17][C:13]=1[C:14](O)=O.N>>[F:22][C:19]1[C:18]([F:23])=[CH:17][C:13]([C:14]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=3)[N:10]=2)=[C:12]([F:11])[C:20]=1[OH:21]
Reactant: NC(=NO)c1cccnc1
Reactant: O=C(O)c1cc(F)c(F)c(O)c1F
Agent: N
Product: Oc1c(F)c(F)cc(-c2nc(-c3cccnc3)no2)c1F

Procedure:
The title compound was prepared according to the procedure of Example 8 using N′-hydroxynicotinimidamide (Aldrich) and 2,4,5-trifluoro-3-hydroxybenzoic acid (Aldrich). 1H NMR (300 MHz, CD3OD) δ 7.63-7.76 (m, 2 H), 8.44 (dt, J=7.9, 2.0 Hz, 1 H), 8.83 (dd, J=4.8, 1.6 Hz, 1 H), 9.25 (d, J=1.6 Hz, 1 H) ppm; MS (DCI/NH3) m/z 294 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:7][NH2:8])=[O:6].[C:12]1(=[O:18])[O:17][C:15](=[O:16])[CH2:14][CH2:13]1>C(OCC)(=O)C.CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:7][NH:8][C:12](=[O:18])[CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[O:6]
Reactant: O=C1CCC(=O)O1
Reactant: NNC(=O)c1cccc(Cl)c1
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: O=C(O)CCC(=O)NNC(=O)c1cccc(Cl)c1
Yield: 94.2 %

Procedure:
3-Chloro-benzoic acid hydrazide (3.4 g, 20 mmol) and succinic anhydride (2. g, 20 mmol) was mixed in ethyl acetate (50 ml) at room temperature for 15 min. The reaction mixture was diluted with ether and the precipitate was filtered to give 5.1 g of 4-[N′-(3-chloro-benzoyl)-hydrazino]-4-oxo-butyric acid. 1H-NMR(CDCl3+DMSO-d6) d(ppm): 10.01 (s, 1H), 9.53 (s, 1H), 7.68 (s, 1H), 7.55 (d, 1H), 7.21 (d, 1H), 7.12 (t, 1H) and 2.35 (m, 4H). This solid was mixed with conc. H2SO4 and stirred at room temperature for 45 min and the reaction mixture was carefully added to crashed ice (400 g). The precipitate was filtered to give 4.07 g (80.6%) of 3-[5-(3-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-propionic acid as white solid. 1H-NMR(DMSO-d6) d(ppm): 12.4 (w, 1H), 7.96 (s, 1H), 7.91 (d, 1H), 7.71 (d, 1H), 7.63 (t, 1H), 3.15 (t, 2H) and 2.82 (t, 2H). Step 2: 3-[5-(3-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-propionic acid hydrazide: 3-[5-(3-Chloro-phenyl)-[1,3,4)oxadiazol-2-yl]-propionic acid (2.52 g, 10 mmol) was mixed with iodomethane (5.68 g, 40 mmol) and K2CO3 (5.52 g, 40 mmol) in DMF (25 ml) at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with water 3 times, dried with MgSO4 and concentrated to give 2.57 g of 3-[5-(3-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-propionic acid methyl ester. The methyl ester (2.54 g, 9.52 mmol) was mixed with 98% hydrazine hydrate (4.76 g, 95.2 mmol) in methanol (10 ml) for an h. The reaction mixture was concentrated, diluted with water, filtered to give 2.17 g (81.4%) of 3-[5-(3-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-propionic acid hydrazide as white solid. 1H-NMR(CDCl3+DMSO-d6) d(ppm): 8.75 (w, 1H), 7.91 (s, 1H), 7.82 (d, 1H), 7.42 (m, 2H), 3.45 (w, 2H), 3.19 (t, 2H) and 2.68 (t, 2H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([OH:23])[CH:12]([CH3:22])[CH2:13][N:14]2[CH2:19][CH:18]([CH3:20])[O:17][CH:16]([CH3:21])[CH2:15]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:31][C:32]1[CH:33]=[C:34]([N:39]=[C:40]=[O:41])[CH:35]=[CH:36][C:37]=1[Cl:38]>C(#N)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]([O:23][C:40](=[O:41])[NH:39][C:34]2[CH:35]=[CH:36][C:37]([Cl:38])=[C:32]([Cl:31])[CH:33]=2)[CH:12]([CH3:22])[CH2:13][N:14]2[CH2:15][CH:16]([CH3:21])[O:17][CH:18]([CH3:20])[CH2:19]2)=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1CN(CC(C)C(O)c2ccc(C(C)(C)C)cc2)CC(C)O1
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC1CN(CC(C)C(OC(=O)Nc2ccc(Cl)c(Cl)c2)c2ccc(C(C)(C)C)cc2)CC(C)O1
Yield: 76.9 %

Procedure:
6.8 g (0.021 mole) of 1-(p-tert.-butyl-phenyl)-2-methyl-3-(2,6-dimethylmorpholin-4-yl)-1-propanol (obtained according to Example 2) and 0.6 mole of triethylamine were dissolved in 60 ml of acetonitrile, and a solution of 4.0 g of 3,4-dichlorophenyl isocyanate in 10 ml of acetonitrile was added dropwise at room temperature. The mixture was subsequently stirred under reflux for one hour, cooled and concentrated. The residue was taken up in ethyl acetate and the ethyl acetate was washed with water, dried over sodium sulphate and concentrated. 8.2 g (70% of theory) of 1-(p-tert.-butyl-phenyl)-1-(3,4-dichlorophenyl-carbamoyloxy)-2-methyl-3-(2,6-dimethylmorpholin-4-yl)-propane were obtained as a viscous oil.