Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([O:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=1[O:17]C(OCC)=O)[CH:10]=[CH:11][CH2:12]Cl)=O)C.[CH2:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][NH:24]1.O>C1C=CC=CC=1>[OH:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=1[OH:17])[CH:10]=[CH:11][CH2:12][N:24]1[CH2:25][C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:23]1
Reactant: c1ccc2c(c1)CNC2
Reactant: CCOC(=O)Oc1ccc(C=CCCl)cc1OC(=O)OCC
Solvent: c1ccccc1
Solvent: O
Product: Oc1ccc(C=CCN2Cc3ccccc3C2)cc1O
Reaction time: 2 h
Yield: 52 %

Procedure:
The process for preparing this compound and its physical properties will be given below. A solution of 2.6 grams of 3,4-diethoxycarbonyloxycinnamyl chloride in 10 milliliters of benzene is added dropwise with stirring to a solution of 3.8 grams of isoindoline in 20 milliliters of benzene while cooling the reaction system with ice. After completion of the dropping, the reaction is carried out for 2 hours at room temperature. On completion of the reaction, water and a large quantity of benzene are added followed by separating and collecting the benzene layer. After concentrating the benzene layer, it is left to stand under cooled conditions to precipitate crystals. When these crystals are recrystallized from a tetrahydrofuran-ether mixture, 1.1 grams (yield 52.1%) of N-(3,4-dihydroxycinnamyl)-isoindoline is obtained as crystals having a melting point of 60.5° C. (decomposition).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1>>[CH2:1]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=3)=[CH:18][CH:19]=2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(N2CCN(Cc3ccccc3)CC2)cc1
Reactant: Cc1ccc(I)cc1
Product: Cc1ccc(Oc2ccc(N3CCN(Cc4ccccc4)CC3)cc2)cc1
Yield: 14.4 %

Procedure:
The title compound (103 mg, 14.3%) was prepared from 4-(4-benzyl-piperazin-1-yl)-phenol (530 mg, 2 mmol) and 1-iodo-4-methyl-benzene (430 mg, 2 mmol) by the procedures described in step 2 of Example 17: MS (ESI) m/z 359 (M+H); 1H NMR (400 MHz, CDCl3) δ 2.30 (s, 3H), 2.62 (t, J=4.8 Hz, 4H), 3.15 (t, J=4.8 Hz, 4H), 3.57 (s, 2H), 6.84-6.94 (m, 6H), 7.08 (dd, J=0.6, 8.4 Hz, 2H), 7.31-7.35 (m, 5H).
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3]([CH2:5][CH2:6][CH2:7][C:8]#[C:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([OH:15])=O)=[O:4].CCN=C=N[CH2:25][CH2:26][CH2:27][N:28](C)C.C(N(CC)CC)C.C1(N)CC1>ClCCl>[CH:27]1([NH:28][C:13](=[O:15])[C:12]2[CH:16]=[CH:17][CH:18]=[C:10]([C:9]#[C:8][CH2:7][CH2:6][CH2:5][C:3](=[O:4])[N:2]([CH3:1])[CH3:19])[CH:11]=2)[CH2:25][CH2:26]1
Reactant: CCN=C=NCCCN(C)C
Reactant: CN(C)C(=O)CCCC#Cc1cccc(C(=O)O)c1
Agent: NC1CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C(=O)CCCC#Cc1cccc(C(=O)NC2CC2)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 89.5 %

Procedure:
To a solution of 3-(5-dimethylcarbamoyl-pent-1-ynyl)-benzoic acid (0.100 g, 0.38 mmol) in dry dichloromethane (1.5 mL) under a nitrogen atmosphere at room temperature, EDCI (0.0728 g, 0.38 mmol) was added followed by triethylamine (0.162 mL, 1.14 mmol), the resulting mixture was stirred at room temperature for further 5 minutes. Cyclopropylamine (0.027 g, 0.38 mmol) was then added and the mixture stirred at room temperature for 16 hrs. The reaction mixture was washed with a mixture of saturated brine and saturated sodium bicarbonate (1:1; 2×150 mL) followed by saturated brine solution (100 mL). The organic layer was separated and dried over magnesium sulfate and the solvent evaporated under vacuum. The residue was purified by flash column chromatography on silica gel (DCM:MeOH, 95% to 5% methanol gradient) to afford N-cyclopropyl-3-(5-dimethylcarbamoyl-pent-1-ynyl)benzamide (25) (0.10 g, 0.34 mmol, 91% yield).
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[C:10](=[O:17])[N:9]3[OH:18])[CH:5]=[CH:4][N:3]=[CH:2]1.C(O)C.[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>P([O-])(O)(O)=O.[K+]>[CH2:22]([O:18][N:9]1[C:8]2[C:13](=[CH:14][CH:15]=[C:6]([N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)[CH:7]=2)[NH:12][C:11](=[O:16])[C:10]1=[O:17])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=c1[nH]c2ccc(-n3ccnc3)cc2n(O)c1=O
Reactant: BrCc1ccccc1
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: CCO
Product: O=c1[nH]c2ccc(-n3ccnc3)cc2n(OCc2ccccc2)c1=O
Reaction time: 8 h
Yield: 68.8 %

Procedure:
To a solution of 6-(1H-imidazol-1-yl)-4-hydroxyquinoxaline-2,3(1H,4H)-dione (10.4 g; ~42.6 mmol) in 500 ml 1M potassium dihydrogen phosphate buffer pH 7.4, was added 500 ml ethanol and then 15.0 ml (~126 mmol) benzylbromide. Stirring was continued at 25° C. overnight. The precipitate was filtered off and washed with ethanol to give the title compound (9.8 g; 69%). M.p. 230° C. (decomp.).
Reaction SMILES: [Cl:1][C:2]1[CH:40]=[CH:39][CH:38]=[CH:37][C:3]=1[C:4]([C:6]1[CH:10]=[C:9]([CH2:11][CH3:12])[S:8][C:7]=1[N:13]1[C:17]([CH3:18])=[N:16][N:15]=[C:14]1[CH2:19][NH:20][C:21](=[O:36])[NH:22][C:23]1[CH:24]=[C:25]([CH:33]=[CH:34][CH:35]=1)[C:26]([O:28]C(C)(C)C)=[O:27])=[O:5]>C(O)=O>[Cl:1][C:2]1[CH:40]=[CH:39][CH:38]=[CH:37][C:3]=1[C:4]([C:6]1[CH:10]=[C:9]([CH2:11][CH3:12])[S:8][C:7]=1[N:13]1[C:17]([CH3:18])=[N:16][N:15]=[C:14]1[CH2:19][NH:20][C:21](=[O:36])[NH:22][C:23]1[CH:24]=[C:25]([CH:33]=[CH:34][CH:35]=1)[C:26]([OH:28])=[O:27])=[O:5]
Reactant: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CNC(=O)Nc2cccc(C(=O)OC(C)(C)C)c2)s1
Solvent: O=CO
Product: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CNC(=O)Nc2cccc(C(=O)O)c2)s1
Reaction time: 24 h
Yield: 80.3 %

Procedure:
tert-Butyl 3-(3-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl[1,2,4]triazol-3-ylmethyl)ureido)benzoate (800 mg) was dissolved in formic acid (20 ml), and the solution was allowed to stand for one day. The reaction mixture was concentrated, and the obtained crude crystals were recrystallized from isopropyl alcohol to give 580 mg of 3-(3-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl[1,2,4]triazol-3-ylmethyl)ureido)benzoic acid.
Reaction SMILES: [Cl-].[CH2:2]([N-:4][CH2:5]C)C.[CH2:7]([N-:9][CH2:10]C)C.[CH:12]1([Ti+3:21])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13]1.[CH2:22]([N-:25][CH2:26][CH2:27][CH3:28])[CH2:23][CH3:24].[Li+]>C(OCC)C>[CH2:22]([N-:25][CH2:26][CH2:27][CH3:28])[CH2:23][CH3:24].[CH3:2][N-:4][CH3:5].[CH3:7][N-:9][CH3:10].[CH:12]1([Ti+3:21])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13]1
Reactant: CC[N-]CC
Agent: [Ti+3]C1C=Cc2ccccc21
Agent: CCC[N-]CCC
Agent: [Cl-]
Solvent: CCOCC
Product: C[N-]C
Temperature: -78 °C

Procedure:
A 250 mL Schlenk flask is charged with indenyltitanium bis(diethylamide) chloride, 1 g (2.92 mmole), and diethylether, 100 mL. The mixture is chilled to -78° C. in a dry ice acetone bath and stirred magentically. The lithium di-n-propylamide prepared in Example 4D, step 1, is added to the flask via cannula. The mixture is slowly warmed to room temperature while stirring. The mixture is then refluxed approximately 2 hours. All volatiles are removed under vacuum at room temperature leaving a deeply colored yellow-brown, viscous oil. The residue is placed under high vacuum, 1×10-6Torr, for a few hours in order to remove any unreacted indene. Chloride analysis and NMR indicate the product is sufficiently pure indenyltitanium bis(diethylamide) di-n-propylamide, IX, and is used without further purification.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][CH:13]2[CH2:18][CH2:17][N:16]([CH2:19][C:20]3[C:25]([O:26][CH2:27][CH2:28][N:29]([CH3:31])[CH3:30])=[CH:24][CH:23]=[CH:22][C:21]=3[N:32]([CH3:34])[CH3:33])[CH2:15][CH2:14]2)[C:9]2[C:4](=[CH:5][C:6]([O:37][CH3:38])=[C:7]([O:35][CH3:36])[CH:8]=2)[N:3]=1.[NH2:39][CH2:40][CH:41]1[CH2:44][N:43](C(OC(C)(C)C)=O)[CH2:42]1.C(=O)([O-])N.C(C(O)=O)(F)(F)F>>[NH:43]1[CH2:44][CH:41]([CH2:40][NH:39][C:2]2[N:11]=[C:10]([NH:12][CH:13]3[CH2:18][CH2:17][N:16]([CH2:19][C:20]4[C:25]([O:26][CH2:27][CH2:28][N:29]([CH3:30])[CH3:31])=[CH:24][CH:23]=[CH:22][C:21]=4[N:32]([CH3:33])[CH3:34])[CH2:15][CH2:14]3)[C:9]3[C:4](=[CH:5][C:6]([O:37][CH3:38])=[C:7]([O:35][CH3:36])[CH:8]=3)[N:3]=2)[CH2:42]1
Reactant: CC(C)(C)OC(=O)N1CC(CN)C1
Reactant: COc1cc2nc(Cl)nc(NC3CCN(Cc4c(OCCN(C)C)cccc4N(C)C)CC3)c2cc1OC
Agent: NC(=O)[O-]
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2nc(NCC3CNC3)nc(NC3CCN(Cc4c(OCCN(C)C)cccc4N(C)C)CC3)c2cc1OC

Procedure:
Following General Procedure D, Compound 75 (100 mg, 0.18 mmol) and tert-butyl 3-(aminomethyl)azetidine-1-carboxylate (62 mg, 0.31 mmol) were converted into the carbamate product. The crude carbamate product was treated with CF3CO2H and purified using neutral alumina prep TLC, eluting with 5% NH3-MeOH and 95% CH2Cl2 to isolate the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N+:6]([O-])=[C:5](C)[C:4]=1[N+:11]([O-:13])=[O:12].[C:14](=[O:17])([O-])[O-:15].[K+].[K+].[Mn]([O-])(=O)(=O)=O.[K+]>C(OC(=O)C)(=O)C.CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:14]([OH:15])=[O:17])[C:4]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C([O-])[O-]
Reactant: COc1cc[n+]([O-])c(C)c1[N+](=O)[O-]
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CO
Solvent: CC(=O)OC(C)=O
Product: COc1ccnc(C(=O)O)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Methoxy-2-methyl-3-nitropyridine-N-oxide (mixture with the positional isomer, 10.97 g, 48.5 mmol) was stirred in acetic anhydride (100 mL) at 80° C. for 8 hours. The reaction solution was concentrated under reduced pressure, and in methanol (100 mL), potassium carbonate (33 g, 0.243 mol) was added to the resulting residue at room temperature and stirred at that temperature for 2 hours. The solvent was evaporated off under reduced pressure, and the resulting residue was diluted with ethyl acetate, and washed with water. The resulting organic layer was dried with magnesium sulfate, and the solvent was evaporated off under reduced pressure. The resulting residue was suspended in water (100 mL), and potassium permanganate (23 g, 0.145 mol) was added thereto at room temperature. The reaction solution was stirred at 90° C. for 16 hours, then potassium permanganate (20 g, 0.126 mol) was added thereto and stirred at 90° C. for 3 hours. The reaction solution was cooled to room temperature, methanol was added thereto, and stirred at room temperature for 2 hours. The reaction liquid was filtered, concentrated, and 2 N hydrochloric acid was added to the resulting residue, and the solution was controlled to have a pH of 2. The reaction solution was stirred at 0° C. for 1 hour, then the resulting milky white solid was taken out through filtration and dried to obtain the intended compound (1.35 g, 3 steps, 14%).
Reaction SMILES: C([C:4]1[C:5](=[O:25])[NH:6][CH:7]=[C:8]([C:10]2[C:11]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:12][N:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=23)[CH:9]=1)(O)=O.C>C(Cl)(Cl)Cl.CO>[O:25]=[C:5]1[CH:4]=[CH:9][C:8]([C:10]2[C:11]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:12][N:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=23)=[CH:7][NH:6]1
Reactant: O=C(O)c1cc(-c2c(-c3ccccc3)nn3ccccc23)c[nH]c1=O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=c1ccc(-c2c(-c3ccccc3)nn3ccccc23)c[nH]1
Yield: 28.8 %

Procedure:
3-(3-Carboxy-2-oxo-1,2-dihydropyridin-5-yl)-2-phenylpyrazolo[1,5-a]pyridine (120 mg) was melted by an electric hot plate at 370° C. This was dissolved in a mixture of chloroform (26 ml) and methanol (13 ml), and silica gel (1 g) and charcoal (0.2 g) were added thereto and then this mixture was filtered. The solvent of the filtrate was removed and chromatographed on silica gel (3 g) with a mixture of chloroform, methanol and triethylamine (200:10:1). The fractions containing the object compound were combined and evaporated in vacuo and recrystallized from ethyl acetate to give 3-(2-oxo-1,2-dihydropyridin-5-yl)-2-phenylpyrazolo[1,5-a]pyridine (30 mg).
Reaction SMILES: [S:1]1[C:5]([C:6]2[C:7]([O:16][CH3:17])=[C:8]([CH:11]=[CH:12][C:13]=2[O:14][CH3:15])[CH:9]=O)=[CH:4][C:3]2[CH:18]=[CH:19][CH:20]=[CH:21][C:2]1=2.[C:22]([C:25]1[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=1)(=[O:24])[CH3:23]>>[S:1]1[C:5]([C:6]2[C:7]([O:16][CH3:17])=[C:8](/[CH:9]=[CH:23]/[C:22]([C:25]3[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=3)=[O:24])[CH:11]=[CH:12][C:13]=2[O:14][CH3:15])=[CH:4][C:3]2[CH:18]=[CH:19][CH:20]=[CH:21][C:2]1=2
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Reactant: COc1ccc(C=O)c(OC)c1-c1cc2ccccc2s1
Product: COc1ccc(/C=C/C(=O)c2ccc(C(=O)O)cc2)c(OC)c1-c1cc2ccccc2s1
Yield: 64 %

Procedure:
The title compound was prepared by condensing 3-benzo[b]thiophen-2-yl-2,4-dimethoxy-benzaldehyde (Ex-44B) and 4-acetylbenzoic acid in a similar manner as described in Ex-3. Yellow solid, mp 237° C. (dec.), 64% yield. 1H-NMR (DMSO-d6) δ 13.37 (bs, 1H), 8.20–8.25 (m, 3H), 8.11 (d, J=8 Hz, 2H), 8.02 (d, J=8 Hz, 1H), 7.96 (d, J=9 Hz, 2H), 7.88–7.91 (m, 1H), 7.65 (s, 1H), 7.35–7.43 (m, 2H), 7.14 (d, J=9 Hz, 1H), 3.90 (s, 3H), 3.53 (s, 3H). HRMS m/z=calc. 445.1110, found 445.1112.
Reaction SMILES: C[O:2][C:3]1[N:8]=[C:7]([C:9]([O:11]C)=[O:10])[CH:6]=[CH:5][C:4]=1[N:13]1[CH:17]=[C:16]([CH3:18])[N:15]=[CH:14]1.[BrH:19]>C(O)(=O)C>[BrH:19].[CH3:18][C:16]1[N:15]=[CH:14][N:13]([C:4]2[C:3](=[O:2])[NH:8][C:7]([C:9]([OH:11])=[O:10])=[CH:6][CH:5]=2)[CH:17]=1
Reactant: COC(=O)c1ccc(-n2cnc(C)c2)c(OC)n1
Agent: Br
Solvent: CC(=O)O
Product: Cc1cn(-c2ccc(C(=O)O)[nH]c2=O)cn1
Temperature: 25 °C

Procedure:
A solution of C2 (3.82 g, 15.9 mmol) in acetic acid (30 mL) and aqueous hydrobromic acid (48%, 30 mL) was heated at reflux for 4 hours. The reaction was allowed to cool to room temperature, and then chilled in an ice bath; the resulting precipitate was collected via filtration and washed with ice water (30 mL). Recrystallization from ethanol (20 mL) provided the title compound as a light yellow solid. Yield: 3.79 g, 12.6 mmol, 79%. LCMS m/z 220.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 12.6 (v br s, 1H), 9.58-9.60 (m, 1H), 8.07 (d, J=7.6 Hz, 1H), 7.88-7.91 (m, 1H), 7.09 (d, J=7.4 Hz, 1H), 2.34 (br s, 3H).
Reaction SMILES: C[Si](C)(C)CCOC[N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[CH:16]=O.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][NH:27][S:28]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37][NH:38][CH:39]2[C:48]3[N:47]=[CH:46][CH:45]=[CH:44][C:43]=3[CH2:42][CH2:41][CH2:40]2)[CH:32]=1)(=[O:30])=[O:29].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[NH:9]1[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:7]=[C:8]1[CH2:16][N:38]([CH2:37][C:33]1[CH:32]=[C:31]([S:28]([NH:27][CH2:26][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][N:20]=2)(=[O:29])=[O:30])[CH:36]=[CH:35][CH:34]=1)[CH:39]1[C:48]2[N:47]=[CH:46][CH:45]=[CH:44][C:43]=2[CH2:42][CH2:41][CH2:40]1
Reactant: O=S(=O)(NCc1ccccn1)c1cccc(CNC2CCCc3cccnc32)c1
Reactant: C[Si](C)(C)CCOCn1c(C=O)nc2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=S(=O)(NCc1ccccn1)c1cccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)c1
Yield: 46.9 %

Procedure:
Using general procedure B: Reaction of 1-(2-Trimethylsilanyl-ethoxymethyl)-1H-benzimidazole-2-carbaldehyde (192 mg, 0.70 mmol), N-Pyridin-2-ylmethyl-3-[(5,6,7,8-tetrahydro-quinolin-8-ylamino)-methyl]-benzenesulfonamide (284 mg, 0.70 mmol), acetic acid (0.2 mL) and sodium triacetoxyborohydride (442 mg, 2.08 mmol) in THF (7 mL) at room temperature under N2 for 40 min., followed by purification of the crude material by chromatography on silica gel (1:1:98 CH3OH—NH3H2O—CH2Cl2,), afforded the title compound (177 mg, 38%) as a white foam.
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([CH3:8])[N:6]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)[CH:4]=1.[I-:20].[Na+].COC(C)(C)C>CC(C)=O>[I:20][CH2:2][C:3]1[N:7]([CH3:8])[N:6]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)[CH:4]=1
Reactant: Cn1nc(-c2ccc(OC(F)(F)F)cc2)cc1CCl
Reactant: [I-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: CC(C)=O
Product: Cn1nc(-c2ccc(OC(F)(F)F)cc2)cc1CI

Procedure:
A suspension of 5-chloromethyl-1-methyl-3-(4-trifluoromethoxy-phenyl)-1H-pyrazole (3.2 g, 11 mmol; example 19 a]) and sodium iodide (8.25 g, 55 mmol) in acetone (56 ml) was heated under reflux conditions for 30 min. Tert butyl methyl ether was added, the solid was filtered off and the filtrate was brought to dryness under reduced pressure. The residue was dissolved in tert butyl methyl ether, washed with ice water/brine 1/1 and the aqueous layer was extracted two times with tert butyl methyl ether. The combined extracts were washed with aqueous sodium thiosulfate solution and brine and dried over sodium sulfate. The solvent was removed under reduced pressure to give the title compound as yellow oil which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][C@@H:15]([CH3:17])[NH:14][CH2:13][C@@H:12]1[CH3:18].C=O.[BH3-][C:22]#N.[Na+].C(O)(=O)C>C(#N)C>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][C@@H:15]([CH3:17])[N:14]([CH3:22])[CH2:13][C@@H:12]1[CH3:18]
Reactant: C[C@@H]1CN(c2ccc([N+](=O)[O-])cc2F)[C@@H](C)CN1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: C[C@@H]1CN(c2ccc([N+](=O)[O-])cc2F)[C@@H](C)CN1C
Temperature: 0 °C
Yield: 100 %

Procedure:
Racemic-1-(2-Fluoro-4-nitrophenyl)-trans-2,5-dimethylpiperazine (5.71 g, 24.3 mmol) and formalin (24 mL) are dissolved in 70 mL of acetonitrile. The solution is cooled to 0° C. and 2.44 g of NaBH3CN (38.8 mmol) is added in small portions. Acetic acid (2 mL) is added until no further effervescence is observed. The crude reaction mixture is then filtered through a thick plug of silica gel that is rinsed with 10% MeOH in CH2Cl2. Concentration in vacuo gives a yellow solid that is further purified by addition of ethyl acetate and filtration. Concentration in vacuo of the filtrate gave 6.1 g of racemic-1-(2-fluoro-4-nitrophenyl)-trans-2,4,5-trimethylpiperazine as an off-white solid (24.3 mmol, 100%). 1H NMR (300 MHz, CDCl3) δ 1.04 (d, J=4.9 Hz, 1H), 1.07 (d, J=5.2 Hz, 1H), 2.20 (dd, J=11.5, 8.8 Hz, 1H), 2.32 (s, 3H), 2.41-2.50 (m, 1H), 2.65 (dd, J=11.6, 8.9 Hz, 1H), 2.90 (dd, J=11.5, 3.3 Hz, 1H), 3.25 (dd, J=11.8, 3.0 Hz, 1H), 3.44-3.53 (m, 1H), 7.10 (t, J=8.5 Hz, 1H), 7.90 (dd, J=11.5, 2.7 Hz, 1H), 7.95-8.00 (m, 1H). LCMS-ESI (m/z): calcd for C13HBFN3O2, 267.14; [M+H]+ found, 268.2.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:6]([NH:8][C@H:9]([C:18]([OH:20])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:7])[CH:3]([CH3:5])[CH3:4].[N:31]1([NH-:37])[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>CO.[Pd]>[NH2:1][C@H:2]([C:6]([NH:8][C@H:9]([C:18]([OH:20])=[O:19])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1)=[O:7])[CH:3]([CH3:5])[CH3:4].[N:31]1([NH-:37])[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Agent: [Pd]
Agent: [NH-]N1CCOCC1
Solvent: CO
Product: CC(C)[C@H](N)C(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O

Procedure:
Hydrogenation in the presence of 1 g of 10% Pd/C for 1.5 h at RT of a solution of 4.83 g (10 mmol) of Z-(L)-Val-(L)-Tyr-morpholin-4-ylamide in 182 ml of methanol, followed by filtration through ®Celite, concentration of the filtrate by evaporation and column chromatography (SiO2, methylene chloride/methanol 9:1), yields the title compound: TLC Rf (F)=0.30; FAB-MS (M+H)+ =350.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[CH2:6][N:7]([CH3:25])[C:8](=[O:24])[C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][C:12]([C:22]#[CH:23])=[N:11][CH:10]=1.[N+:35]([CH2:38][CH3:39])([O-])=[O:36].C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>C(#N)C.C1(C)C=CC=CC=1>[F:30][C:29]([F:32])([F:31])[C:27]1[CH:26]=[C:5]([CH:4]=[C:3]([C:2]([F:33])([F:1])[F:34])[CH:28]=1)[CH2:6][N:7]([CH3:25])[C:8](=[O:24])[C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][C:12]([C:22]2[O:36][N:35]=[C:38]([CH3:39])[CH:23]=2)=[N:11][CH:10]=1
Reactant: C#Cc1cc(-c2ccccc2C)c(C(=O)N(C)Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)cn1
Reactant: CC[N+](=O)[O-]
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: Cc1ccccc1
Solvent: CC#N
Product: Cc1cc(-c2cc(-c3ccccc3C)c(C(=O)N(C)Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)cn2)on1
Temperature: 25 °C
Reaction time: 24 h
Yield: 32.8 %

Procedure:
To a solution of 55 mg (0.12 mmol) N-(3,5-bis-trifluoromethyl-benzyl)-6-ethynyl-N-methyl-4-o-tolyl-nicotinamide (Example 63), 0.026 ml (0.35 mmol) nitroethane and 1 mg (0.01 mmol) 4-N,N-dimethylaminopyridine in 0.5 ml acetonitrile a solution of 77 mg (0.35 mmol) di-tert-butyl dicarbonate in 0.1 ml toluene was added, and the mixture was stirred at room temperature over night. Another portion of 0.026 ml (0.35 mmol) nitroethane and 77 mg (0.35 mmol) di-tert-butyl dicarbonate were added, and stirring was continued for 24 h. Quenching with water was followed by extraction with two portions of ethyl acetate. The combined organic extracts were dried with sodium sulfate and concentrated. Column chromatography afforded 21 mg (34%) of the title compound as a light yellow amorphous mass.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14][C:15](=[O:19])[N:16]([CH3:18])[CH3:17])[CH2:9]2)[CH:5]=[N:4][C:3]=1[C:20]#[N:21].[NH2:22][C:23]1[CH:24]=[N:25][N:26]([CH:28]2[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]2)[CH:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:20]([C:3]1[C:2]([NH:22][C:23]2[CH:24]=[N:25][N:26]([CH:28]3[CH2:29][CH2:30][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:32][CH2:33]3)[CH:27]=2)=[N:7][C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14][C:15]([N:16]([CH3:18])[CH3:17])=[O:19])[CH2:9]2)=[CH:5][N:4]=1)#[N:21]
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(N)cn2)CC1
Reactant: CN(C)C(=O)N[C@@H]1CCCN(c2cnc(C#N)c(Cl)n2)C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CN(C)C(=O)N[C@@H]1CCCN(c2cnc(C#N)c(Nc3cnn(C4CCN(C(=O)OC(C)(C)C)CC4)c3)n2)C1
Temperature: 115 °C
Reaction time: 2 h

Procedure:
The mixture of (R)-3-(1-(6-chloro-5-cyanopyrazin-2-yl)piperidin-3-yl)-1,1-dimethylurea (222, 330 mg, 1.07 mmol), tert-butyl 4-(4-amino-1H-pyrazol-1-yl)piperidine-1-carboxylate (275, 426 mg, 1.60 mmol), fine-powder cesium carbonate (1.05 g, 3.21 mmol), Pd(OAc)2 (72 mg, 0.32 mmol), BINAP (200 mg, 0.32 mmol) in 60 mL dioxane was degassed with nitrogen stream for 3 min. It was then stirred in 115° C. bath in nitrogen atmosphere for 2 hours. The mixture was cooled to RT, diluted with 60 mL EtOAc, and filtered. The filtrate was concentrated in vacuo and subjected to silica flash column using 0 to 6% MeOH in chloroform to isolate (R)-tert-butyl 4-(4-(3-cyano-6-(3-(3,3-dimethylureido)piperidin-1-yl)pyrazin-2-ylamino)-1H-pyrazol-1-yl)piperidine-1-carboxylate (276). It was dissolved in 20 mL MeOH and 4 mL DMSO. To it were added one NaOH solid bead (about 100 mg) and then 0.5 mL 30% H2O2. The mixture was stirred at RT for 2 hours, diluted with 10 mL MeCN, stirred for 5 min, concentrated in vacuo, diluted with EtOAc 150 mL, washed with water ×3, dried, concentrated in vacuo to afford crude (R)-tert-butyl 4-(4-(3-carbamoyl-6-(3-(3,3-dimethylureido)piperidin-1-yl)pyrazin-2-ylamino)-1H-pyrazol-1-yl)piperidine-1-carboxylate (277).