Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9](Cl)=[C:8]([N+:13]([O-])=O)[CH:7]=1)=[O:5].[H][H].O.N>[Pd].O1CCOCC1>[NH2:13][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)[C:4]([C:3]1[CH:2]=[CH:19][CH:18]=[C:17]([NH2:20])[CH:16]=1)=[O:5]
Reactant: [H][H]
Reactant: O=C(c1ccc(Cl)c([N+](=O)[O-])c1)c1cc([N+](=O)[O-])ccc1Cl
Agent: [Pd]
Agent: N
Solvent: C1COCCO1
Solvent: O
Product: Nc1cccc(C(=O)c2cccc(N)c2)c1
Temperature: 30 °C

Procedure:
In a closed glass vessel with a thermometer and a stirrer, there are charged 102.3 g (0.3 moles) of 2,4'-dichloro-5,3'-dinitro benzophenone, 5 g of 5% palladium/active carbon catalyst (from Nihon-Engelhardt Co.) and 300 ml of dioxane. At 70°-80° C., hydrogen is introduced into the vessel while the mixture being stirred, so that 42 l (1.88 moles) of hydrogen is absorbed in the mixture during ten hours. After being cooled to 30° C., the mixture is added with 55 g (0.9 moles) of 28% ammonia water and then introduced with hydrogen while being stirred at 30°-40° C. so as to absorb 13.2 l (0.59 moles) of hydrogen during 5 hours. The reaction mixture is subject to filtering at 30°-40° C. to remove the catalyst. On cooling, there is obtained 3,3'-diamino benzophenone as yellow crystals. The crystals are filtered, washed with 30 ml of 50% aqueous solution of dioxane and dried. Yield 56.5 g (89%). M.P. 149°-150.5° C. Recrystallization from ethanol gives yellow needle-like pure crystals of said benzophenone. M.P. 150°-151° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][N:6]=[C:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].[F:21][C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([F:31])[C:29]=1[F:30])[CH2:25]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:20])[CH:5]([CH2:25][C:24]1[CH:23]=[C:22]([F:21])[C:29]([F:30])=[C:28]([F:31])[CH:27]=1)[N:6]=[C:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH3:2]
Reactant: Fc1cc(CBr)cc(F)c1F
Reactant: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1cc(F)c(F)c(F)c1)N=C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.9 %

Procedure:
A solution of N-(Diphenylmethylene)glycine ethyl ester (1.10 g, 4.1 mmol) and 3,4,5-trifluorobenzylbromide (0.91 g, 4.0 mmol) in dimethylformamide (10 mL) was treated with anhydrous potassium carbonate (2.83 g, 20.5 mmol) and stirred for 18 hrs at 25° C. The mixture was filtered and the filtrate was evaporated to dryness to give crude product. It was purified by column chromatography on silica gel (hexane:ethyl acetate=4:1) to give title compound (1.2 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH:9]=O)=[C:4]([Cl:11])[N:3]=1.C(O)(=O)C.Cl.[NH2:17][OH:18]>C(O)C>[NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH:9]=[N:17][OH:18])=[C:4]([Cl:11])[N:3]=1
Reactant: NO
Reactant: Nc1nc(Cl)c(C=O)c(Cl)n1
Agent: Cl
Solvent: CC(=O)O
Solvent: CCO
Product: Nc1nc(Cl)c(C=NO)c(Cl)n1
Yield: 84.1 %

Procedure:
Following the method of Bell et al. (J. Heterocyclic Chem. 1983, 20, 41), to a solution of 29.6 g (154 mmol) 2-amino-4,6-dichloro-pyrimidine-5-carbaldehyde in 31 acetic acid in a 2-necked flask at room temperature was added dropwise with stirring a solution of 11.8 g (170 mmol) hydroxylamine hydrochloride in 2.31 ethanol. Stirring was continued for 3 h at room temperature during which time crystallisation occurred. The crystals were collected by filtration to afford 26.8 g (84%) 2-amino-4,6-dichloro-pyrimidine-5-carbaldehyde oxime as a light yellow crystalline solid. ES-MS m/e (%): 209 ([M{37Cl, 37Cl}-H]−, 20), 207 ([M{37Cl, 35Cl}-H]−, 55), 205 ([M{35Cl, 35Cl}-H]−, 100).
Reaction SMILES: S(O[CH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)(C1C=CC(C)=CC=1)(=O)=O.BrCC1CCCCO1.[F:34][C:35]1[C:36]([F:53])=[CH:37][C:38]2[O:52][CH2:51][C:41]3([C:49]4[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=4)[NH:43][C:42]3=[O:50])[C:39]=2[CH:40]=1>>[F:34][C:35]1[C:36]([F:53])=[CH:37][C:38]2[O:52][CH2:51][C:41]3([C:49]4[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=4)[N:43]([CH2:12][CH:13]4[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH2:17][CH2:18]4)[C:42]3=[O:50])[C:39]=2[CH:40]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: O=C1Nc2ccccc2C12COc1cc(F)c(F)cc12
Agent: BrCC1CCCCO1
Product: CC(C)(C)OC(=O)N1CCC(CN2C(=O)C3(COc4cc(F)c(F)cc43)c3ccccc32)CC1

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using tert-butyl 4-(tosyloxymethyl)piperidine-1-carboxylate to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 5,6-difluorospiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3-indol]-2″(1H)-one, tert-butyl 4-[(5,6-difluoro-2′-oxospiro[1-benzofuran-3,3-indol]-1′(2′H)-yl)methyl]piperidine-1-carboxylate was obtained (57%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 7.34 (ddd, J=9.0, 7.6, 1.5 Hz, 1H), 7.16-7.06 (m, 2H), 6.92 (d, J=7.8 Hz, 1H), 6.78 (dd, J=10.3, 6.3 Hz, 1H), 6.49 (dd, J=10.3, 6.3 Hz, 1H), 4.95 (d, J=9.0 Hz, 1H), 4.70 (d, J=9.0 Hz, 1H), 4.13 (br s, 2H), 3.74-3.56 (m, 2H), 2.69 (t, J=12.4 Hz, 2H), 2.07-1.96 (m, 1H), 1.68-1.63 (m, 2H), 1.45 (s, 9H), 1.32-1.26 (m, 2H); MS (ES+) m/z 493.3 (M+23).
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20](F)=[CH:19][C:18]=3[Cl:24])(=[O:16])=[O:15])[CH2:11][N:10]2[C:25]2[N:26]([CH:31]3[CH2:34][CH2:33][CH2:32]3)[N:27]=[C:28]([CH3:30])[CH:29]=2)=[O:8])[CH2:5][CH2:4]1)#[N:2].[NH:35]1[CH:39]=[CH:38][CH:37]=[N:36]1>>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([N:35]4[CH:39]=[CH:38][CH:37]=[N:36]4)=[CH:19][C:18]=3[Cl:24])(=[O:16])=[O:15])[CH2:11][N:10]2[C:25]2[N:26]([CH:31]3[CH2:34][CH2:33][CH2:32]3)[N:27]=[C:28]([CH3:30])[CH:29]=2)=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: Cc1cc(N2C[C@H](S(=O)(=O)c3ccc(F)cc3Cl)C[C@H]2C(=O)NC2(C#N)CC2)n(C2CCC2)n1
Reactant: c1cn[nH]c1
Product: Cc1cc(N2C[C@H](S(=O)(=O)c3ccc(-n4cccn4)cc3Cl)C[C@H]2C(=O)NC2(C#N)CC2)n(C2CCC2)n1

Procedure:
In analogy to the procedure described in example 392, (2S,4R)-4-(2-chloro-4-fluoro-benzenesulfonyl)-1-(2-cyclobutyl-5-methyl-2H-pyrazol-3-yl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide (example 385b) was reacted with pyrazole (CAS Reg. No. 288-11-9) to give the title compound as colorless oil. MS (ESI): m/z=554.3 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C@@H:5]([C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1[CH3:26])[C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1.CCN(CC)CC.Cl[C:35]([O:37][CH3:38])=[O:36]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:25][C:23]1[CH:22]=[CH:21][C:20]([CH3:26])=[C:19]([C@H:5]([O:4][CH2:3][CH2:2][NH:1][C:35]([O:37][CH3:38])=[O:36])[C@@H:6]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]2)[CH:24]=1
Reactant: Cc1ccc(Cl)cc1[C@H](OCCN)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reactant: COC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)NCCO[C@@H](c1cc(Cl)ccc1C)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 2.5 °C
Reaction time: 1.5 h
Yield: 21 %

Procedure:
To a solution of (R)-tert-butyl 3-((R)-(2-aminoethoxy)(5-chloro-2-methylphenyl)methyl)piperidine-1-carboxylate (6.2 g, 16.2 mmol) and DMAP (0.2 g, 1.62 mmol) in dry CH2Cl2 (70 mL), Et3N (8 g, 81 mmol) was added. The resulting mixture was cooled to 0-5° C. in ice-water bath, a solution of methyl chloroformate (3.1 g, 32.4 mmol) in dry CH2Cl2 (30 mL) was added dropwise. After addition, the reaction mixture was stirred for 1-2 hr at 0-5° C. The reaction was quenched with water. The aqueous layer was extracted with CH2Cl2 (3×30 mL), the combined organic layers were washed with brine, then dried over Na2SO4, filtered and concentrated to give the crude product, which was firstly purified by column chromatography and then by preparative HPLC to give (R)-tert-butyl 3-((R)-(5-chloro-2-methylphenyl)(2-(methoxycarbonylamino)ethoxy)methyl)piperidine-1-carboxylate (1.5 g). 1H NMR (CD3OD, 400 MHz) δ 7.30 (s, 1H), 7.20-7.10 (d, 2H), 4.81 (s, 1H), 4.46-4.30 (d, 1H), 4.29-4.15 (d, 1H), 3.95-3.83 (d, 1H), 3.62 (s, 3H), 3.30 (s, 4H), 2.90-2.65 (dd, 2H), 2.30 (s, 3H), 1.70 (s, 1H), 1.59 (s, 1H), 1.41 (s, 9H), 1.35-1.20 (m, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:40][S:41]([CH3:44])(=[O:43])=[O:42])[C:8]([O:38][CH3:39])=[C:9]([NH:11][C:12]([C:14]2[N:15]([CH3:37])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:23][N:24]2[CH2:29][CH2:28][N:27]([C:30]([C@H:32]3[CH2:36][CH2:35][NH:34][CH2:33]3)=[O:31])[CH2:26][CH2:25]2)=[O:13])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:45]=O>CO.O.[Pd]>[C:1]([C:5]1[CH:6]=[C:7]([NH:40][S:41]([CH3:44])(=[O:43])=[O:42])[C:8]([O:38][CH3:39])=[C:9]([NH:11][C:12]([C:14]2[N:15]([CH3:37])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:23][N:24]2[CH2:29][CH2:28][N:27]([C:30]([C@H:32]3[CH2:36][CH2:35][N:34]([CH3:45])[CH2:33]3)=[O:31])[CH2:26][CH2:25]2)=[O:13])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1c(NC(=O)c2cc3cccc(CN4CCN(C(=O)[C@H]5CCNC5)CC4)c3n2C)cc(C(C)(C)C)cc1NS(C)(=O)=O
Reactant: C=O
Agent: [Pd]
Solvent: CO
Solvent: O
Product: COc1c(NC(=O)c2cc3cccc(CN4CCN(C(=O)[C@H]5CCN(C)C5)CC4)c3n2C)cc(C(C)(C)C)cc1NS(C)(=O)=O

Procedure:
100 mg of (S)-1-methyl-7-[4-(pyrrolidine-3-carbonyl)-piperazin-1-ylmethyl]-1H-indole-2-carboxylic acid (5-tert-butyl-3-methanesulphonylamino-2-methoxy-phenyl)-amide are dissolved in 10 ml of methanol, combined with 14 μl of a 37% solution of formaldehyde in water and 20 mg of palladium on charcoal (10%) and hydrogenated for 4 hours at 4 bar. The catalyst is filtered off, the solvents are eliminated in vacuo and the residue is chromatographed on aluminium oxide (dichloromethane/methanol 95:5 to 80:20).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH:13]=[O:14])([O-:3])=[O:2].[C:15](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[CH3:15][N:9]1[C:10]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)[C:7]([CH:13]=[O:14])=[CH:8]1
Reactant: O=Cc1c[nH]c2ccc([N+](=O)[O-])cc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1cc(C=O)c2cc([N+](=O)[O-])ccc21
Temperature: 60 °C
Reaction time: 24 h
Yield: 92.7 %

Procedure:
5-Nitroindole-3-carboxaldehyde (2 g) was dissolved in N,N-dimethylformamide (40 ml), and potassium carbonate (4.0 g) and methyl iodide (5 ml) were added thereto, followed by stirring at 60° C. for 24 hours. The reaction solution was subjected to partitioning with chloroform, methanol and water, and the organic layer was dried over magnesium sulfate. After concentration under reduced pressure, the residue was rinsed with ethyl acetate to give 1-methyl-5-nitroindole-3-carboxaldehyde (Compound III-2, 1.99 g).
Reaction SMILES: [OH:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[N:9]([C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([O:21]C)=[O:20])=[CH:14][CH:13]=1)=[C:10]=[O:11]>>[OH:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:10](=[O:11])[NH:9][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][C:19]([OH:21])=[O:20])=[CH:16][CH:17]=1
Reactant: COC(=O)Cc1ccc(N=C=O)cc1
Reactant: Nc1ccccc1O
Product: O=C(O)Cc1ccc(NC(=O)Nc2ccccc2O)cc1

Procedure:
4-(2-Hydroxyphenylureido)phenylacetic acid was prepared using procedure C with 2-hydroxyaniline and KCl: 1H NMR (CD3SOCD3, 300 MHz, ppm) 9.90 (s, 1H), 9.25 (s, 1H), 8.12 (s, 1H), 8.02 (bd, 1H), 7.37 (d, 2H), 7.13 (d, 2H), 6.70-6.97 (m, 3H), 3.48 (s, 2H).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH:11]1[CH:16]([OH:17])[CH2:15][CH2:14][N:13]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:12]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH3:35]I>C1COCC1>[C:31]([O:30][C:28]([N:10]([C:8]([O:7][C:3]([CH3:6])([CH3:5])[CH3:4])=[O:9])[C@H:11]1[C@H:16]([O:17][CH3:35])[CH2:15][CH2:14][N:13]([C:18]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:19])[CH2:12]1)=[O:29])([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1CN(C(=O)OCc2ccccc2)CCC1O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CO[C@@H]1CCN(C(=O)OCc2ccccc2)C[C@H]1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 16 h
Yield: 71 %

Procedure:
To a solution of NaH (1.3 equiv.) in THF (0.1M) was added benzyl 3-(bis(tert-butoxycarbonyl)amino)-4-hydroxypiperidine-1-carboxylate (1.0 equiv.) and the reaction was heated to 50° C. for 10 min. Upon cooling to room temperature, MeI (1.5 equiv.) was added and the solution was allowed to stir for 16 h. The reaction was quenched with water, then extracted with EtOAc, the organic was dried with brine and Na2SO4, and concentrated. The crude material was purified via silica gel column chromatography eluting with EtOAc and hexanes (1:3) to give a clear oil in 71% yield. LCMS (m/z): 365.0 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][N:6]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[F:18][C:19]([F:32])([CH:29]([F:31])[F:30])[CH2:20]OS(C(F)(F)F)(=O)=O>CC(C)=O.C(OCC)C>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:20][C:19]([F:32])([F:18])[CH:29]([F:31])[F:30])=[CH:7][N:6]=1)=[O:4]
Reactant: O=S(=O)(OCC(F)(F)C(F)F)C(F)(F)F
Reactant: COC(=O)c1ccc(O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC(C)=O
Product: COC(=O)c1ccc(OCC(F)(F)C(F)F)cn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 5-hydroxy-pyridine-2-carboxylic acid methyl ester (2.0 g, 13.1 mmol) in acetone (40 ml) was treated with potassium carbonate (5.415 g, 39.2 mmol) and trifluoro-methanesulphonic acid 2,2,3,3-tetrafluoropropyl ester. After 4 hours stirring at room temperature the suspension was diluted with diethylether. After filtration the solution was evaporated and the yellow solid purified by chromatography on silica gel using a gradient of heptane/ethyl acetate=100:0 to 30:70 as the eluent. The 5-(2,2,3,3-tetrafluoro-propoxy)-pyridine-2-carboxylic acid methyl ester was obtained as a light yellow solid (3.49 g, 76% of theory). MS (ISP): m/z=468.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:10]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[CH2:18]([NH2:22])[CH2:19][CH2:20][CH3:21]>O>[CH2:18]([NH:22][C:2]1[C:10]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16])[CH2:19][CH2:20][CH3:21]
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Cl
Reactant: CCCCN
Solvent: O
Product: CCCCNc1c([N+](=O)[O-])cc(C(=O)O)cc1S(N)(=O)=O
Temperature: 90 °C
Reaction time: 1.5 h

Procedure:
A mixture of 4-chloro-3-nitro-5-sulphamyl-benzoic acid (8.4 g), n-butylamine (8.7 g), and water (25 ml) was stirred at 90°C for 1.5 hours. After cooling, the pH was adjusted to pH 2, and the precipitated 4-butylamino-3-nitro-5-sulphamyl-benzoic acid was collected by filtration. After several recrystallizations from aqueous methanol the melting point was 192.5°C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]1([CH2:13][O:14][C:15]2[CH:23]=[CH:22][C:21]([S:24]([N:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)(=[O:26])=[O:25])=[CH:20][C:16]=2[C:17]([OH:19])=O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[N:33]1[CH:38]=[CH:37][CH:36]=[C:35]([NH2:39])[CH:34]=1.C(N(C(C)C)CC)(C)C>ClCCl>[C:7]1([CH2:13][O:14][C:15]2[CH:23]=[CH:22][C:21]([S:24]([N:27]3[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]3)(=[O:25])=[O:26])=[CH:20][C:16]=2[C:17]([NH:39][C:35]2[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=2)=[O:19])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Nc1cccnc1
Reactant: O=C(O)c1cc(S(=O)(=O)N2CCCCC2)ccc1OCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccnc1)c1cc(S(=O)(=O)N2CCCCC2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Oxalyl chloride (0.05 ml, 0.59 mmol) in dichloromethane (5 ml) was added dropwise over 1 min to a stirred solution of 2-[(phenylmethyl)oxy]-5-(1-piperidinylsulfonyl)benzoic acid (may be prepared as described in Description 69; 220 mg, 0.59 mmol) in dichloromethane (5 ml) at 0° C. The reaction mixture was stirred at 25° C. for 0.5 h, and then concentrated under reduced pressure to give crude acyl chloride. A solution of this crude acyl chloride in dichloromethane (5 ml) was added dropwise over 5 min to a stirred solution of 3-pyridinamine (55.1 mg, 0.59 mmol) and diisopropylethylamine (0.10 ml, 0.59 mmol) in dichloromethane (20 ml) under nitrogen at 0° C. The reaction mixture was stirred at 25° C. for 1 h. The organic phase was washed with water (25 ml) three times, saturated brine (10 ml) two times, dried over sodium sulfate, and evaporated in vacuo to give crude product as a orange oil. The product was crystallized from methanol to yield the title compound as a white solid. 125 mg.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:15][S:16](Cl)(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][O:21][C:22]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:23]=1[CH2:24][NH2:25]>C1COCC1.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:15][S:16]([NH:25][CH2:24][C:23]2[CH:26]=[CH:27][C:28]([O:30][CH3:31])=[CH:29][C:22]=2[O:21][CH3:20])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)Cc1cccc(OCc2ccccc2)c1
Reactant: COc1ccc(CN)c(OC)c1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(CNS(=O)(=O)Cc2cccc(OCc3ccccc3)c2)c(OC)c1
Reaction time: 0.5 h

Procedure:
Under inert gas, 4.89 g of (3-benzyloxyphenyl)methanesulfonyl chloride were initially charged in 50 ml of THF, then, at a temperature of −20° C., 3.00 ml of 2,4-dimethoxybenzylamine were added dropwise and the reaction solution was allowed to come to 0° C. within 30 minutes. The reaction solution was diluted with 80 ml of ethyl acetate and washed with water, with 10% aqueous potassium hydrogensulfate solution, saturated aqueous sodium hydrogencarbonate solution and saturated sodium chloride solution. The organic phase was dried over MgSO4 and concentrated by rotary evaporation. The crude product was purified by means of normal phase chromatography using a Flashmaster with an n-heptane/ethyl acetate gradient. The product-containing fractions were combined, concentrated by rotary evaporation and dried under high vacuum. This gave the product (3.12 g) with a molecular weight of 427.5 g/mol (C23H25NO5S).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([NH:13][NH2:14])=[O:12])[CH:9]=2)[N:4]([S:15]([C:18]2[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH:3]=1.C(N(C(C)C)C(C)C)C.C1N=CN([C:39](N2C=NC=C2)=[O:40])C=1>CN(C=O)C>[I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[O:12][C:39](=[O:40])[NH:14][N:13]=3)[CH:9]=2)[N:4]([S:15]([C:18]2[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=2)(=[O:16])=[O:17])[CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(C(=O)NN)ccc32)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4n[nH]c(=O)o4)ccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.5 %

Procedure:
To a solution of 3-iodo-1-tosyl-1H-indole-5-carbohydrazide (2.00 g, 4.39 mmol) in DMF (10 mL) at RT was added N-ethyl-N-isopropylpropan-2-amine (1.68 mL, 9.66 mmol) and CDI (0.784 g, 4.83 mmol). The reaction was stirred at RT for 30 min, followed by 65° C. in an oil bath for 15 min. It was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel (eluted with 20-70% EtOAc in Hex) to afford 5-(3-iodo-1-tosyl-1H-indol-5-yl)-1,3,4-oxadiazol-2(3H)-one (1.7 g, 80%) as an off white crystalline solid. MS (ESI, pos. ion) m/z: 482.0 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=[C:6]([N+:14]([O-:16])=[O:15])[C:5]=1Cl)([O-:3])=[O:2].[CH3:18][NH:19][CH3:20].C(O)C>O>[CH3:18][N:19]([CH3:20])[C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15]
Reactant: CNC
Reactant: CC(C)(C)c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Solvent: O
Solvent: CCO
Product: CN(C)c1c([N+](=O)[O-])cc(C(C)(C)C)cc1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
Two and six-tenths grams (.01 mole) of 2,6-dinitro-4-t-butylchlorobenzene was reacted with 3.1 grams of 40% aqueous solution of dimethylamine in 50 ml. ethanol. The temperature was slowly increased as follows: 30° C. for 1 hour, 40° C. for 1 hour, 50° C. for one hour, then 80° C. for five hours. When the reaction was complete, about 100 ml. H2O was added, precipitating the product. This was filtered, washed with portions of H2O and upon recrystallization from ethanol yielded 2.5 grams of N,N-dimethyl-2,6-dinitro-4-t-butylaniline in the form of orange-yellow needles melting at 101-102° C.
Reaction SMILES: CC1C=[C:6]([N:8]2C=N[N:10]=[N:9]2)C=CC=1CC(O)=O.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]([OH:27])=[O:26])=[C:20]([C:28]([F:31])([F:30])[F:29])[CH:19]=1>>[N:17]1([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][C:25]([OH:27])=[O:26])=[C:20]([C:28]([F:29])([F:30])[F:31])[CH:19]=2)[CH:6]=[N:8][N:9]=[N:10]1
Reactant: Nc1ccc(CC(=O)O)c(C(F)(F)F)c1
Reactant: Cc1cc(-n2cnnn2)ccc1CC(=O)O
Product: O=C(O)Cc1ccc(-n2cnnn2)cc1C(F)(F)F

Procedure:
[4-(1H-tetrazol-1-yl)-2-(trifluoromethyl)phenyl]acetic acid was prepared in a similar fashion to that described for the synthesis of [2-methyl-4-(1H-tetrazol-1-yl)phenyl]acetic acid starting from [4-amino-2-(trifluoromethyl)phenyl]acetic acid. LC-MS (IE, m/z): 273 [M+1]+.
Reaction SMILES: C([NH:8][C:9]1[C:19]([N+:20]([O-])=O)=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([O:23][CH2:24][CH3:25])[CH:10]=1)C1C=CC=CC=1.C(O)C>[Pd].C1COCC1>[NH2:8][C:9]1[C:19]([NH2:20])=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([O:23][CH2:24][CH3:25])[CH:10]=1
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c(NCc2ccccc2)cc1OCC
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(N)c(N)cc1OCC

Procedure:
Palladium on charcoal (3.50 g 10%) was added to the product obtained at (655c) (16.7 g, 46.1 mmol) in 200 mL THF with 200 mL ethanol and the mixture was hydrogenated using a Parr apparatur at 60 psi H2 pressure and 50° C. for 3 h. The mixture was filtered, washed with ethanol and the filtrate concentrated i. vac. The residue was triturated with dichloromethane and evaporated to dryness. The product was reacted without further purification.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([C:19]([O:21]C)=[O:20])[CH:16]=[CH:15][N:14]=2)[N:10]=[CH:9]1)(=O)=O.[Cl:23][C:24]1[CH:34]=[CH:33][C:27]([CH2:28][NH:29][CH:30]2[CH2:32][CH2:31]2)=[CH:26][CH:25]=1>>[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([CH2:28][N:29]([CH:30]2[CH2:31][CH2:32]2)[CH2:6][CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[C:17]([C:19]([OH:21])=[O:20])[CH:16]=[CH:15][N:14]=3)[N:10]=[CH:9]2)=[CH:33][CH:34]=1
Reactant: COC(=O)c1ccnc(-c2cn(CCOS(C)(=O)=O)cn2)c1
Reactant: Clc1ccc(CNC2CC2)cc1
Product: O=C(O)c1ccnc(-c2cn(CCN(Cc3ccc(Cl)cc3)C3CC3)cn2)c1
Yield: 8 %

Procedure:
The title compound was prepared in 8% yield from methyl 2-(1-{2-[(methylsulfonyl)oxy]ethyl}-1H-imidazol-4-yl)pyridine-4-carboxylate (PREPARATION 6) and (4-chlorobenzyl)cyclopropylamine according to the procedure for the preparation of Example 58. 1HNMR (400 MHz, DMSO): δ 0.17 (2H, m), 0.40 (2H, m), 1.83 (1H, m), 2.88 (2H, t, J=6.4 Hz), 3.72 (2H, s), 4.10 (2H, t, J=6.2 Hz), 7.26 (1H, d, J=8.4 Hz), 7.32 (2H, t, J=8.4 Hz), 7.45 (1H, dd, J=3.7 Hz), 7.64 (2H, d, J=4.4 Hz), 8.21 (1H, s), 8.31 (1H, s), 8.40 (1H, d, J=4.8 Hz). [M+H] Calc'd for C21H21ClN4O2, 398. Found, 398.