Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=[CH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21]C(=O)C)=[CH:17][CH:16]=2)C(O)=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(O)C.Cl>O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]=[CH:14][C:15]2[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC(=O)Oc1ccc(C=C(C(=O)O)c2ccc([N+](=O)[O-])cc2)cc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1ccc(C=Cc2ccc(O)cc2)cc1
Temperature: 95 °C

Procedure:
A portion (36.75 grams) of a-p-nitrophenyl-p-acetoxycinnamic acid from A. above, ethanol (300 mL) and concentrated hydrochloric acid (300 mL) are added to a reactor equipped with a reflux condenser and stirred under a nitrogen atmosphere. Heating commenced and a reflux is achieved at 93° C. Refluxing continued over the next 262 minutes at which time the temperature has increased to 95° C. At this time, the contents of the reactor are poured into deionized water (one liter) and the resultant precipitate recovered by filtration. The wet filter cake is washed with two portions (500 mL) of deionized water then dissolved in stirred ethanol (750 mL) maintained at 82° C. The resultant solution is maintained at 4° C. for 15 hours. The precipitate is recovered by filtration and dried at 75° C. under a vacuum of 2 mm Hg to a constant weight of 22.70 grams of light orange colored crystalline needles. Fourier transform infrared spectrophotometric analysis of a potassium chloride pellet of a portion of the product revealed the presence of the expected hydroxyl group O--H stretching centered at 3422 cm-1 (broad), conjugated nitro group absorbances at 1516 and 1337 (1317 shoulder) cm-1 (sharp) and the ethylene C-H out-of-plane deformation at 972 cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:44])[CH:5]=[C:6]([Cl:43])[C:7]=1[CH2:8][C@@H:9]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH:35]([F:37])[F:36])=[C:30]([O:38][CH2:39][CH:40]2[CH2:42][CH2:41]2)[CH:29]=1)[O:10][C:11](=[O:27])[CH2:12][NH:13][S:14]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=1)(=[O:16])=[O:15].Cl[CH2:46][CH2:47][N:48]1[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:44])[CH:5]=[C:6]([Cl:43])[C:7]=1[CH2:8][C@@H:9]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH:35]([F:36])[F:37])=[C:30]([O:38][CH2:39][CH:40]2[CH2:42][CH2:41]2)[CH:29]=1)[O:10][C:11](=[O:27])[CH2:12][N:13]([CH2:46][CH2:47][N:48]1[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1)[S:14]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=1)(=[O:15])=[O:16]
Reactant: ClCCN1CCOCC1
Reactant: COc1ccc(S(=O)(=O)NCC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(S(=O)(=O)N(CCN2CCOCC2)CC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1OC
Temperature: 40 °C
Reaction time: 6 h
Yield: 79 %

Procedure:
(S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(3,4-dimethoxyphenylsulfonamido)acetoxy)ethyl)pyridine 1-oxide (30 mg, 0.04 mmol) was dissolved in DMF (1 ml), then 4-(2 chloroethyl)morpholine free base (33 mg, 0.22 mmol), K2CO3 (12 mg, 0.088 mmol) and KI (7 mg, 0.0044 mmol) were added, and the mixture was stirred at 40° C. for 6 hours. The reaction was diluted with water, and the product was extracted with EtOAc. The organic phase was dried over Na2SO4 and evaporated under vacuum. The crude product was purified by Preparative reverse-phase HPLC to give 25 mg of the final product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]1NN=[N:26][N:25]=1.C1(N=C=NC2CCCCC2)CCCCC1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15]1[O:17][C:24]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=2)=[N:25][N:26]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: c1ccc(-c2nnn[nH]2)nc1
Reactant: CC(C)(C)OC(=O)N1CCCCC1CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: CC(C)(C)OC(=O)N1CCCCC1Cc1nnc(-c2ccccn2)o1
Yield: 59.5 %

Procedure:
The title compound (1.39 g) was prepared from 2-carboxymethyl-piperidine-1-carboxylic acid tert butyl ester (1.65 g), 5-(pyridin-2-yl)tetrazole (1.0 g) and dicyclohexylcarbodiimide (1.43 g) according to the method of description 1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH3:14])=[C:12]([CH:15]([CH3:17])[CH3:16])[N:11]=[C:10]([N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])[N:9]=2)=[CH:4][CH:3]=1.BrN1C(=[O:30])CCC1=O.C([O-])(O)=O.[Na+].O>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:13]([CH2:14][OH:30])=[C:12]([CH:15]([CH3:17])[CH3:16])[N:11]=[C:10]([N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1c(-c2ccc(F)cc2)nc(N(C)S(C)(=O)=O)nc1C(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1CO
Temperature: 25 °C
Yield: 95 %

Procedure:
N-(4-(4-fluorophenyl)-5-methyl-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide (112.5 mg, 0.33 mmol, 1 equiv.) and N-bromosuccinimide (NBS) (118.7 mg, 0.66 mmol, 2 equiv.) were dissolved in 2 mL of acetonitrile. The mixture was irradiated with light of a wavelength A=310 nm for 4 hours at ambient temperature (about 20° C.). The obtained yellow solution was diluted with 1 mL of acetonitrile. After 2 mL of saturated NaHCO3 solution was added, the obtained mixture was further stirred under reflux for 4 hours. Then the mixture was cooled to room temperature, water (10 mL) was added and the mixture was extracted with CH2Cl2 (3×10 mL). The combined organic phases were washed with 10 mL of brine, and the obtained solution was dried with Na2SO4. Solvent was removed under the reduced pressure to give 110.8 mg (95%) of crude N-(4-(4-fluorophenyl)-5-(hydroxymethyl)-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide (III) which contained 77% of N-(4-(4-fluorophenyl)-5-(hydroxymethyl)-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide (III) as determined by 1H-NMR integral. This product can be further purified by crystallization from MTBE/hexane mixture to afford pure material (HPLC area %=99.6) with Tm=140-141° C.
Reaction SMILES: [CH2:1]([Li])CCC.CCCCCC.[Si:12]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH:24]([C:35]1[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:36]=1[F:42])[S:25]([C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)(=[O:27])=[O:26])([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].IC>O1CCCC1.O>[Si:12]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([C:35]1[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:36]=1[F:42])([S:25]([C:28]1[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=1)(=[O:27])=[O:26])[CH3:1])([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]
Reactant: CC(C)(C)[Si](C)(C)OCCCCC(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Solvent: CCCCCC
Product: CC(C)(C)[Si](C)(C)OCCCCC(C)(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In an argon gas stream and at −78° C., n-butyl lithium (a 1.57M hexane solution, 0.294 ml, 0.461 mmol) was added to a solution of 2-[5-(t-butyldimethylsilyloxy)-1-[(4-chlorophenyl)sulfonyl]pentyl]-1,4-difluorobenzene (205 mg, 0.419 mmol) in tetrahydrofuran (4 ml). The mixture was stirred at room temperature for 1 hour. After cooling to −78° C., iodomethane (0.339 ml, 0.545 mmol) was added dropwise to the reaction mixture and the mixture was stirred at room temperature for 4 hours. Water was added to the reaction mixture, followed by extraction with diethyl ether. The extracts were combined, washed successively with water and brine, dried over MgSO4, and then concentrated. The residue thus obtained was purified by medium-pressure chromatography on a silica gel column (6% ethyl acetate-hexane), whereby the title compound (168 mg, 80%) was obtained as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([NH:7][C:8]([C:10]2[C:15]([NH2:16])=[CH:14][CH:13]=[C:12]([CH3:17])[N:11]=2)=[O:9])[N:6]=1.Br[C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1>>[CH3:1][C:2]1[S:3][CH:4]=[C:5]([NH:7][C:8]([C:10]2[C:15]([NH:16][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)=[CH:14][CH:13]=[C:12]([CH3:17])[N:11]=2)=[O:9])[N:6]=1
Reactant: Cc1ccc(N)c(C(=O)Nc2csc(C)n2)n1
Reactant: Brc1cccnc1
Product: Cc1ccc(Nc2cccnc2)c(C(=O)Nc2csc(C)n2)n1

Procedure:
The title compound, was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid (2-methyl-thiazol-4-yl)-amide and 3-Bromopyridine in accordance with the general method of example 20 to yield the final compound as a yellow crystalline solid, MS (ISP): m/e=326.0 (M+H+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3([C:18]([NH:20][NH:21]C(OC(C)(C)C)=O)=[O:19])[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)=[N:7][CH:8]=1)#[N:2]>Cl.O1CCOCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3([C:18]([NH:20][NH2:21])=[O:19])[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)=[N:7][CH:8]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)NNC(=O)C1(c2ccc(-c3ccc(C#N)cn3)cc2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1ccc(-c2ccc(C3(C(=O)NN)CC3)cc2)nc1
Temperature: 25 °C
Yield: 96.8 %

Procedure:
A solution of the compound (72.7 g, 192 mmol) obtained in Example 60-2) in 2 N hydrochloric acid-dioxane (728 mL) was stirred at room temperature for 30 min and further at 50° C. for 30 min. The reaction mixture was cooled to room temperature, the solvent was distilled off under reduced pressure, dichloromethane was added to the residue, and the organic layer was washed with saturated sodium hydrogencarbonate and saturated sodium chloride solution in this order and then dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was solidified with a mixed solvent (600 mL) of ethyl acetate and hexane (1:5) and collected by filtration. The obtained solid was dried under reduced pressure to obtain the title compound (51.7 g, 97%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:17][N:18]([CH3:22])[C:19](Cl)=[O:20]>>[Cl:1][C:2]1[C:3]([O:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:19](=[O:20])[N:18]([CH3:22])[CH3:17])=[CH:12][CH:11]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Oc1ccc(Oc2ncc(Cl)cc2Cl)cc1
Reactant: CN(C)C(=O)Cl
Product: CN(C)C(=O)Oc1ccc(Oc2ncc(Cl)cc2Cl)cc1

Procedure:
The title compound was prepared from 4-(3,5-dichloro pyridin-2-yloxy)-phenol and dimethyl-carbamoyl chloride. The crude product was purified by preparative HPLC (38%). HPLC-MS m/z=327.0 (M+1), Rt: 4.7 min.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]3[C:16](=[O:18])[C:15]([CH3:20])([CH3:19])[CH2:14][CH2:13][C:12]=3[N:11]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[C:10](=[O:31])[NH:9]2)=[CH:4][CH:3]=1.O.[CH3:33][N:34](C)C=O>[C-]#N.[Zn+2].[C-]#N>[CH3:20][C:15]1([CH3:19])[CH2:14][CH2:13][C:12]2[N:11]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:29])[F:30])[CH:22]=3)[C:10](=[O:31])[NH:9][CH:8]([C:5]3[CH:4]=[CH:3][C:2]([C:33]#[N:34])=[CH:7][CH:6]=3)[C:17]=2[C:16]1=[O:18]
Reactant: CC1(C)CCC2=C(C1=O)C(c1ccc(Br)cc1)NC(=O)N2c1cccc(C(F)(F)F)c1
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: CC1(C)CCC2=C(C1=O)C(c1ccc(C#N)cc1)NC(=O)N2c1cccc(C(F)(F)F)c1
Temperature: 110 °C

Procedure:
Under an atmosphere of argon, a mixture of 4-(4-bromophenyl)-6,6-dimethyl-1-(3-(tri-fluoromethyl)phenyl)-3,4,7,8-tetrahydroquinazoline-2,5(1H,6H)-dione (intermediate 7, 372 mg, 0.754 mmol), zinc cyanide (110 mg, 0.937 mmol) and tetrakis(triphenyl-phosphine)palladium(O) (50 mg, 43 μmol) in N,N-dimethylformamide (2 mL) is heated at 110° C. over night. Water is added and the mixture is filtered. The precipitate is purified by flash chromatography on silica (gradient cyclohexane/ethyl acetate 80:20 to 60:40). Yield: 220 mg; ESI mass spectrum [M+H]+=440; Retention time HPLC: 1.26 min (Z005—001).
Reaction SMILES: [CH2:1]([O:8][C:9]([C@@H:11]1[N:15]2[C:16](=[O:21])[C@@H:17]([C@H:18]([OH:20])[CH3:19])[C@H:14]2[S:13](=[O:23])(=[O:22])[C:12]1([CH3:25])[CH3:24])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26]([Si:30]([CH3:33])([CH3:32])Cl)([CH3:29])([CH3:28])[CH3:27].N1C=CN=C1>>[CH2:1]([O:8][C:9]([C@@H:11]1[N:15]2[C:16](=[O:21])[C@@H:17]([C@H:18]([O:20][Si:30]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:33])[CH3:32])[CH3:19])[C@H:14]2[S:13](=[O:22])(=[O:23])[C:12]1([CH3:24])[CH3:25])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H](O)[C@@H]1C(=O)N2[C@@H](C(=O)OCc3ccccc3)C(C)(C)S(=O)(=O)[C@H]12
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H]1C(=O)N2[C@@H](C(=O)OCc3ccccc3)C(C)(C)S(=O)(=O)[C@H]12

Procedure:
In a manner analogous to that described in Examples (1ba) to (1bc), by reaction of (3S,5R,6R)-2,2-dimethyl-6-[(1R)-1-hydroxyethyl]-penam-3-carboxylic acid benzyl ester 1,1-dioxide (German Offenlegungsschrift No. 3039504) with tert.-butyldimethylchlorosilane and imidazole, (3S,5R,6R)-2,2-dimethyl-6-[(1R)-1-(tert.-butyl-dimethyl-silyloxy)-ethyl]-penam-3-carboxylic acid benzyl ester 1,1-dioxide [IR (methylene chloride): 3.42; 5.56; 5.63μ] is obtained, which is treated with DBU and then with DBU/methyl iodide. The resulting 2-[(3S,4R)-3-((1R)-1-(tert.-butyl-dimethyl-silyloxy)-ethyl)-4-methylsulphonyl-2-oxoazetidin-1-yl]-3-methyl-2-butenoic acid benzyl ester [IR (methylene chloride): 5.63; 5.80; 6.15μ] yields the desired product when ozonolised and subsequently treated with methanol.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:14])[C:5]1[CH:10]=[C:9]([NH:11][NH2:12])[CH:8]=[CH:7][C:6]=1[Cl:13].O=[CH:16][C:17]([OH:19])=[O:18]>Cl>[CH3:2][O:3][C:4](=[O:14])[C:5]1[CH:10]=[C:9]([NH:11][N:12]=[CH:16][C:17]([OH:19])=[O:18])[CH:8]=[CH:7][C:6]=1[Cl:13]
Reactant: O=CC(=O)O
Reactant: COC(=O)c1cc(NN)ccc1Cl
Agent: Cl
Product: COC(=O)c1cc(NN=CC(=O)O)ccc1Cl
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
2-Chloro-5-hydrazino-benzoic acid methyl ester hydrochloride salt (2.0 g, 8.5 mmol) and oxoacetic acid (1.0 g, 10 mmol) were taken up in 10% HCl and stirred at ambient temperature for 1.5 hours. The resulting orange precipitate was collected by filtration. The filter cake was taken up in EtOAc, washed with brine, and dried over sodium sulfate. Concentration in vacuo yielded the above named compound (1.2 g).
Reaction SMILES: [CH2:1]1[CH:9]2[N:4]([CH2:5][CH2:6][CH:7]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[N:16][CH:17]=4)[NH:12][CH:11]=3)[CH2:8]2)[CH2:3][CH2:2]1.[C:19]1([S:29](Cl)(=[O:31])=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[CH2:1]1[CH:9]2[N:4]([CH2:5][CH2:6][CH:7]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[N:16][CH:17]=4)[N:12]([S:29]([C:19]4[C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[CH:22]=[CH:21][CH:20]=4)(=[O:31])=[O:30])[CH:11]=3)[CH2:8]2)[CH2:3][CH2:2]1
Reactant: c1cc2[nH]cc(C3CCN4CCCC4C3)c2cn1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(=O)(c1cccc2ccccc12)n1cc(C2CCN3CCCC3C2)c2cnccc21

Procedure:
from 3-(octahydro-7-indolizinyl)-1-H-5-azaindole (10 mg, 0.0415 mmol), 1-naphthalenesulfonyl chloride (17.2 mg, 0.0828 mmol) and 1M NaN(TMS)2 (100 μL, 0.10 mmol) in THF (0.5 mL) at RT.
Reaction SMILES: [OH:1][CH2:2][C:3]([F:42])([F:41])[C:4]([F:40])([F:39])[C:5]([F:38])([F:37])[C:6]([F:36])([F:35])[C:7]([F:34])([F:33])[C:8]([F:32])([F:31])[C:9]([F:30])([F:29])[C:10]([F:28])([F:27])[CH2:11][O:12][C:13]1[CH:26]=[CH:25][C:16]([C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:18])=[CH:15][CH:14]=1.[N+:43]([C:46]1[CH:51]=[C:50]([N+:52]([O-:54])=[O:53])[CH:49]=[CH:48][C:47]=1Cl)([O-:45])=[O:44]>CN1C(=O)CCC1>[N+:43]([C:46]1[CH:51]=[C:50]([N+:52]([O-:54])=[O:53])[CH:49]=[CH:48][C:47]=1[O:1][CH2:2][C:3]([F:41])([F:42])[C:4]([F:39])([F:40])[C:5]([F:37])([F:38])[C:6]([F:35])([F:36])[C:7]([F:33])([F:34])[C:8]([F:31])([F:32])[C:9]([F:29])([F:30])[C:10]([F:28])([F:27])[CH2:11][O:12][C:13]1[CH:26]=[CH:25][C:16]([C:17]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:18])=[CH:15][CH:14]=1)([O-:45])=[O:44]
Reactant: O=C(c1ccccc1)c1ccc(OCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)CO)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: CN1CCCC1=O
Product: O=C(c1ccccc1)c1ccc(OCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)COc2ccc([N+](=O)[O-])cc2[N+](=O)[O-])cc1

Procedure:
A solution of 4-(10-Hydroxy-2,2,3,3,4,4,5,5,6,6,7,7,8,8,9,9-hexadecafluorodecyloxy)benzophenone (6.42 g), 2,4-dinitrochlorobenzene (2.42 g) potassium carbonate (2.76 g) and NMP (15 mL) is heated to 75-80° C. for 24 hrs. The solution is further processed as described in Example 2 to give 4-[10-(2,4-dinitrophenoxy)-2,2,3,3,4,4,5,5,6,6,7,7,8,8,9,9-hexadecafluorodecyloxy]benzophenone.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][N:5]([CH2:7][C:8]([N:10]([CH3:12])[CH3:11])=[O:9])[CH:6]=1.[CH3:13][Si:14]([C:17]#[CH:18])([CH3:16])[CH3:15].C(NC(C)C)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.[Cu]I.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:11][N:10]([CH3:12])[C:8](=[O:9])[CH2:7][N:5]1[CH:6]=[C:2]([C:18]#[C:17][Si:14]([CH3:16])([CH3:15])[CH3:13])[CH:3]=[N:4]1
Reactant: CN(C)C(=O)Cn1cc(I)cn1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: CN(C)C(=O)Cn1cc(C#C[Si](C)(C)C)cn1
Temperature: 60 °C
Yield: 91.1 %

Procedure:
2-(4-Iodo-1H-pyrazol-1-yl)-N,N-dimethylacetamide (Preparation 99, 0.68 g, 2.42 mmol) and trimethylsilylacetylene (0.326 g, 3.32 mmol) were dissolved in dry DMF (5 ml) and placed under argon. Diisopropylamine (0.47 ml, 3.3 mmol), copper (1) iodide (30 mg, 0.16 mmol), triphenylphosphine (126 mg, 0.242 mmol) and palladium acetate (40 mg, 0.16 mmol) were added and the flask was flushed with argon. The reaction was heated to 60° C. for 1 hour. The reaction was cooled to room temperature and diluted with ethyl acetate (30 ml). The organic solution was washed with water, brine, dried over sodium sulphate and filtered. The solvent was removed in vacuum and the crude purified on silica gel column chromatography eluting with neat ethyl acetate to afford the title compound as a pale yellow powder (0.55 g, 91%). 1H-NMR (500 MHz, CDCl3): δ 0.21 (s, 9H), 2.96 (s, 3H), 3.04 (s, 3H), 4.92 (s, 2H), 7.59 (s, 1H), 7.65 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:10][CH:11]2[CH2:16][CH2:15][CH:14]([NH2:17])[CH2:13][CH2:12]2)=[N:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl[C:19]1[NH:23][C:22]2[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=2[N:20]=1>CN1CCCC1=O.O>[NH:20]1[C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=[C:19]1[NH:17][CH:14]1[CH2:15][CH2:16][CH:11]([NH:10][C:5]2[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=[CH:7][N:6]=2)[CH2:12][CH2:13]1
Reactant: Clc1nc2ccccc2[nH]1
Reactant: NC1CCC(Nc2ncccc2[N+](=O)[O-])CC1
Solvent: O
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1cccnc1NC1CCC(Nc2nc3ccccc3[nH]2)CC1
Temperature: 180 °C
Yield: 53.6 %

Procedure:
A mixture of N1-(3-nitropyridin-2-yl)cyclohexane-1,4-diamine (500 mg, 2.11 mmol) and 2-chloro-1H-benzoimidazole (320 mg, 2.11 mmol) in N-methylpyrrolidinone (5 mL) was heated at 180° C. in microwave for 2 hours. The mixture was diluted with water (60 mL), and extracted with ethyl acetate (2×50 mL). The organic layer was dried over sodium sulfate and concentrated to give N1-(1H-benzo[d]imidazol-2-yl)-N4-(3-nitropyridin-2-yl)cyclohexane-1,4-diamine (400 mg, 1.13 mmol, 53.8% yield) which was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([C:14]([F:17])([F:16])[F:15])=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.[CH3:19][NH:20][C@H:21]([C:23]([OH:25])=[O:24])[CH3:22].O.ON1C2C=CC=NC=2C=N1.CN1CCOCC1>O1CCCC1>[CH3:19][N:20]([C:4](=[O:6])[C:3]1[CH:7]=[C:8]([C:14]([F:17])([F:16])[F:15])[CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:2]=1[NH2:1])[C@H:21]([C:23]([OH:25])=[O:24])[CH3:22]
Reactant: CN[C@@H](C)C(=O)O
Reactant: Nc1c(C(=O)O)cc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: Cl
Agent: On1ncc2ncccc21
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](C(=O)O)N(C)C(=O)c1cc(C(F)(F)F)cc([N+](=O)[O-])c1N
Reaction time: 8 h
Yield: 71.2 %

Procedure:
To a cooled (−5° C.) mixture of 20.0 parts of 2-amino-3-nitro-5-(trifluoromethyl)benzoic acid, 11.17 parts of methyl(S)-alanine monohydrochloride, 21.62 parts of 1-hydroxy-1H-1,2,4-benzotriazole monohydrate and 356 parts of tetrahydrofuran under argon there were added 8.1 parts of N-methylmorpholine and, after stirring for 10 min 16.5 parts of N,N-methanetetraylbis[cyclohexanamine]. Stirring was continued for 1 hour at −5° C. and overnight at room temperature. After cooling on ice, the reaction mixture was filtered and the filtrate was evaporated. The residue was dissolved in dichloromethane and this solution was washed with NaHCO3 (aq.), dried, filtered and evaporated. The residue was recrystallized from methylcyclohexane (2×), yielding 19.1 parts (71.2%) of methyl(S)-N-[2-amino-3-nitro-5-(trifluoromethyl)benzoyl]alanine; mp. 136.4° C. (interm. 33).
Reaction SMILES: N1(O[C:11](=[O:21])[C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([O:19][CH3:20])[CH:13]=2)C2C=CC=CC=2N=N1.Cl.Cl.[F:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][CH:30]([NH2:33])[CH2:29][CH2:28]1.CN(C)C=O.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C.[Cl-].[Na+].O.O.C(N(CC)CC)C>[NH2:18][C:15]1[CH:16]=[CH:17][C:12]([C:11]([NH:33][CH:30]2[CH2:31][CH2:32][N:27]([CH2:26][CH2:25][F:24])[CH2:28][CH2:29]2)=[O:21])=[CH:13][C:14]=1[O:19][CH3:20]
Reactant: NC1CCN(CCF)CC1
Reactant: COc1cc(C(=O)On2nnc3ccccc32)ccc1N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)NC2CCN(CCF)CC2)ccc1N
Reaction time: 25 h
Yield: 73.7 %

Procedure:
To a mixture of 0.5432 g (1.91 mmole) of 4-amino-3-methoxy-benzoic acid benzotriazol-1-yl ester, 0.4187 g (1.91 mmole) of 1-(2-fluoro-ethyl)-piperidin-4-ylamine dihydrochloride and 8 mL of dimethylformamide was added 1.3316 mL of triethylamine. The mixture was stirred for 25 hours, then taken up in ethyl acetate and twice with 50 mL 0.5 M sodium carbonate, once with 50 mL water, once with 50 mL brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with acetonitrile-methanol-triethylamine (90:10:0.8), to give 0.4159 g 4-amino-N-[1-(2-fluoro-ethyl)-piperidin-4-yl]-3-methoxy-benzamide.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].Cl[C:6]([O:8][CH2:9][CH:10]([CH3:12])[CH3:11])=[O:7]>C(Cl)Cl>[OH:2][CH2:1][CH2:3][NH:4][C:6](=[O:7])[O:8][CH2:9][CH:10]([CH3:12])[CH3:11]
Reactant: NCCO
Reactant: CC(C)COC(=O)Cl
Solvent: ClCCl
Product: CC(C)COC(=O)NCCO
Temperature: 25 °C
Reaction time: 4 h

Procedure:
42.8 g of ethanolamine are placed in 350 ml of methylene chloride. 47.8 g of isobutyl chloroformate are then added dropwise during 1 hour at 5°-15° C. while cooling with ice. After stirring at room temperature for a further 4 hours, the methylene chloride is removed by evaporation and the residue is distilled. There is obtained pure isobutyl 2-hydroxyethylcarbamate; b.p. 111°-113° C./0.07 Torr.