Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[S:2]([OH:5])(=[O:4])=[O:3].[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[C:17]([C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)=[CH:16][C:15]([C:23]([F:26])([F:25])[F:24])=[N:14]1.[O-]S([O-])(=O)=O.[Na+].[Na+]>C(Cl)Cl>[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[C:17]([C:18]2[S:19][C:20]([S:2]([OH:5])(=[O:4])=[O:3])=[CH:21][CH:22]=2)=[CH:16][C:15]([C:23]([F:26])([F:24])[F:25])=[N:14]1
Reactant: O=S(=O)(O)Cl
Reactant: FC(F)(F)c1cc(-c2cccs2)n(-c2ccccc2Cl)n1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=S(=O)(O)c1ccc(-c2cc(C(F)(F)F)nn2-c2ccccc2Cl)s1
Temperature: -78 °C

Procedure:
Chlorosulfonic acid (1.0 mL, 15 mmol) was added dropwise to a cold (−78° C.) solution of 1-(2-chlorophenyl)-5-(thiophen-2-yl)-3-(trifluoromethyl)-1H-pyrazole (1.0 g, 3.2 mmol) in CH2Cl2 (22 mL) After 75 minutes stirring at −78° C. the cooling bath was removed and the brown solution was allowed to warm to ambient temperature. After 3½ hours stirring at ambient temperature, the reaction mixture was poured onto ice and diluted with CH2Cl2. The milky lower organic phase was separated and dried over Na2SO4. Filtration and concentration under reduced pressure of the organics gave a biphasic mixture that was further pumped down under high vacuum. NMR and GC/MS analysis of this material showed it not to be the product. The aqueous phase from the workup was saturated with Na2SO4 and extracted with EtOAc (3×). These organic extract were dried over Na2SO4, filtered and concentrated under reduced pressure to afford 5-(1-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)thiophene-2-sulfonic acid as a yellow syrup. This crude material was carried on to the sulfonyl chloride formation without purification. MS(ES): 409[M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:26](=[O:27])[N:25]([CH3:28])[C:11]3[N:12]([CH3:24])[C:13]4[C:18]([C:10]=3[CH:9]=2)=[CH:17][C:16]([C:19]2[NH:20][N:21]=[CH:22][CH:23]=2)=[CH:15][CH:14]=4)=[CH:4][CH:3]=1.I[CH2:30][CH3:31]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:26](=[O:27])[N:25]([CH3:28])[C:11]3[N:12]([CH3:24])[C:13]4[C:18]([C:10]=3[CH:9]=2)=[CH:17][C:16]([C:19]2[CH:23]=[CH:22][N:21]([CH2:30][CH3:31])[N:20]=2)=[CH:15][CH:14]=4)=[CH:4][CH:3]=1
Reactant: CCI
Reactant: Cn1c(=O)c(-c2ccc(Br)cc2)cc2c3cc(-c4ccn[nH]4)ccc3n(C)c21
Product: CCn1ccc(-c2ccc3c(c2)c2cc(-c4ccc(Br)cc4)c(=O)n(C)c2n3C)n1

Procedure:
The process is carried out as indicated in Example 36 above, using 3-(4-bromophenyl)-1,9-dimethyl-6-(2H-pyrazol-3-yl)-1,9-dihydropyrido[2,3-b]indol-2-one from Example 60 above and iodoethane.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[O:7].[Na].Br[CH2:10][CH2:11][CH2:12][Cl:13]>C1(C)C(C)=CC=CC=1>[Cl:13][CH2:12][CH2:11][CH2:10][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[O:7]
Reactant: ClCCCBr
Reactant: O=C1CCCCN1
Agent: [Na]
Solvent: Cc1ccccc1C
Product: O=C1CCCCN1CCCCl
Reaction time: 6 h

Procedure:
A mixture of 2-piperidone (1.19 g, 12.0 mmcl) and finely pulverized sodium metal (0.28 g, 12.0 mmol) in dry xylene (70 ml) was heated at 110° C. with vigrous stirring, 1-bromo-3-chloropropane (1.89 g, 12.0 mmol) was added to the stirred reaction mixture after 3 hours and the heating at 110° C. was continued for 6 hours. The reaction mixture was filtered and xylene was removed under reduced pressure. The residue was chromatographed on silica gel using hexane and chloroform as eluant to get 3 (n=2), B.P. 91° C./0.01 mm., yield 1.33 g (63.33%). IR (Neat): 3862, 3298, 2950, 2474, 2324, 1640, 1478, 1432, 1336, 1184, 1096, 754. 1H NMR (CDCl3): 1.79-2.36(m,8H), 3.15-3.67(m,6H). MS: m/z 175 (M+).
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:6]([NH2:12])=[CH:7][CH:8]=[C:9]([CH3:11])[CH:10]=1)([CH3:3])[CH3:2].C1(N=C=NC2CCCCC2)CCCCC1.Br[CH2:29][C:30](O)=[O:31].C(=O)([O-])[O-].[K+].[K+]>ClCCl>[CH:1]([N:4]1[C:5]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:11])[CH:10]=2)[NH:12][C:30](=[O:31])[CH2:29]1)([CH3:3])[CH3:2]
Reactant: O=C(O)CBr
Reactant: Cc1ccc(N)c(NC(C)C)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: Cc1ccc2c(c1)N(C(C)C)CC(=O)N2
Temperature: 60 °C
Reaction time: 1 h
Yield: 7.4 %

Procedure:
Compound 25B (2.17 g, 13.2 mmol) in 40 mL of dichloromethane was treated with a premixed solution of 1,3-dicyclohexylcarbodiimide (3 g, 14.5 mmol) and bromoacetic acid (1.84 mg, 13.2 mmol) in 30 mL of dichloromethane. The reaction was stirred for 1 hour and then quenched with 50 mL of water and extracted with dichloromethane (3×50 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and excess solvent removed via rotary evaporator. The crude product was then dissolved in 30 mL of DMSO and potassium carbonate (2.27 g, 16.5 mmol) was added to the mixture. The reaction was heated to 60° C. overnight then cooled and poured oven ice water. The resulting precipitate was collected be filtration to give 200 mg (7%) of desired product. MS (electrospray): mass calculated for C12H16N2O, 204.13; m/z found 205.1, [M+H]+.
Reaction SMILES: [N:1]([CH:4]([C:6]1[N:7]=[C:8]2[S:16][CH:15]=[CH:14][N:9]2[C:10](=[O:13])[C:11]=1Br)[CH3:5])=[N+:2]=[N-:3].[F:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[C:22]([F:24])[CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:1]([CH:4]([C:6]1[N:7]=[C:8]2[S:16][CH:15]=[CH:14][N:9]2[C:10](=[O:13])[C:11]=1[C:20]1[CH:19]=[C:18]([F:17])[CH:23]=[C:22]([F:24])[CH:21]=1)[CH3:5])=[N+:2]=[N-:3]
Reactant: OB(O)c1cc(F)cc(F)c1
Reactant: CC(N=[N+]=[N-])c1nc2sccn2c(=O)c1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(N=[N+]=[N-])c1nc2sccn2c(=O)c1-c1cc(F)cc(F)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 52.9 %

Procedure:
To a mixture of 7-(1-azidoethyl)-6-bromo-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.50 g, 1.7 mmol) and (3,5-difluorophenyl)boronic acid (0.31 g, 2.0 mmol) in 1,4-dioxane (10 mL) was added a 1N solution of sodium carbonate in water (2.2 mL, 2.2 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.096 g, 0.083 mmol). The mixture was stirred at 100° C. overnight. After cooling, the mixture was diluted with ethyl acetate, washed with water and brine, dried over MgSO4, concentrated, and purified on silica gel (0-45% ethyl acetate/hexanes) to give the desired product (0.30 g, 53%). LCMS calculated for C14H10F2N5OS (M+H)+: m/z=334.1. Found: 334.0.
Reaction SMILES: [CH2:1]([N:8]([CH2:21][CH2:22][O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:9][C@@H:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=1)[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.Cl[Si:37]([CH2:42][CH3:43])([CH2:40][CH3:41])[CH2:38][CH3:39].O>CN(C=O)C>[CH2:1]([N:8]([CH2:21][CH2:22][O:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH2:9][C@@H:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=1)[O:11][Si:37]([CH2:42][CH3:43])([CH2:40][CH3:41])[CH2:38][CH3:39])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC[Si](Cl)(CC)CC
Reactant: O=[N+]([O-])c1cccc([C@@H](O)CN(CCOCc2ccccc2)Cc2ccccc2)c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC[Si](CC)(CC)O[C@@H](CN(CCOCc1ccccc1)Cc1ccccc1)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(R)-2-(Benzyl(2-(benzyloxy)ethyl)amino)-1-(3-nitrophenyl)ethanol (30.371 g) which can be prepared according to the method described in Reference example 57, etc. and imidazole (6.1318 g; manufactured by Tokyo Chemical Industry, Co., Ltd.) were dissolved in dehydrated DMF (150 mL), added with chlorotriethylsilane (15.1 mL; manufactured by Shin-Etsu Chemical Co., Ltd.), followed by stirring overnight at room temperature. The reaction solution was poured to water and extracted twice with ethyl acetate. The organic layer was washed twice with water and once with brine and dried over magnesium sulfate. After concentrating under reduced pressure, the residue was purified by column chromatography (“COLUMN-A”; n-hexane:ethyl acetate=100:0→87:13) to obtain the title compound (36.655 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8](=[O:11])[NH:9][N:10]=2)[N:7]=1.CC(C)([O-])C.[K+].[C:18](#[N:21])[CH:19]=[CH2:20].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8](=[O:11])[N:9]([CH2:20][CH2:19][C:18]#[N:21])[N:10]=2)[N:7]=1
Reactant: O=c1[nH]nc2ccc(Cl)nn12
Reactant: C=CC#N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCCn1nc2ccc(Cl)nn2c1=O
Yield: 11.2 %

Procedure:
To a solution of 6-chloro-2,3-dihydro-s-triazolo[4,3-b]pyridazin-3-on [P. Francabilla and F. Lauria, J. Het. Chem. 8, 415 (1971)] (17 g., 0.1 mole) in dry DMF (300 ml.) was added potassium tert.-butoxide (0.5 g., 4.5 m.moles) with stirring. Acrylonitrile (6.6 g., 0.12 mole) in dry DMF (10 ml.) was added to the mixture. The mixture was stirred at 100°-110° C. for 24 hours, then poured into water (700 ml.) and extracted with ethyl acetate (5 × 400 ml.). The organic extracts were combined, dried over Na2SO4 and evaporated. The residue was crystallized from ethyl acetate to give light yellow needles of 6-chloro-2-(2-cyanoethyl)-2,3-dihydro-s-triazolo[4,3-b]pyridazin-3-on (2.5 g., 11%). M.p. 166°-168° C.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=3)=[C:11]([N+:14]([O-])=O)[CH:12]=2)[N:7]([C:27]([O:29][CH:30]([CH3:32])[CH3:31])=[O:28])[CH2:6][C@@H:5]1[CH3:33])(=[O:3])[CH3:2]>C(O)C.O.Cl.[Fe]>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:17]3[CH:18]=[CH:19][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:21][CH:22]=3)=[C:11]([NH2:14])[CH:12]=2)[N:7]([C:27]([O:29][CH:30]([CH3:32])[CH3:31])=[O:28])[CH2:6][C@@H:5]1[CH3:33])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2cc([N+](=O)[O-])c(-c3ccc(S(C)(=O)=O)cc3)cc2N(C(=O)OC(C)C)C[C@@H]1C
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: CC(=O)N1c2cc(N)c(-c3ccc(S(C)(=O)=O)cc3)cc2N(C(=O)OC(C)C)C[C@@H]1C
Temperature: 90 °C

Procedure:
Iron powder (1.010 g, 18.09 mmol) was added to a solution of isopropyl (S)-4-acetyl-3-methyl-7-(4-(methylsulfonyl)phenyl)-6-nitro-3,4-dihydroquinoxaline-1 (2H)-carboxylate (0.86 g, 1.81 mmol) in ethanol (12 mL) and water (2.4 mL). 1 N aqueous HCl (1 drop) was added, and the reaction was heated at 90° C. for 2 h. The mixture was cooled to rt and filtered through a pad of Celite, washing with ethanol. The filtrate was concentrated, and ethyl acetate was added. The solution was washed with saturated aqueous sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by mass triggered preparatory HPLC. The product-containing fractions were combined and concentrated in a Genevac to afford isopropyl (S)-4-acetyl-6-amino-3-methyl-7-(4-(methylsulfonyl)phenyl)-3,4-dihydroquinoxaline-1(2H)-carboxylate. MS (ESI, pos. ion) m/z 468 [M+Na]+.
Reaction SMILES: C[O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[NH:15][C:14]4[N:22]=[CH:23][CH:24]=[CH:25][C:13]=4[N:12]3[C:26]=2[C:27]2[CH:32]=[CH:31][C:30]([C:33]3([NH:37]C(=O)OC(C)(C)C)[CH2:36][CH2:35][CH2:34]3)=[CH:29][CH:28]=2)=[CH:5][N:4]=1.Cl.O1CCOCC1>CO>[NH2:37][C:33]1([C:30]2[CH:31]=[CH:32][C:27]([C:26]3[N:12]4[C:13]5[CH:25]=[CH:24][CH:23]=[N:22][C:14]=5[NH:15][C:16]5[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=5[C:11]4=[N:10][C:9]=3[C:6]3[CH:7]=[N:8][C:3]([OH:2])=[N:4][CH:5]=3)=[CH:28][CH:29]=2)[CH2:36][CH2:35][CH2:34]1
Reactant: COc1ncc(-c2nc3n(c2-c2ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc2)-c2cccnc2Nc2ccccc2-3)cn1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: NC1(c2ccc(-c3c(-c4cnc(O)nc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Reaction time: 19 h
Yield: 19.2 %

Procedure:
tert-Butyl (1-{4-[2-(2-methoxypyrimidin-5-yl)-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl]phenyl}cyclobutyl)carbamate (45 mg, 0.077 mmol) in MeOH (0.5 mL) was added 4N HCl-dioxane (2 mL) and stirred at r.t for 19 hours. The mixture was concentrated, then sat.NaHCO3 aq. was added. The mixture was extracted with CH2Cl2+MeOH (×3), dried over Na2SO4, then filtrated through Celite pad. The filtrate was concentrated and the residue was purified by preparative thin-layer chromatography (CH2Cl2/MeOH=4:1) to afford the desired product (7 mg, 18%) as a yellow solid. 1HNMR (DMSO-d6) 400 MHz δ: 8.58 (s, 1H), 8.23 (br s, 2H), 8.09 (dd, J=4.6 Hz and 1.7 Hz, 1H), 7.92 (dd, J=4.6 Hz and 1.1 Hz, 1H), 7.51 (d, J=8.6 Hz, 2H), 7.34 (td, J=8.6 Hz and 1.7 Hz, 1H), 7.28 (d, J=8.0 Hz, 1H), 7.23 (d, J=7.4 Hz, 2H), 7.10 (td, J=7.4 Hz and 1.1 Hz, 1H), 6.87 (dd, J=8.0 Hz and 1.7 Hz, 1H), 6.76 (dd, J=8.0 Hz and 4.6 Hz, 1H), 2.44-2.39 (m, 2H), 2.20-2.15 (m2H), 2.09-2.00 (m, 1H), 1.74-1.67 (m, 1H). LCMS: 474 [M+H].
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[CH3:9][NH2:10].C(O)C.O>C(O)(C)C>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:10][CH3:9])[CH:7]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: CN
Solvent: O
Solvent: CC(C)O
Solvent: CCO
Product: CNc1cc(Cl)ncn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
This material was prepared by a modified procedure published in the literature (J. Appl. Chem. 1955, 5, 358): To a suspension of commercially available 4,6-dichloropyrimidine (20 g, 131.6 mmol, 1.0 eq.) in isopropanol (60 ml) is added 33% methylamine in ethanol (40.1 ml, 328.9 mmol, 2.5 eq.) at such a rate that the internal temperature does not rise above 50° C. After completion of the addition the reaction mixture was stirred for 1 h at room temperature. Then, water (50 ml) is added and the suspension formed is chilled in an ice bath to 5° C. The precipitated product is filtered off, washed with cold isopropanol/water 2:1 (45 ml) and water. The collected material is vacuum dried over night at 45° C. to afford the title compound as colorless crystals: tR=3.57 min (purity: >99%, gradient A), ESI-MS: 144.3/146.2 [MH]+.
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:9][C:10]1[CH:15]=[CH:14][N:13]=[CH:12][C:11]=1[C:16](=O)[CH3:17]>>[C:1]1([NH:7][N:8]=[C:16]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][C:10]=2[NH2:9])[CH3:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NNc1ccccc1
Reactant: CC(=O)c1cnccc1N
Product: CC(=NNc1ccccc1)c1cnccc1N
Temperature: 100 °C

Procedure:
Phenylhydrazine (4.0 ml) was added to 5.00 g 1-(4-amino-3-pyridinyl)ethanone, and the mixture was stirred at 100° C. for seventeen hours. A similar procedure was followed using 4.0 g 1-(4-amino-3-pyridinyl)ethanone and 3.20 ml phenylhydrazine. The products of the two reactions were combined and purified by flash chromatography to yield 9.74 g solid. Recrystallization of 1.24 g from CH3OH/water yielded 0.28 g solid, m.p. 168°-170° C.
Reaction SMILES: COC1C=CC(C[S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C@H:11]([C:27]([OH:29])=O)[CH2:10]2)=CC=1.[C:32]([CH:35]1[CH2:40][NH:39][CH2:38][CH2:37][N:36]1[C:41]([O:43][CH2:44][C:45]1[CH:50]=[CH:49][C:48]([N+:51]([O-:53])=[O:52])=[CH:47][CH:46]=1)=[O:42])(=[O:34])[NH2:33]>>[C:32]([CH:35]1[N:36]([C:41]([O:43][CH2:44][C:45]2[CH:50]=[CH:49][C:48]([N+:51]([O-:53])=[O:52])=[CH:47][CH:46]=2)=[O:42])[CH2:37][CH2:38][N:39]([C:27]([C@@H:11]2[CH2:10][C@H:9]([SH:8])[CH2:13][N:12]2[C:14]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=2)=[O:15])=[O:29])[CH2:40]1)(=[O:34])[NH2:33]
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Reactant: NC(=O)C1CNCCN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Product: NC(=O)C1CN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CCN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Yield: 70.7 %

Procedure:
Following a procedure similar to that described in Preparation 8, but using 2.18 g of (2S,4S)-4-(4-methoxybenzylthio)-1-(4-nitrobenzyloxycarbonyl)-2-pyrrolidinecarboxylic acid, 0.79 g of N,N'-carbonyldiimidazole and 1.81 g of 2-carbamoyl-1-(4-nitrobenzyloxycarbonyl)piperazine, 2.13 g of the title compound were obtained as an amorphous solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([CH2:15][CH3:16])[CH2:5][CH2:6][O:7][C:8]1[C:9]([F:14])=[N:10][CH:11]=[CH:12][CH:13]=1.[I:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[CH:24]=[C:23]([C:28](OCC)=[O:29])[CH:22]=[CH:21]2.C(N(CCNC(C1C=NC2C(=CC=C(I)C=2)N=1)=O)CCOC1C(F)=NC=CC=1)C>>[CH2:15]([N:4]([CH2:3][CH2:2][NH:1][C:28]([C:23]1[CH:22]=[CH:21][C:20]2[C:25](=[CH:26][CH:27]=[C:18]([I:17])[CH:19]=2)[CH:24]=1)=[O:29])[CH2:5][CH2:6][O:7][C:8]1[C:9]([F:14])=[N:10][CH:11]=[CH:12][CH:13]=1)[CH3:16]
Reactant: CCN(CCN)CCOc1cccnc1F
Reactant: CCOC(=O)c1ccc2cc(I)ccc2c1
Agent: CCN(CCNC(=O)c1cnc2cc(I)ccc2n1)CCOc1cccnc1F
Product: CCN(CCNC(=O)c1ccc2cc(I)ccc2c1)CCOc1cccnc1F
Yield: 59.7 %

Procedure:
This compound was prepared, starting from compound 5 (200 mg, 0.88 mmol) and ethyl 6-iodonaphthalene-2-carboxylate (69) (194 mg, 0.62 mmol), according to the procedure developed for compound 10. Reaction time under reflux: 12 h; the purification was performed using column chromatography (Al2O3, CH2C2/EtOH, 99.5/0.5, v/v) to give compound 70 (188 mg, 0.37 mmol) as a brown oil. Yield 60%; Rf (Al2O3, CH2Cl2/EtOH, 99.5/0.5, v/v) 0.47; IR (CCl4) ν 1121, 1188, 1246, 1283, 1465, 1515, 1662, 2700-3000, 3250-3400 cm−1; 1H NMR (200 MHz, CDCl3) δ 1.10 (t, 3H, J=7.1 Hz), 2.73 (q, 2H, J=7.1 Hz), 2.84 (t, 2H, J=5.7 Hz), 2.99 (t, 2H, J=5.2 Hz), 3.60 (q, 2H, J=5.7 Hz), 4.11 (t, 2H, J=5.2 Hz), 7.00 (ddd, 1H, 5JH-F=0.7 Hz, J=4.9, 7.9 Hz), 7.14 (m, 1H), 7.19 (ddd, 1H, 4JH-F=10.0 Hz, J=1.7, 7.9 Hz), 7.55 (d, 1H, J=8.6 Hz), 7.65 (m, 1H), 7.66 (d, 1H, J=8.9 Hz), 7.73 (dd, 1H, J=1.9, 8.9 Hz), 7.94 (dd, 1H, J=1.9, 8.9 Hz), 8.23 (se, 2H); ESI-MS m/z 507.9 [M+H]+.
Reaction SMILES: C([O:3][P:4]([C:9]([C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1)([O:12]CC)[PH2:10]=[O:11])(=[O:8])[O:5]CC)C>Cl>[NH2:21][C:18]1[CH:17]=[CH:16][C:15]([C:9]([P:4](=[O:3])([OH:5])[OH:8])([OH:12])[PH2:10]=[O:11])=[CH:20][CH:19]=1
Reactant: CCOC([PH2]=O)(c1ccc(N)cc1)P(=O)(OCC)OCC
Agent: Cl
Product: Nc1ccc(C(O)([PH2]=O)P(=O)(O)O)cc1

Procedure:
A solution of [(4-Amino-phenyl)-ethoxy-phosphinoylmethyl]-phosphonic acid diethyl ester (2.78 g, 8.29 mmol) in 250 mL of conc. HCl was heated at reflux (apparatus equipped with a NaOH trap) for 5 h. Concentrated solution via distillation to provide a sticky yellow-white solid, which was used without purification in the next step: m/z 252 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[C:24]([F:27])([F:26])[F:25])[CH2:13][C@H:12]2[CH3:28])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.C[C:30]([O-])([CH3:32])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:23][C:20]1[CH:21]=[CH:22][C:17]([N:14]2[CH2:15][CH2:16][N:11]([S:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([N:14]4[CH2:32][CH2:30][N:11]([CH3:16])[CH2:12][CH2:13]4)[CH:3]=3)(=[O:10])=[O:9])[C@H:12]([CH3:28])[CH2:13]2)=[C:18]([C:24]([F:27])([F:26])[F:25])[CH:19]=1
Reactant: C[C@@H]1CN(c2ccc(F)cc2C(F)(F)F)CCN1S(=O)(=O)c1cccc(Br)c1
Reactant: CC(C)(C)[O-]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Na+]
Product: C[C@@H]1CN(c2ccc(F)cc2C(F)(F)F)CCN1S(=O)(=O)c1cccc(N2CCN(C)CC2)c1
Temperature: 110 °C
Yield: 155.8 %

Procedure:
A mixture of (2R)-1-[(3-bromophenyl)sulfonyl]-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazine (8 g, 16.667 mmol), N-Me-piperazine (2.22 mL, 20 mmol), bis-t-Bu-biphenylphosphine (298.2 mg, 1.0 mmol), tBuONa (2.4 g, 25 mmol) and Pd2(dba)3 (305.2 mg, 0.333 mmol) was mixed and purged with N2. Anhydrous toluene (80 mL) was added and purged with N2 again. The resultant mixture was heated in an oil bath at 110° C. under N2 for 5 hours. After cooling, diluted with EtOAc (100 mL), filtered through a pad of Celite and washed with EtOAc (100 mL). The combined organic layer washed with aq. NaHCO3. The aqueous layer was back extracted with EtOAc (2×50 mL). The combined organic layer was dried over Na2SO4. The crude product was purified on SiO2 gel column eluted with 0-25% MeOH in EtOAc to give the desired product as a light yellow solid (6.5 g, 78%). HRMS: calcd for C23H28F4N4O2S+H+, 501.19418. found (ESI-FTMS, [M+H]1+), 501.1944.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9][OH:10])[CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[Br:44][C:45]1[C:50](O)=[CH:49][CH:48]=[CH:47][N:46]=1>C1COCC1>[Br:44][C:45]1[C:50]([O:10][CH2:9][CH2:8][CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:49][CH:48]=[CH:47][N:46]=1
Reactant: Oc1cccnc1Br
Reactant: OCCCc1cccnc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Brc1ncccc1OCCCc1cccnc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.5 %

Procedure:
3-(Pyridin-3-yl)-1-propanol (12.3 g, 90 mmol) and triphenylphosphine (34.0 g, 130 mmol) are dissolved in THF (200 ml), and thereto are added successively with stirring diisopropyl azodicarboxylate (22.2 g, 110 mmol) and 2-bromo-3-hydroxypyridine (12.0 g, 69 mmol) under ice-cooling. The mixture is stirred at room temperature for 30 minutes, and then the reaction solution is concentrated under reduced pressure. To the residue is added ethyl acetate (300 ml), and the mixture is extracted with a 10% aqueous hydrochloric acid solution (150 ml×2). The pH value of the aqueous layer is adjusted with potassium carbonate to pH 12, and the mixture is extracted with ethyl acetate (200 ml×2). The organic layer is washed with a saturated brine (50 ml×2), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: ethyl acetate/hexane) to give the title compound (18.3 g) as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[NH:15][CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]([F:29])([F:28])[F:27])[CH:20]=3)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].Cl.[CH2:33]([N:40]1[CH2:45][CH2:44][CH2:43][CH2:42][C@@H:41]1[CH2:46]Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.O>CS(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]([CH2:46][CH:41]3[CH2:42][CH2:43][CH2:44][CH2:45][N:40]3[CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]([F:27])([F:28])[F:29])[CH:20]=3)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrC[C@H]1CCCCN1Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)c[nH]2)CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)cn2CC2CCCCN2Cc2ccccc2)CC1
Reaction time: 0.5 h
Yield: 45.4 %

Procedure:
To a solution of 4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (4.5 g, 0.011 mol, 1.0 eq) in DMSO (100 mL) and add powdered KOH (3.0 g, 0.055 mol, 5.0 eq) at RT under nitrogen atmosphere and stir for 30 minutes. To the resulting solution add (R)-1-benzyl-2-(bromomethyl)piperidine hydrochloride (5.0 g, 0.0165 mol, 1.5 eq) and stir the reaction mass at RT for 16 h. After completion, dilute the reaction with water (100 mL) and extract the compound in EA (3×100 mL). Wash the organic layer with brine (2×50 mL) and dry over anhydrous sodium sulfate. Concentrate the organic layer under reduced pressure and purify on silica (100-200 mesh) using 2% acetone-DCM to get 3.0 g (46%) of the title compound. (ES+): m/z=601 (M+H).