Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[N:13]([CH3:14])[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)=[N:11][C:10]=2[C:21]2[CH:30]=[CH:29][C:24]([C:25]([NH:27][NH2:28])=[O:26])=[CH:23][CH:22]=2)=[CH:4][CH:3]=1.[C:31](N1C=CN=C1)(N1C=CN=C1)=[S:32].C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[N:13]([CH3:14])[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)=[N:11][C:10]=2[C:21]2[CH:22]=[CH:23][C:24]([C:25]3[O:26][C:31](=[S:32])[NH:28][N:27]=3)=[CH:29][CH:30]=2)=[CH:4][CH:3]=1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: Cn1c(-c2ccccn2)nc(-c2ccc(C(=O)NN)cc2)c1Sc1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1c(-c2ccccn2)nc(-c2ccc(-c3n[nH]c(=S)o3)cc2)c1Sc1ccc(Cl)cc1
Reaction time: 1 h

Procedure:
To 4-{5-[(4-chlorophenyl)thio]-1-methyl-2-pyridin-2-yl-1H-imidazol-4-yl}benzohydrazide (Step 1 of Example 48, 50 mg, 0.115 mmol) and 1,1′-carbonothioylbis(1H-imidazole) (41 mg, 0.23 mmol) in dichloromethane (1 mL) was added triethylamine (46 mg, 0.46 mmol) at rt. After 1 h, the reaction was quenched with aq NaHCO3 and the product was extracted 3 times with EtOAc. The combined extracts were concentrated, and the residue was subjected to reverse phase HPLC. The fractions containing the product were collected and concentrated. The residue was diluted with EtOAc, washed with aq NaHCO3, water, and brine. The organic layer was dried over MgSO4, filtered, and concentrated to afford the title compound. 1H NMR (500 MHz, (CDCl3): 8.65 (d, 1H), 8.38 (broad d, 1H), 8.36 (d, 2H), 8.19 (s, 1H), 8.03 (d, 2H), 7.84 (m, 1H), 7.38 (m, 1H), 7.27 (d, 2H), 7.07 (d, 2H), 4.16 (s, 3H). LCMS: m/z 478 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:9]([F:12])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].N(OS(=O)(=O)O)=O.[CH2:20]([N:22]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:21].S(=O)(=O)(O)[NH2:37]>CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O.C(O)(=O)CC.CO>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([S:9]([F:12])(=[O:11])=[O:10])=[CH:3][C:2]=1[N:1]=[N:37][C:26]1[CH:27]=[CH:28][C:23]([N:22]([CH2:20][CH3:21])[CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:24][CH:25]=1
Reactant: NS(=O)(=O)O
Reactant: Nc1cc(S(=O)(=O)F)ccc1Cl
Reactant: CCN(Cc1ccccc1)c1ccccc1
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: O=NOS(=O)(=O)O
Solvent: CCC(=O)O
Solvent: CO
Product: CCN(Cc1ccccc1)c1ccc(N=Nc2cc(S(=O)(=O)F)ccc2Cl)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
3-Amino-4-chloro benzene sulphonyl fluoride (2 parts) was stirred in acetic/propionic acid 86/14 vol/vol (25 parts) and cooled to 0°-5° C. Nitrosyl sulphuric acid solution (3.8 parts) was added dropwise at 0°-5° C. and stirred under these conditions for 2 hours. The diazo solution was then added to a mixture of N-ethyl-N-benzyl aniline (2.7 parts), methanol (100 parts) and sulphamic acid (1 part) stirring at 0°-5° C. After stirring under these conditions for 30 mins, ice/water (100 parts) was added and the mixture stirred for a further 1 hour. The product was isolated by filtration, washed with water and pulled dry. The damp solid was then slurried in methanol (100 parts) and refiltered. Dried at 50° C. to yield 4-(2-chloro-5-fluorosulphonylphenylazo)-N-ethyl-N-benzyl aniline (2.3 parts).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[C:4]([NH2:9])=[N:5][CH:6]=[CH:7][CH:8]=1.[Br:12]N1C(=O)CCC1=O>CC#N>[Br:12][C:7]1[CH:8]=[C:3]([C:2]([F:1])([F:10])[F:11])[C:4]([NH2:9])=[N:5][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1ncccc1C(F)(F)F
Solvent: CC#N
Product: Nc1ncc(Br)cc1C(F)(F)F
Reaction time: 3 h

Procedure:
To a solution of 3-trifluoromethyl-pyridin-2-ylamine (Fluorochem Ltd., Derbyshire, United Kingdom, 5.37 g, 32.8 mmol) in 100 ml of dry CH3CN under argon were added N-bromosuccinimide (6.45 g, 36.2 mmol) in 4 equal portions over a period of 1 h at 0-5° C. The cooling bath was removed and stirring was continued for 3 h. The solvent was evaporated under vacuum, then the residue was dissolved in EtOAc and washed with water and brine. The organic layer was dried over Na2SO4 and evaporated to give the title compound as a orange oil. (M+H=239; 241).
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)[CH3:2].[N+:12]([O-])([OH:14])=[O:13]>O>[N+:12]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:3]=1[CH2:1][CH3:2])[C:7]([OH:9])=[O:8])([O-:14])=[O:13]
Reactant: O=[N+]([O-])O
Reactant: CCc1ccc(C(=O)O)cc1
Solvent: O
Product: CCc1ccc(C(=O)O)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
4-Ethylbenzoic acid (12.0 g, 79.9 mmol) was added portionwise to fuming nitric acid (62 mL) with stirring at room temperature. Following the addition, the mixture was poured into water (500 mL), stirred, and extracted with ethyl acetate (300 mL). Saturated brine (150 mL) was added and the mixture shaken then separated. The organic solution was washed with brine then dried over magnesium sulfate. Filtration, removal of the solvent by rotovap under reduced pressure, and trituration of the residue in hexane afforded the product (13.3 g); pure after recrystallization from hexane/ethyl acetate.
Reaction SMILES: Br[CH2:2][C:3]1[O:4][C:5](=[O:9])[O:6][C:7]=1[CH3:8].[CH3:10][O:11]/[N:12]=[C:13](/[C:37]1[N:38]=[CH:39][S:40][CH:41]=1)\[C:14]([NH:16][CH:17]1[C:35](=[O:36])[N:19]2[C:20]([C:32]([O-:34])=[O:33])=[C:21]([CH2:24][S:25][C:26]3[S:30][N:29]=[C:28]([CH3:31])[N:27]=3)[CH2:22][S:23][C@H:18]12)=[O:15].[Na+].C(OCC)(=O)C.O>CN(C)C=O>[CH3:10][O:11]/[N:12]=[C:13](/[C:37]1[N:38]=[CH:39][S:40][CH:41]=1)\[C:14]([NH:16][CH:17]1[C:35](=[O:36])[N:19]2[C:20]([C:32]([O:34][CH2:2][C:3]3[O:4][C:5](=[O:9])[O:6][C:7]=3[CH3:8])=[O:33])=[C:21]([CH2:24][S:25][C:26]3[S:30][N:29]=[C:28]([CH3:31])[N:27]=3)[CH2:22][S:23][C@H:18]12)=[O:15]
Reactant: Cc1oc(=O)oc1CBr
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)[O-])=C(CSc3nc(C)ns3)CS[C@H]12)c1cscn1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OCc3oc(=O)oc3C)=C(CSc3nc(C)ns3)CS[C@H]12)c1cscn1
Reaction time: 1.3 h
Yield: 62.3 %

Procedure:
4-Bromomethyl-5-methyl-1,3-dioxolene-2-one (386 mg) was added to a solution of sodium 7-[(Z)-2-methoxyimino-2-(thiazol-4-yl)acetamido]-3-(3-methyl-1,2,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylate (536 mg) in dimethylformamide (5 ml) at -5° C. The mixture was stirred at this temperature for 1.3 hr and then poured into a mixture of ethyl acetate (130 ml) and water (30 ml, adjusted to pH 3 with dil HCl) with stirring. The ethyl acetate layer was separated, washed successively with water (30 ml, adjusted to pH 3 with dil. HCl), 10% aqueous K2HPO4 solution (30 ml) twice, and saturated saline water, dried over MgSO4, concentrated in vacuo, and the residue was added dropwise to a mixture of diethyl ether (40 ml) and petroleum ether (40 ml). The formed crystals were filtered, washed with petroleum ether, and dried in vacuo to give the title compound (390 mg). ##STR38##
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:7]=[C:6]([CH3:8])[O:5][N:4]=1.[Si:9](Cl)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].C(N(CC)CC)C.O>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Si:9]([O:1][CH2:2][C:3]1[CH:7]=[C:6]([CH3:8])[O:5][N:4]=1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: Cc1cc(CO)no1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(CO[Si](C)(C)C(C)(C)C)no1
Temperature: 25 °C
Reaction time: 48 h
Yield: 82.3 %

Procedure:
To a chilled (5° C.) solution of 3-hydroxymethyl -5-methylisoxazole (16.8 g, 148 mmol) and tert-butyldimethylsilyl chloride (24.6 g, 163 mmol) in dry methylene chloride (100 mL) was added over 15 minutes a solution of triethylamine (22.7 mL, 163 mmol) in methylene chloride (25 mL). 4-Dimethylaminopyridine (1.81 g, 14.8 mmol) was added and the thick reaction mixture was stirred at room temperature for 48 hours. Water (100 mL) was added and the aqueous layer extracted with methylene chloride (3x). The combined organic phases were washed with brine, dried (MgSO4), filtered through a pad composed of a layer of Florisil and a layer of Silica Gel 60, and concentrated in vacuo. The yellow oil obtained (36.6 g) was purified by chromatography (Silica Gel 60, 2% ethyl acetate in hexanes) to give 27.7 g (81.9%) of pure title compound as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]([F:16])[F:15])[N:11]3[N:17]=[CH:18][C:19]([C:20]#[CH:21])=[C:10]3[N:9]=2)=[CH:4][C:3]=1[CH3:22].[CH3:23][N:24]([CH3:37])[CH2:25][CH2:26][NH:27][S:28]([C:31]1[S:32][C:33](Br)=[CH:34][CH:35]=1)(=[O:30])=[O:29]>>[CH3:23][N:24]([CH3:37])[CH2:25][CH2:26][NH:27][S:28]([C:31]1[S:32][C:33]([C:21]#[C:20][C:19]2[CH:18]=[N:17][N:11]3[C:12]([CH:14]([F:15])[F:16])=[CH:13][C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH3:22])[CH:4]=4)=[N:9][C:10]=23)=[CH:34][CH:35]=1)(=[O:30])=[O:29]
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3ccc(Cl)c(C)c3)nc12
Reactant: CN(C)CCNS(=O)(=O)c1ccc(Br)s1
Product: Cc1cc(-c2cc(C(F)F)n3ncc(C#Cc4ccc(S(=O)(=O)NCCN(C)C)s4)c3n2)ccc1Cl

Procedure:
The title compound was prepared from 5-(4-chloro-3-methyl-phenyl)-7-difluoromethyl-3-ethynyl-pyrazolo[1,5-a]pyrimidine (example C.16) (159 mg, 0.5 mmol) and 5-bromo-thiophene-2-sulfonic acid (2-dimethylamino-ethyl)-amide (example B.49) (157 mg, 0.5 mmol) according to general procedure II. Obtained as a yellow solid (200 mg, 73%). MS (ISN) 548.1 [(M−H)−]; mp 149° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Br[CH2:12][CH2:13][OH:14].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][CH2:12][CH2:13][OH:14])([O-:3])=[O:2]
Reactant: OCCBr
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cccc(OCCO)c1
Temperature: 70 °C
Yield: 74.1 %

Procedure:
A solution of m-nitrophenol (2.0 g, 14 mmol), 2-bromoethanol (1.4 mL, 20 mmol), and potassium carbonate (3.0 g, 22 mmol) in N,N-dimethylformamide (10 mL) was heated at 70° C. for 7 h. The reaction mixture was treated with additional 2-bromoethanol (0.5 mL, 7.2 mmol) and potassium carbonate (1.0 g, 7.2 mmol) and heated at 70° C. for 20 h. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (150 mL). The organic layer was separated and washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to a crude residue. This material was purified by flash column chromatography to give the desired product (1.9 g, 70%) as a white solid. LCMS for C8H10NO4 (M+H)+: m/z=183.9.
Reaction SMILES: [Cl:1][C:2]([Cl:30])([Cl:29])[CH2:3][O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13](=[O:28])[C@@H:14]([NH:20][C:21]([O:23]C(C)(C)C)=O)[CH2:15][O:16][CH:17]([F:19])[F:18])[NH:8]1)=[O:6].FC(F)(F)S(O[Si](C)(C)C)(=O)=O.C(N(CC)C(C)C)(C)C.[C:52]([O:56][C:57]([NH:59][C@H:60](C(O)=O)[CH:61]([CH3:63])[CH3:62])=[O:58])([CH3:55])([CH3:54])[CH3:53].F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C>ClCCl.C(#N)C>[Cl:30][C:2]([Cl:1])([Cl:29])[CH2:3][O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13](=[O:28])[C@@H:14]([NH:20][C:21](=[O:23])[C@@H:60]([NH:59][C:57]([O:56][C:52]([CH3:54])([CH3:53])[CH3:55])=[O:58])[CH:61]([CH3:63])[CH3:62])[CH2:15][O:16][CH:17]([F:18])[F:19])[NH:8]1)=[O:6]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)(C)OC(=O)N[C@@H](COC(F)F)C(=O)N1CCC[C@@H](C(=O)OCC(Cl)(Cl)Cl)N1
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](COC(F)F)C(=O)N1CCC[C@@H](C(=O)OCC(Cl)(Cl)Cl)N1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61.2 %

Procedure:
A cooled (0° C.) solution of (S)-1-((S)-2-tert-butoxycarbonylamino-3-difluoromethoxy-propionyl)-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester (143 mg, 0.287 mmol) in dichloromethane (5 mL) was treated with trimethylsilyl trifluoromethanesulfonate (72 μL, 0.431 mmol). After stirring at 0° C. for 30 minutes the reaction mixture was treated with N,N-diisopropylethylamine (0.2 mL, 1.15 mmol) and the volatiles were removed in vacuo to provide a brown solid which was then dissolved in anhydrous acetonitrile (5 mL) and this mixture was subsequently treated with N-(tert-butoxycarbonyl)-L-valine (75 mg, 0.344 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (153 mg, 0.402 mmol) and N,N-diisopropylethylamine. After stirring at room temperature for 16 h, the volatiles were removed in vacuo and the residue was partitioned between ethyl acetate and water. The organics were dried over anhydrous sodium sulfate, filtered and the volatiles were removed in vacuo. The residue was purified by silica gel chromatography eluting with a stepwise gradient of iso-hexanes/ethyl acetate 1:0 to 1:1 to provide the title compound (105 mg, 61%) as a pale yellow gum and as a complex mixture of rotamers. LCMS (m/z) 597.0, 599.0 [M+H], Tr=3.18 min.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[CH:10]=[CH:9][S:8][C:7]=2[C:6]([CH3:12])=[CH:5][C:4]=1[O:13][C:14](=[CH:17]NC1C=CC=CC=1)[C:15]#[N:16])[CH3:2].Cl.[NH2:26][C:27]([NH2:29])=[NH:28].C[O-].[Na+]>C(O)C.O>[CH2:1]([C:3]1[C:11]2[CH:10]=[CH:9][S:8][C:7]=2[C:6]([CH3:12])=[CH:5][C:4]=1[O:13][C:14]1[C:15]([NH2:16])=[N:28][C:27]([NH2:29])=[N:26][CH:17]=1)[CH3:2]
Reactant: N=C(N)N
Reactant: CCc1c(OC(C#N)=CNc2ccccc2)cc(C)c2sccc12
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCc1c(Oc2cnc(N)nc2N)cc(C)c2sccc12
Yield: 80.2 %

Procedure:
2-(4-Ethyl-7-methyl-benzo[b]thiophen-5-yloxy)-3-phenylamino-acrylonitrile (360 mg, 1 mmol), guanidine HCl (411 mg, 4 mmol) and sodium methoxide (880 ul, 4 mmol, 4.9 M solution in methanol) in 5 mL absolute ethanol were heated to reflux in 5 ml absolute ethanol for 2 hours. Premixed guanidine HCl (411 mg, 4 mmol) and sodium methoxide (880 ul, 4 mmol, 4.9 M solution in methanol) in 1 ml EtOH was added via pipette, and the reaction mixture was heated to reflux for 2 hours. The reaction mixture was cooled, diluted with water, extracted twice with EtOAc, washed with brine, and dried over magnesium sulfate. Solvent was removed in vacuo to give 241 mg of 5-(4-Ethyl-7-methyl-benzo[b]thiophen-5-yloxy)-pyrimidine-2,4-diamine as a white solid (74%). Mass Spec M+H=301, M.P.=181° C. Recrystallization of 175 mg of this product from MeOH and HCl/diethyl ether afforded 98 mg of the corresponding HCl salt 49%., Mass Spec M+H=301, M.P.>300 C.
Reaction SMILES: [CH2:1]([O:4][C:5]([C:7]1[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][CH:8]=1)=[O:6])[CH:2]=[CH2:3].[CH3:16][C:17]1([CH3:32])[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[C:23]2[CH:22]=[C:21]([CH:29]([OH:31])[CH3:30])[CH:20]=[CH:19][C:18]1=2>>[CH3:32][C:17]1([CH3:16])[CH2:26][CH2:25][C:24]([CH3:27])([CH3:28])[C:23]2[CH:22]=[C:21]([CH:29]([O:31][C:11]([C:10]3[CH:14]=[CH:15][C:7]([C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])=[CH:8][CH:9]=3)=[O:12])[CH3:30])[CH:20]=[CH:19][C:18]1=2
Reactant: C=CCOC(=O)c1ccc(C(=O)O)cc1
Reactant: CC(O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Product: C=CCOC(=O)c1ccc(C(=O)OC(C)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1

Procedure:
In a manner similar to Example 4(c), by reaction of 2.1 g (10 mmol) of 4-(allyloxycarbonyl)benzoic acid with 2.3 g (10 mmol) of 1-(5,6,7,8-tetrahydro -5,5,8,8-tetramethyl-2-naphthyl)ethanol, 3.2 g (76%) of the expected allyl ester are obtained in the form of a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C@H:9]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH3:10])[C:5]([N+:17]([O-:19])=[O:18])=[CH:4][C:3]=1[C:20]1[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=1.O[C:30]1[CH:37]=[CH:36][C:33]([CH:34]=[O:35])=[CH:32][CH:31]=1.O>CN(C)C1C=CN=CC=1.ClCCl>[NH2:1][C:2]1[CH:7]=[C:6]([O:8][C@H:9]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH3:10])[C:5]([N+:17]([O-:19])=[O:18])=[CH:4][C:3]=1[C:20]1[CH:28]=[CH:27][C:23]([C:24]([O:26][C:30]2[CH:37]=[CH:36][C:33]([CH:34]=[O:35])=[CH:32][CH:31]=2)=[O:25])=[CH:22][CH:21]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: CCCCCC[C@H](C)Oc1cc(N)c(-c2ccc(C(=O)O)cc2)cc1[N+](=O)[O-]
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CCCCCC[C@H](C)Oc1cc(N)c(-c2ccc(C(=O)Oc3ccc(C=O)cc3)cc2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.6 g of N,N'-dicyclodicyclohexylcarbodiimide was added at room temperature while stirring to a solution of 1.0 g of 4-[4-(2-amino-5-nitro-4-[(S)-2-octyloxy]phenyl)benzoic acid, 0.3 g of 4-hydroxybenzaldehyde and 0.04 g of 4-dimethylaminopyridine in 20 ml of dichloromethane. The reaction mixture was stirred at room temperature overnight, poured into 100 ml of water and then extracted three times with 50 ml of dichloromethane each time. The organic phases were washed twice with 100 ml of water each time, dried over magnesium sulphate, filtered and the filtrate was subsequently concentrated. Chromatographic purification of the residue on silica gel with hexane/ethyl acetate (vol. 1:1) and two-fold recrystallization from ethanol of the fractions which were pure according to thin-layer chromatography gave 0.9 g of 4-[4-(2-amino-5-nitro-4-[(S)-2-octyloxy]phenyl)benzoyloxy]benzaldehyde; m.p. (C-I) 77°-78° C.
Reaction SMILES: Cl[C:2]([O:5][C:6](=[O:12])OC(Cl)(Cl)Cl)(Cl)Cl.[N:13]1[CH:18]=CC=[CH:15][CH:14]=1.O1CCC[CH2:20]1>>[C:6]([O:5][CH2:2][CH2:18][NH:13][CH2:14][CH3:15])(=[O:12])[CH3:20]
Reactant: c1ccncc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C1CCOC1
Product: CCNCCOC(C)=O
Reaction time: 0.17 h

Procedure:
To a solution of bis(trichloromethyl)carbonate (0.59 g) in tetrahydrofuran (30 mL) was added dropwise a solution of pyridine (0.49 mL) in tetrahydrofuran (1 mL) under ice-cooling. The reaction solution was stirred for 10 minutes under ice-cooling, and 2-(ethylamino)ethyl acetate hydrochlride (0.67 g) obtained in Reference Synthetic Example 20 was added. A solution of triethylamine (0.84 mL) in tetrahydrofuran (1 mL) was added dropwise, and stirred at room temperature for 1 hr. The reaction solution was concentrated under reduced pressure, and to the residue was added water (50 mL), and extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (50 mL), and dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, and the residue was dissolved in tetrahydrofuran (20 mL). To the solution were added (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole (1.11 g), triethylamine (0.84 mL) and 4-dimethylaminopyridine (0.037 g), and stirred at 60° C. overnight. The reaction solution was concentrated under reduced pressure, and to the residue was added water (50 mL), and extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated saline (50 mL), and dried over anhydrous magnesium sulfate. After concentrating under reduced pressure, the residue was purified with basic silica gel column chromatography (eluted with ethyl acetate:hexane=3:7, then ethyl acetate) to give title compound as yellow amorphous solid(1.58 g).
Reaction SMILES: [Cl-].[NH4+].[CH2:3]([N:10]1[CH2:15][CH2:14][C:13]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N+:24]([O-])=O)([CH3:16])[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O.CO.O1CCCC1>[CH2:3]([N:10]1[CH2:11][CH2:12][C:13]([NH:17][C:18]2[C:19]([NH2:24])=[CH:20][CH:21]=[CH:22][CH:23]=2)([CH3:16])[CH2:14][CH2:15]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC1(Nc2ccccc2[N+](=O)[O-])CCN(Cc2ccccc2)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC1(Nc2ccccc2N)CCN(Cc2ccccc2)CC1
Temperature: 70 °C
Yield: 54.6 %

Procedure:
168 mg ferrum was added to 160 mL ammonium chloride in 5 mL water. A solution of 244 mg (1-benzyl-4-methyl-piperidin-4-yl)-(2-nitro-phenyl)-amine in 5 mL methanol and 5 mL tetrahydrofuran were added and the mixture was stirred at 70° C. under nitrogen. The mixture was filtered over Celite and water was added to the filtrate. The solution was extracted with ethylacetate. The organic layer was evaporated to yield 121 mg of the desired product.
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[CH2:13]([N:20]1[C:28]2[CH:27]=[C:26]([C:29]([OH:31])=O)[N:25]=[C:24]([NH:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:23]=2[NH:22][C:21]1=[O:40])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[OH:41][NH:42][C:43](=[NH:45])[CH3:44].[Al]>CN(C=O)C>[OH:41][N:42]=[C:43]([NH:45][C:29]([C:26]1[N:25]=[C:24]([NH:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:23]2[NH:22][C:21](=[O:40])[N:20]([CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:28]=2[CH:27]=1)=[O:31])[CH3:44]
Reactant: CC(=N)NO
Reactant: O=C(O)c1cc2c([nH]c(=O)n2Cc2ccccc2)c(NCc2ccccc2)n1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Al]
Solvent: CN(C)C=O
Product: CC(=NO)NC(=O)c1cc2c([nH]c(=O)n2Cc2ccccc2)c(NCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 132.7 %

Procedure:
CDI (52 mg, 0.32 mmol) was added to a solution of 1-benzyl-4-benzylamino-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridine-6-carboxylic acid (80 mg, 0.21 mmol) and Hunnigs base (83 μl, 0.64 mmol) in dry DMF in a ReactiVial. The vial was sealed and the mixture was stirred at room temperature for 15 minutes. N-Hydroxyacetamidine (24 mg, 0.32 mmol) was added and mixture heated to 60° C. in an aluminium block. The mixture was left to stir at this temperature for 3 hrs then allowed to cool and concentrated in vacuo. The residue was partitioned between EtOAc (15 ml) and water (5 ml). The layers were separated and the organic phase was washed with brine (5 ml). At this point, some solid precipitated and was left inside the separating funnel. This was washed into the organic phase with MeOH then the organics were dried (MgSO4) and evaporated to yield the final product as a white solid (120 mg, 130%). Material probably contains inorganic material, but taken on with a view to purification after next step.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH:12]1([NH2:18])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.C1OCCOCCOCCOCCOCCOC1>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:18][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Cl
Reactant: NC1CCCCC1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cc(Cl)ccc1NC1CCCCC1
Yield: 61.5 %

Procedure:
51.5 g (0.27 mol) of 2,5-dichloronitrobenzene, 22.3 g (0.27 mol) of cyclohexylamine, 74.6 g (0.54 mol) of potassium carbonate and 0.5 g of 18-crown-6 were heated in 300 ml of dimethylformamide at 100° C. for 4 h. The mixture was then poured into water and extracted with ethyl acetate. The organic phase was dried and concentrated under reduced pressure. The residue was recrystallized from i-propanol, resulting in 42.3 g (62%) of the product. Melting point 101°-103° C.