Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][C:22]([S:25]([NH:28][C@H:29]([C:33]([OH:35])=[O:34])[CH:30]([CH3:32])[CH3:31])(=[O:27])=[O:26])=[CH:21][CH:20]=4)=[CH:15][CH:14]=3)=[O:11])=[CH:7][C:6]=2[CH:36]=1.C(N(CC)C(C)C)(C)C.[CH3:46][S:47](Cl)(=[O:49])=[O:48]>C(Cl)Cl>[CH3:46][S:47]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:20]=[CH:21][C:22]([S:25]([NH:28][C@H:29]([C:33]([OH:35])=[O:34])[CH:30]([CH3:32])[CH3:31])(=[O:26])=[O:27])=[CH:23][CH:24]=4)=[CH:15][CH:14]=3)=[O:11])=[CH:7][C:6]=2[CH:36]=1)(=[O:49])=[O:48]
Reactant: CC(C)[C@H](NS(=O)(=O)c1ccc(-c2ccc(NC(=O)c3cc4cc(N)ccc4o3)cc2)cc1)C(=O)O
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)[C@H](NS(=O)(=O)c1ccc(-c2ccc(NC(=O)c3cc4cc(NS(C)(=O)=O)ccc4o3)cc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-[(4′-{[(5-amino-1-benzofuran-2-yl)carbonyl]amino}-1,1′-biphenyl-4-yl)sulfonyl]-L-valine-Wang resin (0.3 g), from Example 7, was suspended in methylene chloride (6 mL). To the suspension was added with N,N-diisopropylethylamine (6.0 equiv.) and methanesulfonyl chloride (3.0 equiv.). The reaction was allowed to proceed at room temperature for 1 h and the reagent was removed by filtration. The resin was washed with methylene chloride (2×), methanol and methylene chloride (2×) before being treated with a 95% solution of TFA in methylene chloride (5 mL) and agitated at room temperature for 2 h. The solution was collected by filtration and the solvent was removed via vacuum. The crude product was then purified by flash chromatography to give N-({4′-[({5-[(methylsulfonyl)amino]-1-benzofuran-2-yl}carbonyl)amino]-1,1′-biphenyl-4-yl}sulfonyl)-L-valine LCMS MH+ (m/z) 586. 1H NMR (300 MHz, DMSO-d6): δ 10.53 ppm (s, 1H), 9.59 ppm (s, 1H), 7.78-7.16 ppm (m, 12H), 3.30 ppm (m, 1H), 1.87 ppm (m, 1H), 0.63 ppm (m, 6H).
Reaction SMILES: [OH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][C:10]([Cl:17])=[CH:11][CH:12]=3)[C:7](=[O:18])[C:6]=2[C:5]([NH2:19])=[CH:4][C:3]=1Br.[C:21]1([O-:27])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[OH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][C:10]([Cl:17])=[CH:11][CH:12]=3)[C:7](=[O:18])[C:6]=2[C:5]([NH2:19])=[CH:4][C:3]=1[O:27][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: [O-]c1ccccc1
Reactant: Nc1cc(Br)c(O)c2c1C(=O)c1cc(Cl)ccc1C2=O
Product: Nc1cc(Oc2ccccc2)c(O)c2c1C(=O)c1cc(Cl)ccc1C2=O

Procedure:
When 70.5 g of the 1-hydroxy-2-bromo-4-amino-6-chloroanthraquinone prepared above are subjected to a phenolate fusion as described in Example 467c, then 59 g, corresponding to 80% of theory, of 1-hydroxy-2-phenoxy-4-amino-6-chloroanthraquinone are obtained, the colour shade of which on silica gel is a pink tinged with blue having the Indicator Number 51 (Colour Index Hue Indication Chart).
Reaction SMILES: C(N(CC)CC)C.[C:8](OC(=O)C)(=[O:10])[CH3:9].[CH3:15][O:16][CH2:17][O:18][C:19]1[CH:24]=[C:23]([O:25][CH2:26][O:27][CH3:28])[CH:22]=[CH:21][C:20]=1[CH:29]1[CH2:34][CH2:33][CH2:32][CH:31]([NH2:35])[CH2:30]1>ClCCCl>[CH3:15][O:16][CH2:17][O:18][C:19]1[CH:24]=[C:23]([O:25][CH2:26][O:27][CH3:28])[CH:22]=[CH:21][C:20]=1[CH:29]1[CH2:34][CH2:33][CH2:32][CH:31]([NH:35][C:8](=[O:10])[CH3:9])[CH2:30]1
Reactant: CC(=O)OC(C)=O
Reactant: COCOc1ccc(C2CCCC(N)C2)c(OCOC)c1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: COCOc1ccc(C2CCCC(NC(C)=O)C2)c(OCOC)c1
Reaction time: 0.5 h
Yield: 66 %

Procedure:
Triethylamine (15 μl) and acetic anhydride (10 ml) were added to a stirred solution of (±)-3-[2,4-bis(methoxymethoxy)phenyl]cyclohexylamine (29 mg) in anhydrous 1,2-dichloroethane (2 ml) at room temperature. After 0.5 hr, the reaction mixture was partitioned between water (20 ml) and ethyl acetate (50 ml) and the aqueous layer was extracted with ethyl acetate (3×20 ml). The combined organic extracts were dried over magnesium sulfate and evaporated in vacuo to give the title compound as a solid (22 mg, 66%) and a mixture of diastereoisomers; m/z (ES+) 338 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][CH:3]=1.O.[OH-].[Na+].[H][H]>[Pt].C1C=C2C(C(Cl)=C(Cl)C(=O)C2=CC=1)=O.CCCCCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: [H][H]
Agent: [Pt]
Agent: O=C1C(Cl)=C(Cl)C(=O)c2ccccc21
Agent: [Na+]
Solvent: O
Solvent: CCCCCC
Product: Clc1ccc(NNc2ccc(Cl)cc2)cc1
Reaction time: 4.5 h
Yield: 89.5 %

Procedure:
210 g p-chloronitrobenzene, 600 g water and 180 g sodium hydroxide (corresponding to a 23.1 wt. % aqueous solution), 0.3 g 2,3-dichloronaphthoquinone-1,4, 350 g n-hexane and 0.40 g platinum on activated charcoal (5% Pt) (the quantitative ratio of platinum metal to p-chloronitrobenzene used being 0.000095:1) are hydrogenated by the use of a gas sparger at a hydrogen pressure of 6 bars and at 60° to 65° C. The reduction is completed after 4 to 5 hours. The procedure set forth in Example 1 is followed, 151 g 4,4'-dichlorohydrazobenzene with a melting point of 120° to 121° C. and a purity of 98.5% being obtained, which corresponds to a yield of 88.5% of theory. The possible byproduct p-chloroaniline is not detectable.
Reaction SMILES: [Na].[OH:2][CH2:3][CH:4]([NH:7][C:8]([C:10]1[C:15]([I:16])=[C:14]([OH:17])[C:13]([I:18])=[C:12]([C:19]([NH:21][CH:22]([CH2:25][OH:26])[CH2:23][OH:24])=[O:20])[C:11]=1[I:27])=[O:9])[CH2:5][OH:6]>COCCO>[NH2:7][C:8](=[O:9])[C@H:10]([CH3:11])[O:17][C:14]1[C:15]([I:16])=[C:10]([C:8]([NH:7][CH:4]([CH2:5][OH:6])[CH2:3][OH:2])=[O:9])[C:11]([I:27])=[C:12]([C:19]([NH:21][CH:22]([CH2:25][OH:26])[CH2:23][OH:24])=[O:20])[C:13]=1[I:18]
Reactant: O=C(NC(CO)CO)c1c(I)c(O)c(I)c(C(=O)NC(CO)CO)c1I
Agent: [Na]
Solvent: COCCO
Product: C[C@H](Oc1c(I)c(C(=O)NC(CO)CO)c(I)c(C(=O)NC(CO)CO)c1I)C(N)=O
Temperature: 80 °C
Reaction time: 8 h
Yield: 90.3 %

Procedure:
To a solution of 21.8 g of N,N'-bis[2-hydroxy-1-(hydroxymethyl)ethyl]-5-hydroxy-2,4,6-triiodo-1,3-benzenedicarboxamide sodium salt (prepared according to the procedure described in patent EP 185130) (0.03 mol) in 70 mL of methyl cellosolve, heated to 80° C., 14.6 g of R-2-[[(4-methylphenyl)sulfonyl]oxy]propanamide (prepared according to the procedure described in Markert, F. Chem. Ber. 1927, 60, 2456) (0.056 mol) are added and the resulting mixture is kept under stirring in the same conditions for 8 h. After removing methyl cellosolve by evaporation under reduced pressure, the oily residue is treated with CH2Cl2 (2×250 mL). The solid, filtered and dried is dissolved in abs. EtOH (190 mL) and after filtration of sodium p-toluensulfonate, the solution is concentrated to dryness. The treatment is repeated with abs. EtOH (150 mL) and after evaporation the resulting residue is crystallized from abs. EtOH (75 mL). 10.5 g of the desired product (0.0135 mol) are recovered.
Reaction SMILES: [C-:1]#[N:2].[K+].[C-]#N.[Na+].C1OCCOCCOCCOCCOCCOC1.Br[CH2:26][C@H:27]1[N:31]([CH3:32])[C:30](=[O:33])[CH2:29][CH2:28]1>CC#N>[CH3:32][N:31]1[C:30](=[O:33])[CH2:29][CH2:28][C@H:27]1[CH2:26][C:1]#[N:2]
Reactant: CN1C(=O)CC[C@H]1CBr
Reactant: [C-]#N
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [Na+]
Solvent: CC#N
Product: CN1C(=O)CC[C@H]1CC#N

Procedure:
KCN (886 mg, 13.6 mmols), NaCN (666 mg, 13.6 mmols) and 18-crown-6 (207 mg, 1.02 mmols) were added to a CH3CN (25 ml) solution of the (5S)-5-(bromomethyl)-1-methylpyrrolidin-2-one (1.31 g, 6.8 mmols), and the mixture was heated for 43 hours under reflux. The inorganic matter was filtered off, and the filtrate was diluted with AcOEt (50 ml). The dilution was washed with a saturated solution (30 ml) of NaCl, and dried over MgSO4. The solvent was distilled off under reduced pressure, and then the residue was subjected to silica gel column chromatography (SiO2 50 g, MeOH—CHCl3 1:9 v/v) to obtain 2-((2S)-1-methyl-5-oxopyrrolidin-2-yl)ethanenitrile as a mixture (1.05 g) with impurities difficult to separate: IR νmax (film) cm−1: 2246, 1685. 1H-NMR (CDCl3)δ: 3.85-3.76 (1H, m), 2.88 (3H, s), 2.68 (1H, dd, J=17.0, 4.4 Hz), 2.61 (1H, dd, J=17.0, 6.0 Hz), 2.62-2.48 (1H, m), 2.46-2.30 (2H, m), 2.00-1.86 (1H, m). MS m/z: 138 (M+), 98 (100%). HRMS: Calcd. for C7H10N2O: 138.0793 (M+). Found: 138.0794 (M+).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH:16]1[CH2:19][CH2:18][CH2:17]1)=[O:14].[CH3:20][O:21][C:22]1[CH:27]=[CH:26][N:25]=[CH:24][C:23]=1B(O)O>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][C:22]=3[O:21][CH3:20])[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH:16]1[CH2:19][CH2:18][CH2:17]1)=[O:14]
Reactant: COc1ccncc1B(O)O
Reactant: Nc1c(C(=O)NC2CCC2)nnc2c(Br)cccc12
Product: COc1ccncc1-c1cccc2c(N)c(C(=O)NC3CCC3)nnc12
Yield: 19.7 %

Procedure:
Using Method A, 4-amino-8-bromo-N-cyclobutyl-cinnoline-3-carboxamide (145 mg) and 4-methoxypyridin-3-yl boronic acid (172 mg) were reacted to afford the title compound (31 mg) as white solid. 1H NMR (500 MHz, DMSO-d6) δ 9.24 (d, 1H), 8.52 (m, 1H), 8.44 (m, 1H), 8.33 (s, 1H), 7.78 (m, 2H), 7.18 (d, 1H), 4.49 (m, 1H), 3.72 (s, 3H), 2.26-2.10(m, 4H), 1.72-1.62 (m, 2H). MS APCI, m/z=350 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][C@H:11]([CH2:13][OH:14])[O:10][C:9]2=[O:15])[CH:5]=[CH:4][C:3]=1[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][O:23][C@@H:24]2[CH2:29][O:28][C:27]3=[N:30][C:31]([N+:33]([O-:35])=[O:34])=[CH:32][N:26]3[CH2:25]2)=[CH:18][CH:17]=1.C([SiH2]OC(C)(C)[C@@H]1OC(=O)N(C2C=CC(C3C=CC(CO[C@@H]4COC5=NC([N+]([O-])=O)=CN5C4)=CC=3)=C(F)C=2)C1)(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CCOC(C)=O>[F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][C@@H:11]([CH2:13][OH:14])[O:10][C:9]2=[O:15])[CH:5]=[CH:4][C:3]=1[C:16]1[CH:17]=[CH:18][C:19]([CH2:22][O:23][C@H:24]2[CH2:29][O:28][C:27]3=[N:30][C:31]([N+:33]([O-:35])=[O:34])=[CH:32][N:26]3[CH2:25]2)=[CH:20][CH:21]=1
Reactant: O=C1O[C@@H](CO)CN1c1ccc(-c2ccc(CO[C@@H]3COc4nc([N+](=O)[O-])cn4C3)cc2)c(F)c1
Agent: CC(C)(C)[SiH2]OC(C)(C)[C@H]1CN(c2ccc(-c3ccc(CO[C@@H]4COc5nc([N+](=O)[O-])cn5C4)cc3)c(F)c2)C(=O)O1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C1O[C@H](CO)CN1c1ccc(-c2ccc(CO[C@H]3COc4nc([N+](=O)[O-])cn4C3)cc2)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
3-[2-Fluoro-4′-(2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6(S)-yloxymethyl)-biphenyl-4-yl]-5(R)-hydroxymethyl-oxazolidin-2-one. To a solution of 5(R)-(tert-butyl-dimethyl-silanyloxymethyl)-3-[2-fluoro-4′-(2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6(S)-yloxymethyl)-biphenyl-4-yl]-oxazolidin-2-one (70 mg, 0.117 mmol) in THF (8.0 mL) was added TBAF (1.0 mL, 1.0 mmol, 1.0 M in THF). The mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with EtOAc, washed with brine, purified by flash chromatography to give the title product (36 mg, 64%) as a yellow solid. ESI MS m/z 485.3 (M+H+); 1H NMR (400 MHz, DMSO) δ 8.03 (s, 1H), 7.60 (dd, J=13.6, 2.4 Hz, 1H), 7.56-7.50 (m, 3H), 7.44-7.38 (m, 3H), 5.23 (t, J=5.6 Hz, 1H), 4.74-4.66 (m, 4H), 4.46 (d, J=12.0 Hz, 1H), 4.26-4.20 (m, 2H), 4.10 (t, J=9.2 Hz, 1H), 3.85 (dd, J=8.8, 6.0 Hz, 1H), 3.68-3.64 (m, 1H), 3.58-3.52 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]([O:11][CH:12]([C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([F:21])[C:15]=3[Cl:22])[CH3:13])[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.[CH3:23][N:24]([CH3:36])[C:25]([C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1)=[O:26]>>[Cl:22][C:15]1[C:16]([F:21])=[CH:17][CH:18]=[C:19]([Cl:20])[C:14]=1[CH:12]([O:11][N:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:31]3[CH:32]=[C:27]([CH:28]=[CH:29][CH:30]=3)[C:25]([N:24]([CH3:36])[CH3:23])=[O:26])[CH:3]=2)[CH:8]=[CH:9]1)[CH3:13]
Reactant: CN(C)C(=O)c1cccc(B(O)O)c1
Reactant: CC(On1ccc2ncc(Br)cc21)c1c(Cl)ccc(F)c1Cl
Product: CC(On1ccc2ncc(-c3cccc(C(=O)N(C)C)c3)cc21)c1c(Cl)ccc(F)c1Cl

Procedure:
The entitled compound was prepared from 6-bromo-1-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-1H-pyrrolo[3,2-b]pyridine and [3-(dimethylcarbamoyl)phenyl]boronic acid according to the procedure described in example 4.
Reaction SMILES: [N:1]1C2C(=CC=CC=2)C=C[CH:2]=1.[CH:11]([C:13]1[CH:14]=[CH:15][C:16]2[O:20][CH:19]=[CH:18][C:17]=2[CH:21]=1)=O>>[O:20]1[C:16]2[CH:15]=[CH:14][C:13]([CH2:11][C:2]#[N:1])=[CH:21][C:17]=2[CH:18]=[CH:19]1
Reactant: c1ccc2ncccc2c1
Reactant: O=Cc1ccc2occc2c1
Product: N#CCc1ccc2occc2c1

Procedure:
The acid was decarboxylated by treating with quinoline (using the same method as that used for 5-formylbenzofuran in Chimica Therapeutica 1966, 225) to give benzofuran-5-acetonitrile. (t.l.c./silica/toluene, RF 0.33).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([CH3:16])[C:11]([O:13]CC)=O)=[CH:5][CH:4]=1>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6]([CH2:9][CH:10]([CH3:16])[C:11]2=[O:13])=[CH:7][CH:8]=1
Reactant: CCOC(=O)C(C)Cc1ccc(OC)cc1
Solvent: O
Product: COc1ccc2c(c1)C(=O)C(C)C2
Temperature: 50 °C

Procedure:
Ethyl β-(p-methoxyphenyl)-α-methylpropionate is added to 56 g of polyphosphoric acid with stirring at 50° C. The mixture is then heated to 83°-90° C for two hours. The cooled reaction mixture is poured slowly into a mixture of water and crushed ice with stirring and extracted with 3 × 300 ml of ether. The etheral solution is washed with 10% sodium bicarbonate solution followed by cold water to neutral, then with saturated sodium chloride solution and dried over magnesium sulfate for 1.5 hours and filtered. The solvent is removed on an evaporator and the residue distilled to obtain 6-methoxy-2-methylindanone.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[Cl:10].C1N2CN3CN(C2)CN1C3.Cl.C(O)(=[O:24])C.O>>[Cl:10][C:4]1[C:5]([CH3:9])=[CH:6][CH:7]=[CH:8][C:3]=1[CH:2]=[O:24]
Reactant: Cc1cccc(CBr)c1Cl
Reactant: CC(=O)O
Agent: C1N2CN3CN1CN(C2)C3
Agent: Cl
Solvent: O
Product: Cc1cccc(C=O)c1Cl

Procedure:
A suspension of 2-chloro-m-xylene (15 ml), N-bromosuccinimide (23.3 g) and benzoyl peroxide (200 mg) in carbon tetrachloride (150 ml) was heated under reflux for 6 hours. The insoluble material was filtered off and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent:hexane) to give 2-bromomethyl-1-chloro-6-methylbenzene (16.0 g) as a colorless oil. 2-Bromomethyl-1-chloro-6-methylbenzene (25.4 g) and hexamethylenetetramine (32.4 g) were dissolved in acetic acid-water (1:1, 10 ml) and the mixture was heated under reflux for 5 hours. To the reaction mixture was added concentrated hydrochloric acid (40 ml) and the mixture was heated under reflux for 1 hour. The reaction mixture was extracted with ethyl acetate. The extract was washed with an aqueous sodium hydrogencarbonate solution and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated to give 2-chloro-3-methylbenzaldehyde (19.4 g) as a yellow oil. Subsequently, the title compound was prepared from 2-chloro-3-methylbenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH2:8]([CH:10]1[C:14]2[C:15]([O:19][C:20]3[N:25]=[CH:24][C:23]([NH:26][C:27]([C@H:29]([NH:32]C(=O)OC(C)(C)C)[CH2:30][CH3:31])=[O:28])=[CH:22][CH:21]=3)=[CH:16][CH:17]=[CH:18][C:13]=2[CH2:12][O:11]1)[CH3:9]>ClCCl>[NH2:32][C@H:29]([CH2:30][CH3:31])[C:27]([NH:26][C:23]1[CH:24]=[N:25][C:20]([O:19][C:15]2[C:14]3[CH:10]([CH2:8][CH3:9])[O:11][CH2:12][C:13]=3[CH:18]=[CH:17][CH:16]=2)=[CH:21][CH:22]=1)=[O:28]
Reactant: CCC1OCc2cccc(Oc3ccc(NC(=O)[C@@H](CC)NC(=O)OC(C)(C)C)cn3)c21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC1OCc2cccc(Oc3ccc(NC(=O)[C@H](N)CC)cn3)c21
Temperature: 0 °C
Reaction time: 1 h
Yield: 91.6 %

Procedure:
In a 50 ml round-bottomed flask 1,1-dimethylethyl {(1R)-1-[({6-[(3-ethyl-1,3-dihydro-2-benzofuran-4-yl)oxy]-3-pyridinyl}amino)carbonyl]propyl}carbamate (Intermediate 109, 12.7 mg) was dissolved in dichloromethane (3 ml) to give a colourless solution. The reaction mixture was cooled at 0° C. TFA (1.5 ml, 19.47 mmol) was added at that temperature. The reaction mixture was stirred at 0° C. After 1 hour, the reaction was completed. The reaction mixture was evaporated under vacuum affording the crude product which was charged on a 2 g SCX cartridge. It was then flushed with 15 ml of MeOH followed by 15 ml of a solution of ammonia in MeOH (2M). The ammonia eluate was evaporated under vacuum to afford the title compound as a colorless oil (9.0 mg).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8].[OH:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][OH:21])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:8][C:7]1[O:6][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:4][C:3]=1[CH2:2][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][OH:21])=[CH:18][CH:17]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Reactant: OCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CO)cc1
Temperature: 50 °C
Reaction time: 3.5 h
Yield: 96.3 %

Procedure:
4-(Chloromethyl)-5-methyl-2-phenyl-1,3-oxazole (5.00 g), parahydroxybenzyl alcohol (3.29 g) and potassium carbonate (6.66 g) were suspended in dimethylformamide (25 ml) and the suspension was stirred at 50° C. for 3.5 hr. The reaction mixture was cooled and water (25 ml) was added at not higher than 15° C. The mixture was stirred for about 5 min and at about 5° C. for 1 hr under ice-cooling. The crystals were collected by filtration, washed twice with water (15 ml) and dried under reduced pressure at 50° C. to give the objective product (6.85 g) in a yield of 96%.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[CH3:18][N:19]1[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][CH2:27][NH2:28])[CH2:21][CH2:20]1.O>CC(O)C>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:28][CH2:27][CH2:26][CH2:25][N:22]2[CH2:21][CH2:20][N:19]([CH3:18])[CH2:24][CH2:23]2)[CH:7]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: CN1CCN(CCCN)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Solvent: O
Product: CN1CCN(CCCNc2cc(Cl)ncn2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.9 %

Procedure:
To a solution of 4,6-dichloro-pyrimidine (1.5 g, 10 mmol) and DIPEA (1.55 g, 12 mmol) in iPrOH (50 mL) was added a solution of 3-(4-methyl-piperazin-1-yl)-propylamine (1.73 g, 11 mmol) at room temperature. The resulting mixture was stirred at room temperature for 2 hours. Water was added and the mixture was extracted with DCM. The combined extracts were washed with brine, dried over anhydrous Na2SO4, and concentrated to afford the title compound (1.4 g, 51%), which was used directly in the next step without further purification. MS (ESI): 270 [M+H]+.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:15]=[CH:14][C:8]([CH:9]=[CH:10][C:11](Cl)=[O:12])=[CH:7][C:6]=1[O:16][CH3:17])(=[O:3])[CH3:2].[NH2:18][CH:19]1[CH2:24][CH2:23][CH:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:21][CH2:20]1>N1C=CC=CC=1>[C:1]([O:4][C:5]1[CH:15]=[CH:14][C:8]([CH:9]=[CH:10][C:11]([NH:18][CH:19]2[CH2:20][CH2:21][CH:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:23][CH2:24]2)=[O:12])=[CH:7][C:6]=1[O:16][CH3:17])(=[O:3])[CH3:2]
Reactant: COc1cc(C=CC(=O)Cl)ccc1OC(C)=O
Reactant: CCOC(=O)C1CCC(N)CC1
Solvent: c1ccncc1
Product: CCOC(=O)C1CCC(NC(=O)C=Cc2ccc(OC(C)=O)c(OC)c2)CC1
Yield: 60.2 %

Procedure:
Using 2.5 g of 4-acetoxy-3-methoxycinnamoyl chloride, 3.7 g of ethyl 4-amino-1-cyclohexanecarboxylate described in the literature [V. Skaric, M. Kovacevic, and D. Skaric, J. Chem. Soc. Perkin I, 1199-1201 (1976)], and 100 ml of pyridine, a reaction similar to that conducted in Example 53 was carried out. As a result, 2.3 g of ethyl 4-(4-acetoxy-3-methoxycinnamamido)-1-cyclohexanecarboxylate (a compound of the present invention) was obtained as pale yellowish white crystal, which had the following physiochemical properties:
Reaction SMILES: [Na].[NH2:2][C:3]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:18][C:19](=[O:22])[NH:20][OH:21])[CH:9]=[CH:10]2)[C:4]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24].Br[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>>[NH2:2][C:3]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:18][C:19](=[O:22])[NH:20][O:21][CH2:29][C:30](=[O:31])[O:32][CH2:33][CH3:34])[CH:9]=[CH:10]2)[C:4]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)CBr
Reactant: CCOC(=O)c1c2ccc(CC(=O)NO)ccc-2c(C(=O)OCC)c1N
Agent: [Na]
Product: CCOC(=O)CONC(=O)Cc1ccc2c(C(=O)OCC)c(N)c(C(=O)OCC)c-2cc1
Yield: 24 %

Procedure:
In an analogous manner to that described in Example 1, from diethyl 2-amino-6-[(hydroxycarbamoyl)-methyl]-azulene-1,3-dicarboxylate sodium and ethyl bromoacetate the title compound is obtained in 24% yield as a wax.
Reaction SMILES: [CH3:1][C:2]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)=[O:3].B(O[O-])=O.[Na+].B(O)(O)O>C(O)(=O)C>[NH:4]([C:5]1[CH:10]=[CH:9][C:8]([N:11]=[N:11][C:8]2[CH:7]=[CH:6][C:5]([NH:4][C:2]([CH3:1])=[O:3])=[CH:10][CH:9]=2)=[CH:7][CH:6]=1)[C:2]([CH3:1])=[O:3]
Reactant: CC(=O)Nc1ccc(N)cc1
Agent: O=BO[O-]
Agent: OB(O)O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(N=Nc2ccc(NC(C)=O)cc2)cc1
Reaction time: 0.08 h

Procedure:
69 parts of 82% pure 4-aminoacetanilide, 80 parts of sodium perborate and 20 parts of boric acid in 1,000 parts by volume of glacial acetic acid are stirred at room temperature. After 5 minutes, a violet solution is produced, which is heated to 60°. At this temperature, an exothermic reaction takes place, and the temperature rises, without heating, to 70°. A beige precipitate separates out. The suspension thus obtained is stirred for a further 6 hours at 60° and is then cooled to 20° and filtered. The filter residue is washed with water until neutral and is dried in vacuo at 60°. The product is a beige powder which melts between 286° and 290°, with decomposition. The yield is 39.4 parts (70% of theory).
Reaction SMILES: [C:1]1([C:7]2[N:8]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][P:31]([O:36]CC)(=[O:35])[O:32]CC)[C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si](I)(C)C>C(Cl)(Cl)Cl>[C:1]1([C:7]2[N:8]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][P:31]([OH:36])(=[O:32])[OH:35])[C:9]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOP(=O)(CCCCCCCn1c(-c2ccccc2)nc(-c2ccccc2)c1-c1ccccc1)OCC
Agent: C[Si](C)(C)I
Solvent: ClC(Cl)Cl
Product: O=P(O)(O)CCCCCCCn1c(-c2ccccc2)nc(-c2ccccc2)c1-c1ccccc1
Temperature: -40 °C
Reaction time: 3 h
Yield: 51.1 %

Procedure:
Diethyl 7-(2,4,5-triphenylimidazol-1-yl)heptane-phosphonate (0.35 g) was dissolved in dry chloroform, cooled to -40° C. and to it was added trimethylsilyl iodide (0.66 g) over 2 minutes under an atmosphere of nitrogen. The cooling bath was removed and the reaction mixture was stirred for 3 hours at room temperature then evaporated to an oil and revaporated evaporated from methanol and water respectively. The oil was taken up in methanol, treated with excess aqueous sodium bicarbonate, evaporated to dryness then taken up in ethanol, filtered and the filtrate evaporated to an oil. This was taken up in water, filtered and dilute hydrochloric acid added to pH4. The precipitated oil was washed with water, taken up in methanol and precipitated with ether to give 7-(2,4,5-triphenylimidazol-1-yl)heptane-phosphonic acid (0.16 g, 51%) as a light brown oil. Found: C, 68.12; H, 6.39, N, 5.60% C28H31N2O3P+4% H2O requires: C, 68.03; H 6.76); N, 5.66%.