Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C@H:1]1([OH:8])[CH2:6][CH2:5][CH2:4][C@@H:3]([OH:7])[CH2:2]1.CC(C)([O-])C.[K+].Br[CH2:16][C:17]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:18]=1[C:19]([O:21][CH3:22])=[O:20].CC1C=CC=C(C)C=1C(OC)=O>C(COC)OC.C(OC)(C)(C)C.O>[OH:7][C@@H:3]1[CH2:4][CH2:5][CH2:6][C@H:1]([O:8][CH2:16][C:17]2[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:18]=2[C:19]([O:21][CH3:22])=[O:20])[CH2:2]1
Reactant: O[C@@H]1CCC[C@H](O)C1
Reactant: COC(=O)c1c(C)cccc1CBr
Agent: CC(C)(C)[O-]
Agent: COC(=O)c1c(C)cccc1C
Agent: [K+]
Solvent: COCCOC
Solvent: COC(C)(C)C
Solvent: O
Product: COC(=O)c1c(C)cccc1CO[C@H]1CCC[C@@H](O)C1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 14.2 %

Procedure:
5 g (42.8 mmol) of cis-1,3-cyclohexanediol were dissolved in 50 ml of dimethoxyethane (DME), admixed at 20–23° C. with 3.36 g (30 mmol) of potassium tert-butoxide (KOtBu) and stirred. After about 30 minutes, the mixture is cooled to 5° C. and 3.7 g (approx. 50%) of methyl 2-bromomethyl-6-methylbenzoate, which may be prepared, for example, by methanolyzing the acid bromide (2-bromomethyl-6-methylbenzoyl bromide) or by brominating methyl 2,6-dimethylbenzoate, are added dropwise. The mixture is stirred at 5–10° C. for 1 h and then at 20–23° C. overnight. Water and methyl tert-butyl ether (MTBE) are added, the mixture is stirred vigorously, the phases are separated, the aqueous phase is washed once more with MTBE and the combined organic phases are concentrated under reduced pressure. The residue is chromatographed on silica gel (1:1 ethyl acetate/n-heptane). 600 mg of the desired compound are obtained as a light yellow oil, 1H NMR (CDCl3), δ =1.27 (m, 1H), 1.45 (m, 1H), 1.55 (m, 1H), 1.74 (m, 1H), 1.83 (m, 1H), 2.05 (m, 1H), 2.34 (s, 3H), 3.47 (m, 1H), 3.72 (m, 1H), 3.91 (s, 3H), 4.58 (dd, 2H), 7.15 (d, 1H), 7.20 (d, 2H), 7.27 (m, 1H).
Reaction SMILES: [C:1]1([CH:9]=[CH:8][CH:7]=[C:5]([OH:6])[C:3]=1[OH:4])[OH:2].CO[C:12](OC)([CH3:14])[CH3:13]>>[CH3:13][C:12]1([CH3:14])[O:2][C:1]2[CH:9]=[CH:8][CH:7]=[C:5]([OH:6])[C:3]=2[O:4]1
Reactant: COC(C)(C)OC
Reactant: Oc1cccc(O)c1O
Product: CC1(C)Oc2cccc(O)c2O1

Procedure:
The pyrogallol is particularly suitable for reaction with 2,2-dimethoxypropane to form 2,2-dimethyl-4-hydroxy-1,3-benzodioxole, and then reaction of this with methyl isocyanate to produce the pesticide 2,2-dimethyl-1,3-benzodioxol-4-yl methylcarbamate.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10]C)=[O:9])=[C:6]([Cl:12])[N:5]=[CH:4][CH:3]=1.[Li+].[OH-]>O1CCOCC1.CO.O>[NH2:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([Cl:12])[N:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1c(N)ccnc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1COCCO1
Product: Nc1ccnc(Cl)c1C(=O)O
Temperature: 85 °C
Yield: 66.7 %

Procedure:
Methyl 4-amino-2-chloronicotinate (21.0 g, 112.9 mmol) and LiOH (10.3 g, 247.5 mmol) was taken in a mixture of dioxane:MeOH:water (3:2:1, ml) and the reaction mixture was heated to 85° C. for 2 hours. The solvent was evaporated under reduced pressure, the residue was dissolved in minimum volume of water and acidified (up to pH 4) with saturated citric acid. The aqueous solution was concentrated until precipitation just started. The mixture was allowed to stand overnight at 10° C. for complete precipitation. The resultant white solid was collected by filtration and recrystallized from isopropyl alcohol-hexane to afford 4-amino-2-chloronicotinic acid (13 g, 66% yield). 1H NMR (400 MHz, DMSO-d6): δ 7.59 (d, 1H), 6.47 (d, 1H), 6.37 (brs, 2H).
Reaction SMILES: [Cl:1][CH2:2][N:3]1[CH2:8][C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][CH2:5][C:4]1=[O:21].[CH3:22][NH2:23]>C1(C)C=CC=CC=1.C1COCC1>[ClH:1].[CH3:22][NH:23][CH2:2][N:3]1[CH2:8][C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][CH2:5][C:4]1=[O:21]
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)CN1CCl
Reactant: CN
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CNCN1CC(c2ccccc2)(c2ccccc2)CCC1=O
Product: Cl
Temperature: 25 °C

Procedure:
1-(Chloromethyl)-5,5-diphenyl-2-piperidinone (27 g) was added portionwise during 20 min. to a solution of methylamine (120ml) in a mixture of toluene (100 ml) and THF (100 ml) at -30° C. with stirring and the mixture was allowed to warm to room temperature overnight. The reaction mixture was partitioned between ethyl acetate and water and the organic solvent layer was washed with water and brine. The aqueous layers were re-extracted with ethyl acetate and then chloroform. All the organic extracts were combined and concentrated to give the crude title product as a solid which was converted to the hydrochloride salt by dissolution in isopropanol:methanol(5:1) and then adding portionwise a solution of hydrogen chloride in isopropanol until the medium was acidic. The solution was cooled overnight at 0°-5° C. and the hydrochloride salt of the title product was filtered of as a solid, mp 169°-171° C.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][CH2:8]O)[N:5]=[CH:4][C:3]=1[C:10]#[N:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:32].CCOC(C)=O>ClCCl>[NH2:1][C:2]1[N:6]([CH2:7][CH2:8][Cl:32])[N:5]=[CH:4][C:3]=1[C:10]#[N:11]
Reactant: N#Cc1cnn(CCO)c1N
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: N#Cc1cnn(CCCl)c1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 5-amino-4-cyano-1-(2hydroxyethyl)pyrazole (40 g.) and triphenylphosphine (82.7 g.) in dichloromethane (300 ml.) was cooled in a room temperature water bath while carbon tetrachloride (127 ml.) was added dropwise over 45 minutes. The resulting suspension was stirred at room temperature under nitrogen overnight, and the volatiles were then removed on a rotary evaporator, leaving an orange semisolid. This was treated with boiling EtOAc (500 ml.), chilled at 0° , filtered, and the filtrate evaporated to dryness. The residue was redissolved in THF (300 ml.) and evaporated onto flash silica gel (160 g.). This material was placed atop a column of flash silica gel (300 g.) and the desired product eluted with EtOAc/hexane (1:1 v/v). Contaminating triphenylphosphine oxide was removed by trituration with dichloromethane/hexane (1:1 v/v). The remaining solid was then recrystallized from EtOAc to give 5-amino-1-(2-chloroethyl)-4-cyanopyrazole (29.07 g.) as white crystals: m.p. 155.5-156.5 °.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:18]2[C:13](=[C:14](Br)[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=2)[CH2:12][NH:11][C:10]1=[O:22].[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.CCO.O.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>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:18]2[C:13](=[C:14]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[Cl:23])[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=2)[CH2:12][NH:11][C:10]1=[O:22]
Reactant: COc1cc(Br)c2c(c1)N(c1c(Cl)cccc1Cl)C(=O)NC2
Reactant: OB(O)c1ccccc1Cl
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: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc(-c2ccccc2Cl)c2c(c1)N(c1c(Cl)cccc1Cl)C(=O)NC2
Temperature: 25 °C

Procedure:
Palladium tetrakis triphenylphosine (140 mg, 0.12 mmol) was added to 1-(2,6-dichlorophenyl)-5-bromo-7-methoxy-3,4-dihydro-2(1H)-quinazolinone (1.02 g, 2.54 mmol) (INTERMEDIATE 23), 2-chlorophenyl boronic acid (642 mg, 4.11 mmol) and sodium carbonate (436 mg, 4.11 mmol) in 150 mL toluene, 40 mL EtOH and 40 mL water under an argon atmosphere. After refluxing 3 h the solution was cooled to RT and partition between water and EtOAc. The organic phase was washed with water′(1×) and brine (1×) and dried over MgSO4. The solution was filtered and concentrated. The residue was absorbed on SiO2 and purified by silica gel bromatography using 3 to 5% acetone in DCM to give 1-(2,6-dichlorophenyl)-5-(2-chlorophenyl)-7-methoxy-3,4-dihydro-2(1H)-quinazolinone as a white solid. 1H NMR(CDCl3, 500 MHz): δ 3.68 (s, 3H), 4.17 (d, 1H, J=14.0 Hz), 4.36 (d, 1H, J=14.0 Hz), 5.28 (s, 1H), 5.74 (d, 1H, J=2.3 Hz), 6.43 (d, 1H, J=2.5 Hz), 7.29-7.37 (m, 4H), 7.47-7.51 (m, 3H). MS(ES) 433 (M+H); LC 1: 3.12 min.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[C:11]([OH:12])=[CH:10][C:9]([C:13]([F:16])([F:15])[F:14])=[N:8]2)=[CH:3][CH:2]=1.[F-].[K+].Br[CH2:20][N:21]1[C:25](=[O:26])[C:24]2[C:27]([CH:33]([CH3:35])[CH3:34])=[CH:28][C:29]([O:31][CH3:32])=[CH:30][C:23]=2[S:22]1(=[O:37])=[O:36]>CN(C=O)C>[CH:33]([C:27]1[C:24]2[C:25](=[O:26])[N:21]([CH2:20][O:12][C:11]3[N:7]([C:4]4[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=4)[N:8]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:10]=3)[S:22](=[O:37])(=[O:36])[C:23]=2[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=1)([CH3:35])[CH3:34]
Reactant: Oc1cc(C(F)(F)F)nn1-c1ccncc1
Reactant: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(CBr)C2=O
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(COc1cc(C(F)(F)F)nn1-c1ccncc1)C2=O
Reaction time: 0.33 h
Yield: 43.2 %

Procedure:
To a mixture of 1-(4-pyridyl)-3-trifluoromethyl-5-hydroxypyrazole (316 mg; 1.36 mmol) in DMF (20 ml) was added 128 mg (2.24 mmol) of KF at room temperature under nitrogen, and the mixture was stirred for 20 minutes. To the above solution was added 2-bromomethyl-4-isopropyl-6-methoxy-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (400 mg, 1.12 mmol) and the resulting mixture was stirred at room temperature for 45 minutes. The above mixture was quenched with ice/saturated ammonium chloride, extracted with ether (3×) and the organic layer was washed with water, dried over magnesium sulfate, and concentrated in vacuo. The residual yellow solid was purified by column chromatography (silica gel; 30-50% ethyl acetate in hexane) to afford 240 mg (43%) of 4-isopropyl-6-methoxy-2-[1-(4-pyridyl)-3-trifluoromethylpyrazol-5-yl-oxymethyl]-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (Formula I: R1 =4-pyridyl; R2 =CF3 ; R3 =H; R4 =CH(CH3)2 ; R5 =6-OCH3) as a white solid, m.p. 161°-162° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]3[CH:18]=[CH:17][C:14]([CH2:15][NH2:16])=[CH:13][CH:12]=3)=[CH:9][N:10]=[C:4]2[CH:3]=1.C(Cl)Cl.[F:22][C:23]([F:35])([F:34])[C:24]1[CH:25]=[C:26]([CH2:30][C:31](Cl)=[O:32])[CH:27]=[CH:28][CH:29]=1.C(NCC)(C)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]3[CH:18]=[CH:17][C:14]([CH2:15][NH:16][C:31](=[O:32])[CH2:30][C:26]4[CH:27]=[CH:28][CH:29]=[C:24]([C:23]([F:34])([F:22])[F:35])[CH:25]=4)=[CH:13][CH:12]=3)=[CH:9][N:10]=[C:4]2[CH:3]=1
Reactant: O=C(Cl)Cc1cccc(C(F)(F)F)c1
Reactant: NCc1ccc(-c2cnc3cc(Cl)ccn23)cc1
Agent: CCNC(C)C
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(Cc1cccc(C(F)(F)F)c1)NCc1ccc(-c2cnc3cc(Cl)ccn23)cc1
Temperature: 40 °C

Procedure:
In a 40 mL septum capped vial purged with N2, add 4-(7-chloro-imidazo[1,2-a]pyridin-3-yl)-benzylamine (125 mg, 0.48 mmol), magnetic stir bar, CH2Cl2 (6 mL), cool the vial in an ice bath and slowly add 1 mL (CH2Cl2 solution of m-trifluoromethyl-phenylacetyl chloride, 0.48 mmol). Add isopropyl ethyl amine (0.8 mL) with THF (2 mL). Remove the vial from the ice bath and heat to 40° C. for 6 hours. Add a trace of MeOH and evaporate the solvents under vacuum and take up the oil into a minimal amount of CH2Cl2 and chromatograph using SiO2 eluting with a gradient of 0.5% to 5% of 2 M NH3 in MeOH with the balance CH2Cl2. Isolate the product, dry in a vacuum oven at 40° C. for 24 hours to give 144 mg (67%) MS (ES), m/z 444 (M+1).
Reaction SMILES: [CH3:1][I:2].[CH2:3]([O:8][C:9]1[C:10]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[N:11][S:12][N:13]=1)[CH2:4][C:5]#[C:6][CH3:7]>CC(C)=O>[I-:2].[CH2:3]([O:8][C:9]1[C:10]([C:14]2[CH:15]=[N+:16]([CH3:1])[CH:17]=[CH:18][CH:19]=2)=[N:11][S:12][N:13]=1)[CH2:4][C:5]#[C:6][CH3:7]
Reactant: CI
Reactant: CC#CCCOc1nsnc1-c1cccnc1
Solvent: CC(C)=O
Product: CC#CCCOc1nsnc1-c1ccc[n+](C)c1
Product: [I-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of methyl iodide (0.6 ml, 9 mmol) and 3-(4-(3-pentynyloxy)-1,2,5-thiadiazol-3-yl)pyridine (3 mmol) in acetone (10 ml) was stirred at room temperature for 18 h. The title compound precipitated from the solution and was collected by filtration to yield 0.68 g (59%).
Reaction SMILES: C[O:2][C:3](=[O:23])[C:4]1[CH:16]=[C:15]([N:17]2[CH2:21][CH2:20][CH2:19][C:18]2=[O:22])[CH:14]=[C:6]([C:7]([N:9]([CH3:13])[CH2:10][CH2:11][CH3:12])=[O:8])[CH:5]=1>[OH-].[Na+].CO.O>[CH3:13][N:9]([CH2:10][CH2:11][CH3:12])[C:7](=[O:8])[C:6]1[CH:5]=[C:4]([CH:16]=[C:15]([N:17]2[CH2:21][CH2:20][CH2:19][C:18]2=[O:22])[CH:14]=1)[C:3]([OH:23])=[O:2]
Reactant: CCCN(C)C(=O)c1cc(C(=O)OC)cc(N2CCCC2=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCN(C)C(=O)c1cc(C(=O)O)cc(N2CCCC2=O)c1

Procedure:
Stir N-methyl-5-(2-oxopyrrolidin-1-yl)-N-propyl-isophthalamic acid methyl ester (100 mg, 0.314 mmol) in 1 N NaOH (0.5 mL) and methanol (0.5 mL) at room temperature for 3 days. Dilute the mixture with water (1 mL) and wash the aqueous solution with diethyl ether. Acidify with 1 N HCl (0.55 mL) and extract with ethyl acetate (3×2 mL). Concentrate the organic layers to give the title compound as a crude residue which is used in the next step without further purification.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2.Br[CH:14]([CH3:18])[C:15]([NH2:17])=[O:16].O>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH:14]([CH3:18])[C:15]([NH2:17])=[O:16])[CH:8]=[CH:7]2
Reactant: CC(Br)C(N)=O
Reactant: Clc1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C(N)=O)n1ccc2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A dispersion of 60% NaH (6.85 g, 0.17 mol) was added to an ice-cooled solution of 5-chloroindole (20 g, 0.13 mol) in 250 ml of dry DMF. The stirring was continued for 20 minutes at room temperature, and the mixture was cooled again with an ice bath. After portionwise addition of solid 2-bromopropanamide (24.1 g, 0.15 mol), the reaction mixture was stirred for 1 h 30 at room temperature, then poured into cold water and extracted 3 times with AcOEt. The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by silica gel chromatography (AcOEt/hexane 50/50) to give pure 2-(5-chloro-1H-indol-1-yl)propanamide 25 as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[C:4]([C:20]([F:23])([F:22])[F:21])[CH:3]=1.[NH2:24][CH:25]([CH2:28][CH3:29])[CH2:26][CH3:27]>>[CH2:26]([CH:25]([NH:24][C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[C:4]([C:20]([F:23])([F:22])[F:21])[CH:3]=1)[CH2:28][CH3:29])[CH3:27]
Reactant: CCC(N)CC
Reactant: O=C(Nc1nc2cc(C(F)(F)F)cc(Cl)n2n1)c1cccnc1
Product: CCC(CC)Nc1cc(C(F)(F)F)cc2nc(NC(=O)c3cccnc3)nn12
Temperature: 120 °C
Yield: 41.9 %

Procedure:
The title compound was prepared following procedure and work up described for example 118, but starting from N-[5-chloro-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide ((B7), 50 mg; 0.14 mmol; 1.0 eq) and 3-aminopentane (86 μL; 0.73 mmol; 5.0 eq), heated at 120° C., to give the title compound as a white solid (23 mg, 40%). HPLC, Rt: 3.66 min. (purity 96%). LC/MS, M+(ESI): 392.9, M−(ESI): 391.0.
Reaction SMILES: OCC(N1[CH2:10][CH2:9][N:8]([C:11]2[CH:33]=[CH:32][C:14]([NH:15]C3N=C(C4N(C(C)C)C(C)=NC=4)C(Cl)=CN=3)=[CH:13][CH:12]=2)[CH2:7]C1)=O.CC[OH:36]>[Pd]>[NH2:15][C:14]1[CH:32]=[CH:33][C:11]([N:8]2[CH2:7][CH:10]([OH:36])[CH2:9]2)=[CH:12][CH:13]=1
Reactant: CCO
Reactant: Cc1ncc(-c2nc(Nc3ccc(N4CCN(C(=O)CO)CC4)cc3)ncc2Cl)n1C(C)C
Agent: [Pd]
Product: Nc1ccc(N2CC(O)C2)cc1
Reaction time: 0.25 h

Procedure:
A stirred solution of 1-(4-nitrophenyl)-azetidin-3-ol (Method 36; 15.15 g, 87 mM) in EtOH (250 ml) was hydrogenated over 10% Pd/C (1.5 g) for 18 hrs at atmospheric pressure. The reaction mixture was filtered and the filtrate was evaporated and triturated with ether giving the title compound as a grey crystalline solid. Much of the product had precipitated from the reaction mixture and been filtered off with catalyst. This was stirred with DMF (100 ml) for 15 mins and the catalyst filtered off. The filtrate was evaporated (Hi-Vac) and triturated with a little EtOH. The second crop of product was filtered off, washed with ether and dried. NMR: 3.35 (m+water, 2H), 3.90 (t, 2H), 4.32 (s, 2H), 4.45 (m, 1H), 5.41 (d, 1H), 6.20 (d, 2H), 6.45 (d, 2H); m/z 165.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[N:16]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]OS(C1C=CC(C)=CC=1)(=O)=O)=[N+:17]=[N-:18].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:10][O:9][C:7](=[O:8])[C:6]1[CH:11]=[C:2]([O:1][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][N:16]=[N+:17]=[N-:18])[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=1
Reactant: Cc1ccc(S(=O)(=O)OCCCCCCN=[N+]=[N-])cc1
Reactant: COC(=O)c1cc(O)cc(C(=O)OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(OCCCCCCN=[N+]=[N-])cc(C(=O)OC)c1
Temperature: 80 °C
Reaction time: 17 h

Procedure:
5-(6-Azidohexoxy)isophthalic Acid Dimethyl Ester was prepared as follows: A mixture of dimethyl 5-hydroxyisophthalate 4 (1.05 g, 5 mmol), 6-azido-1-(p-toluenesulfonyloxy)hexane (1.57 g, 5 mmol) and K2CO3 (1.38 g, 10 mmol) in DMF (15 mL) was stirred for 17 h at 80° C. After cooling down, H2O (150 mL) was added and the mixture was extracted with EtOAc, washed with water, dried (MgSO4), and the solvent was evaporated off. The pure title compound was obtained as a colorless oil (1.51 g, 90%) after column chromatography (SiO2: CH2Cl2).
Reaction SMILES: OC([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:10][C:9]=2[CH:19]=1)C#N.C.[C:21]([OH:24])(=[O:23])[CH3:22]>[Pd]>[C:13]1([C:11]2[O:12][C:8]3[CH:7]=[CH:6][C:5]([CH2:22][C:21]([OH:24])=[O:23])=[CH:19][C:9]=3[N:10]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(=O)O
Reactant: N#CC(O)c1ccc2oc(-c3ccccc3)nc2c1
Agent: [Pd]
Product: O=C(O)Cc1ccc2oc(-c3ccccc3)nc2c1
Reaction time: 4 h

Procedure:
A solution of α-hydroxy-2-phenyl-5-benzoxazolyl-acetonitrile (2 g.) in acetic acid (30 ml.) containing palladium or charcoal was hydrogenated for 4 hours. The catalyst was filtered off and the solution was evaporated to dryness. The residue was recrystallised to give pure 2-phenyl-5-benzoxazolylacetic acid m.p. 175° C.
Reaction SMILES: [C:1]1([N:7]2[N:11]=[C:10]([OH:12])[CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:13]Br>C(Cl)(Cl)Cl>[C:1]1([N:7]2[N:11]=[C:10]([OH:12])[C:9]([Br:13])=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Oc1cnn(-c2ccccc2)n1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: Oc1nn(-c2ccccc2)nc1Br

Procedure:
32.2 g of 2-phenyl-4-hydroxy-1,2,3-triazole is stirred in 400 ml of chloroform with 32 g of bromine at room temperature for 16 hours. The solvent is evaporated off and the residue is stirred into petroleum ether and filtered off under suction.
Reaction SMILES: [CH2:1]([O:19][C:20](=[O:31])[CH:21]([NH2:30])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].Cl[C:33](Cl)([O:35]C(=O)OC(Cl)(Cl)Cl)Cl.[O:44]1CCOC[CH2:45]1>C1(C)C=CC=CC=1.CCCCCC>[CH2:1]([O:19][C:20](=[O:31])[CH:21]([N:30]=[C:45]=[O:44])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:33]=[O:35])=[CH:25][CH:24]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: C1COCCO1
Reactant: CCCCCCCCCCCCCCCCCCOC(=O)C(N)Cc1ccc(N)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CCCCCCCCCCCCCCCCCCOC(=O)C(Cc1ccc(N=C=O)cc1)N=C=O
Temperature: 80 °C

Procedure:
Into a solution of 2-Amino-3-(4-amino-phenyl)-propionic acid octadecyl ester (100 g) in dry 1,4-dioxane (2000 ml) under Nitrogen atmosphere maintained at 20° C. was added a solution of triphosgene (163 g) in 1,4-Dioxane (200 ml) in one lot. The reaction mixture was heated and refluxed for 3 hours. The condenser was then arranged for distillation and solvent removed by distillation at atmospheric pressure until the volume of the reaction mixture was reduced to approximately one third. Fresh dry dioxane (200 ml) was added and distilled off under vacuum. The residue was dissolved in Toluene (200 ml) and charcoal (5 g) was added. The solution was filtered hot and the solvent was distilled under vacuum to yield crude diisocyanate which was again dissolved in a mixture of toluene: hexane (6:4; 400 ml) by heating to 80° C. for 15 minutes. The solution was filtered and the solvent mixture was distilled off under vacuum. Hexane was added to the precipitate and pure diisocyanate was filtered, dried and packed in tight container to yield 65 g of pure 2-Isocyanato-3-(4-Isocyanato-phenyl)-propionic acid octadecyl ester as a white powder with a melting point of 78-80° C. The product was further characterized by IR: 2261 cm-1 and IH NMR (CDCl3) δ 3.15-3.30 (m, 2H, CH2), 3.70 (s, 3H, OCH3), 5.05 (m, 1H, CH), 6.60 (d, 1H, NH), 7.00 (d, 2H, Ar), 7.05 (d, 2H, Ar), 7.15 (d, 2H, Ar), 7.60 (d, 2H, Ar)
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][NH:6][S:7]([C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[C:12]([N+:17]([O-])=O)[C:11]=1[OH:20])(=[O:9])=[O:8])[CH3:2].[H][H]>[Pd]>[CH2:1]([O:3][CH2:4][CH2:5][NH:6][S:7]([C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[C:12]([NH2:17])[C:11]=1[OH:20])(=[O:9])=[O:8])[CH3:2]
Reactant: [H][H]
Reactant: CCOCCNS(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1O
Agent: [Pd]
Product: CCOCCNS(=O)(=O)c1c(Cl)ccc(N)c1O

Procedure:
Following the general hydrogenation procedure outlined in example 15, crude N-(2-ethoxyethyl)-6-chloro-2-hydroxy-3-nitrobenzenesulfonamide (0.98 g) was reduced with hydrogen and Pd/C (250 mg). The crude product (1.01 g) was carried onto the next step without purification. 1H NMR (MeOD-d4): δ 6.88 (m, 2H), 3.40 (t, 2H), 3.36 (m, 2H), 3.13 (t, 2H), 1.08 (t, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][NH:6]2.OC1C=C2C(=CC=1)N([CH2:21][C:22]1([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:27][O:26][C:25]([CH3:29])([CH3:28])[O:24][CH2:23]1)CC2>>[OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][N:6]2[CH2:21][C:22]1([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:27][O:26][C:25]([CH3:28])([CH3:29])[O:24][CH2:23]1
Reactant: CC(C)(C)OC(=O)NC1(CN2CCc3cc(O)ccc32)COC(C)(C)OC1
Reactant: Oc1cccc2c1CCN2
Product: CC(C)(C)OC(=O)NC1(CN2CCc3c(O)cccc32)COC(C)(C)OC1
Yield: 74 %

Procedure:
When the product of Step A was substituted for tert-butyl 5-((5-hydroxyindolin-1-yl)methyl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate in Example 8, Step G, the identical process afforded the title compound in 74% yield, as a creamy solid. 1H-NMR (CDCl3) 1.4-1.65 (m, 15H+H2O); 2.94 (tr, 2H, J=8.4 Hz); 3.5 (tr, 2H, J=8.4 Hz); 3.52 (s, 2H); 3.8-3.99 (m, 4H); 4.64 (broad s, 1H); 4.7 (broad s, 1H); 6.15-6.23 (m, 2H); 6.93 (tr, 1H, J=7.96 Hz).