Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[CH:8]C(C#N)=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1.S(=O)(=O)(O)O.[OH-].[Na+].[C:20]([O:23][CH2:24][CH3:25])(=[O:22])[CH3:21]>C(O)C.ClCCl>[NH2:1][C:2]1[C:7]2=[CH:8][C:21]([C:20]([O:23][CH2:24][CH3:25])=[O:22])=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1
Reactant: N#Cc1cc2c(N)ncnn2c1
Reactant: CCOC(C)=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)c1cc2c(N)ncnn2c1
Temperature: 25 °C

Procedure:
A solution of 4-aminopyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile (3.9 g, 24.5 mmol; preparation described in PCT Int. Pat. Appl. WO 2007/064883) in ethanol (124.8 ml) was stirred with concentrated sulfuric acid (62.4 ml) at 80° C. overnight. After cooling to rt, the reaction mixture was poured onto 800 g of ice and brought to pH 6-7 with concentrated aq. sodium hydroxide solution. Ethyl acetate (500 ml) and dichloromethane (500 ml) were added to the suspension, and the resulting mixture was filtered over kieselguhr. The organic layer was separated from the aqueous layer. The solid was dissolved in hot water (1 L), and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulfate and evaporated. The residue was triturated with an isopropanol/diethylether mixture, and the solid was filtered off yielding 2.5 g (49% of th.) of the title compound.
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[CH3:5][C:6]([C:9]1[CH:10]=[C:11]([CH:18]=[C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:20]=1[OH:21])[O:12][CH2:13][C:14]([NH:16][NH2:17])=[O:15])([CH3:8])[CH3:7]>O1CCCC1.C(OCC)(=O)C>[CH3:8][C:6]([C:9]1[CH:10]=[C:11]([CH:18]=[C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:20]=1[OH:21])[O:12][CH2:13][C:14]1[O:15][C:1](=[S:2])[NH:17][N:16]=1)([CH3:5])[CH3:7]
Reactant: CC(C)(C)c1cc(OCC(=O)NN)cc(C(C)(C)C)c1O
Reactant: S=C(Cl)Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(OCc2n[nH]c(=S)o2)cc(C(C)(C)C)c1O
Reaction time: 0.5 h

Procedure:
Thiophosgene (0.10 mL, 1.36 mmol) is added dropwise to a -78° C. solution of [3,5-bis(1,1-dimethylethyl)-4-hydroxyphenoxy-acetic acid hydrazide (0.40 g, 1.36 mmol) in tetrahydrofuran (25 mL). The reaction mixture is stirred for 30 minutes, diluted with ethyl acetate, and washed three times with water and once with brine. Drying the organic phase over magnesium sulfate and evaporation gives a pale yellow oil which is crystallized from ethyl acetate/hexane yielding 0.36 g (78%) of 5-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenoxymethyl]-1,3,4-oxadiazole-2(3H)-thione, mp 195.0°-196.5° C.
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)([CH3:6])([CH3:5])[CH3:4].C(N)=O.[O-]C1C=CC=CC=1.[C:24]([O:27][CH2:28][CH2:29][CH2:30][CH2:31]Cl)(=[O:26])[CH3:25]>CN(C)C=O>[C:24]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][O:13][C:10]1[CH:9]=[CH:8][C:7]([C:3]([CH3:6])([CH3:4])[CH3:5])=[CH:12][CH:11]=1)(=[O:26])[CH3:25]
Reactant: CC(C)(C)c1ccc(O)cc1
Reactant: CC(=O)OCCCCCl
Agent: [H-]
Agent: [Na+]
Agent: [O-]c1ccccc1
Solvent: NC=O
Solvent: CN(C)C=O
Product: CC(=O)OCCCCOc1ccc(C(C)(C)C)cc1

Procedure:
To a stirred slurry of 1.6 g sodium hydride (as 50% dispersion in oil) in 50 ml dry dimethyl formamide was added, dropwise, a solution of 5.0 g p-tert-butylphenol (33.3 mmoles) in 50 ml dry diemthyl formamide and the solution stirred under nitrogen until the phenoxide had totally formed. To the phenoxide was added a solution of 5.0 g 4-chlorobutyl acetate (33.3 mmoles) in 50 ml dry dimethyl formamide and the solution was stirred for fourteen hours. The reaction mixture was partitioned between water/ toluene. The organic layer was removed, washed with water, then 1 N sodium bicarbonate. The organic layer was removed, dried and evaporated to an orange oil, 5.6g. The oil was chromatographed on 500 g, 90 to 200 mesh silica gel (CH2Cl2 eluent) yielding pure 4-(p-tert-butylphenoxy)-butyl acetate.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[CH2:3][CH2:4][CH2:5][NH:6][C:7]1[C:15]([S:16](=[O:19])(=[O:18])[NH2:17])=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][C:8]=1[N+:20]([O-])=O.[H][H]>[OH-].[Na+].[Pd]>[NH2:20][C:8]1[CH:9]=[C:10]([CH:14]=[C:15]([S:16](=[O:19])(=[O:18])[NH2:17])[C:7]=1[NH:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:23])[CH3:1])[C:11]([OH:13])=[O:12]
Reactant: [H][H]
Reactant: CN(C)CCCNc1c([N+](=O)[O-])cc(C(=O)O)cc1S(N)(=O)=O
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Product: CN(C)CCCNc1c(N)cc(C(=O)O)cc1S(N)(=O)=O

Procedure:
4-(3-Dimethylaminopropylamino)-3-nitro-5-sulphamyl-benzoic acid (6.92 g) was dissolved in 2N sodium hydroxide (25 ml), and the solution was hydrogenated at room temperature and 1.1 atmospheres hydrogen pressure after the addition of a palladium-on-carbon catalyst (0.35 g catalyst containing 10% Pd.). After the hydrogen uptake had become negligible, the catalyst was removed by filtration, and the filtrate was adjusted to a pH of 8 by addition of 4N hydrochloric acid. The precipitated 3-amino-4-(3-dimethylaminopropylamino)-5-sulphamyl-benzoic acid was collected by suction and recrystallized from water. After drying in vacuo at 115°C for 2 hours, the melting point was 264°C (decomp.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=[O:15])[C:10]2([CH3:14])[CH3:13])=[CH:5][CH:4]=1.C1C(=O)N([Br:23])C(=O)C1.O>CC#N>[Br:23][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:3]=1[O:2][CH3:1])[C:10]([CH3:13])([CH3:14])[C:9](=[O:15])[CH2:8][CH2:7]2
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc2c(c1)C(C)(C)C(=O)CC2
Solvent: CC#N
Solvent: O
Product: COc1cc2c(cc1Br)CCC(=O)C2(C)C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 92 %

Procedure:
7-Methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one (Compound A2, 2.0 g, 9.791 mmol) was dissolved in CH3CN (40 mL), added with NBS (1.92 g, 1.1 eq.), and the mixture was stirred at room temperature for 2.5 hr. The reaction solution was added to water (40 mL), and the precipitated solid was filtered to obtain the title compound (white powder, 2.55 g, 92%).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:10][CH3:11])[CH2:4][NH:5][C:6](=[O:9])[CH:7]=[CH2:8].[NH:12]1[CH2:16][CH2:15][CH2:14][C:13]1=[O:17]>>[CH3:1][O:2][CH:3]([O:10][CH3:11])[CH2:4][NH:5][C:6](=[O:9])[CH2:7][CH2:8][N:12]1[CH2:16][CH2:15][CH2:14][C:13]1=[O:17]
Reactant: C=CC(=O)NCC(OC)OC
Reactant: O=C1CCCN1
Product: COC(CNC(=O)CCN1CCCC1=O)OC
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
10 g (62.8 mmol) of the acrylamido acetal from Example 2 are mixed with 6 g (70.5 mmol) of pyrrolidone and, after addition of one drop of Triton B, the mixture is warmed to 80° C. After 10 minutes, the reaction is terminated. The thin-layer chromatogram shows no UV absorbing acetal. The product is subsequently freed from traces of solvent under a high vacuum. It is a single compound according to TLC. NMR data: 2 methylene protons at each of 2.0, 2.4, 2.5, 3.3, 3.4 and 3.6 ppm(t), 6 methoxy protons at 3.35 ppm(s), 1 acetal proton at 4.4 ppm(t), 1 amide proton at 7.2 ppm.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:27][CH2:28][CH2:29][NH2:30])[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].[F:32][C:33]1[CH:34]=[C:35]([N:39]=[C:40]=[O:41])[CH:36]=[CH:37][CH:38]=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:27][CH2:28][CH2:29][NH:30][C:40]([NH:39][C:35]3[CH:36]=[CH:37][CH:38]=[C:33]([F:32])[CH:34]=3)=[O:41])[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31]
Reactant: Cc1cc(F)ccc1-c1nc(NCCN)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: O=C=Nc1cccc(F)c1
Product: Cc1cc(F)ccc1-c1nc(NCCNC(=O)Nc2cccc(F)c2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Yield: 67.6 %

Procedure:
The title compound from Example 157 (42.3 mg, 0.0001 mol) was treated with 3-fluorophenylisocyanate (12 mg, 0.0001 mol) in the same manner as described in Example 158. Purification afforded 38 mg (67.6%) of the title compound as a light yellow solid (m.p. 131°-144°) LC MS (m/e)=563 (MH+). Rt=2.22 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]4[CH2:24][CH2:23][CH2:22][CH2:21]4)=[CH:13][CH:12]=3)[S:8][C:7]=2[CH:25]=1.[Cl:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][N:28]=1>>[Cl:26][C:27]1[N:28]=[CH:29][C:30]([C:31]([C:10]2[C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:25][C:7]=3[S:8][C:9]=2[C:11]2[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH2:19][N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:15][CH:16]=2)=[O:32])=[CH:34][CH:35]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: COc1ccc2cc(-c3ccc(OCCN4CCCC4)cc3)sc2c1
Product: COc1ccc2c(C(=O)c3ccc(Cl)nc3)c(-c3ccc(OCCN4CCCC4)cc3)sc2c1
Yield: 51 %

Procedure:
The title compound was prepared from 6-methoxy-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophene (Example 1, Part B) and 6-chloronicotinic acid in 51% yield (based on 6-methoxy-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophene) by essentially following the procedures described in Example 1, Part C.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH:7]([CH3:15])[CH:8]([OH:14])[CH2:9][CH:10]=[C:11]([CH3:13])[CH3:12])(=[O:3])[CH3:2].[CH2:16]([O:18][CH:19]=[CH2:20])[CH3:17].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>CCOCC>[C:1]([O:4][CH2:5][CH2:6][CH:7]([CH3:15])[CH:8]([O:14][CH:16]([O:18][CH2:19][CH3:20])[CH3:17])[CH2:9][CH:10]=[C:11]([CH3:13])[CH3:12])(=[O:3])[CH3:2]
Reactant: C=COCC
Reactant: CC(=O)OCCC(C)C(O)CC=C(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CCOC(C)OC(CC=C(C)C)C(C)CCOC(C)=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 8-acetoxy-2,6-dimethyl-5-hydroxy-2-octene (2.27 g, 10.6 mmole), ethyl vinylether (0.82 g. 11.4 mmole), p-toluenesulfonic acid monohydrate (catalytic amount) and ether (50 ml) is stirred at room temperature for 16 hours. The resulting mixture is treated with ether (150 ml) and washes with 5% sodium bicarbonate solution (2×100 ml). The organic phase is dried (Na2SO4), and evaporated in vacuo to give the crude product. The crude material is further purified by column chromatography on silica gel (25 g, 5% ethyl acetate in hexane) to give 8-acetoxy-2,6-dimethyl-5-[(1-ethoxyethoxy)]-2-octene as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](Cl)=[N:4][N:3]=1.O.[NH2:14][NH2:15]>C(O)C>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:14][NH2:15])=[N:4][N:3]=1
Reactant: Clc1nnc(Cl)c2ccccc12
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNc1nnc(Cl)c2ccccc12
Temperature: 25 °C

Procedure:
10 g commercially available dichlorophthalazine are added portionwise at 90° C. to a solution of 50 ml ethanol and 20 ml hydrazine hydrate. After 10 min the reaction mixture is cooled to ambient temperature, the precipitate is filtered with suction and rinsed with ethanol to yield 8.4 g of the title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]([C:15]2[S:22][C:21]([CH3:23])=[C:20]3[C:16]=2[CH2:17][C@H:18]2[C:24]([CH3:26])([CH3:25])[C@H:19]23)=[O:14])=[CH:7][CH:6]=1.CCN(C(C)C)C(C)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>C(Cl)Cl>[O:14]=[C:13]([C:15]1[S:22][C:21]([CH3:23])=[C:20]2[C:16]=1[CH2:17][C@H:18]1[C:24]([CH3:26])([CH3:25])[C@H:19]12)[CH2:12][CH2:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:4][CH2:3][CH2:2][O:1][S:37]([CH3:36])(=[O:39])=[O:38])=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1sc(C(=O)CCc2ccc(CCCO)cc2)c2c1[C@H]1[C@@H](C2)C1(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1sc(C(=O)CCc2ccc(CCCOS(C)(=O)=O)cc2)c2c1[C@H]1[C@@H](C2)C1(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98.5 %

Procedure:
A solution of 3-[4-(3-hydroxy-propyl)-phenyl]-1-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propan-1-one (147 mg, 0.40 mmol), DIPEA (0.11 mL, 0.642 mmol) in DCM (5 mL) is treated with methane sulfonylchloride (40 μL, 0.481 mmol) at 0° C. The solution is stirred at 0° C. for 30 min, then at rt for 1 h before it is diluted with DCM and washed with 0.1 N aq. NaOH solution, followed by 10% aq. citric acid solution. The organic layer is separated, dried over Na2SO4 and evaporated to give methanesulfonic acid 3-{4-[3-oxo-3-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propyl]-phenyl}-propyl ester (176 mg) as a colourless oil; LC-MS: tR=1.14 min, [M+1]+=447.25.
Reaction SMILES: C[CH:2]([O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][NH:16][CH2:17][CH:18]([OH:27])[CH2:19][O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:9][CH:8]=1)[C:3]([O-:5])=O.[CH3:28][O:29][CH2:30][CH2:31][NH2:32].CCOCC.[ClH:38]>ClCCl>[ClH:38].[OH:27][C@H:18]([CH2:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:17][NH:16][CH2:15][CH2:14][O:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:2][C:3]([NH:32][CH2:31][CH2:30][O:29][CH3:28])=[O:5])=[CH:8][CH:9]=1
Reactant: COCCN
Reactant: CC(Oc1ccc(OCCNCC(O)COc2ccccc2)cc1)C(=O)[O-]
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: COCCNC(=O)COc1ccc(OCCNC[C@H](O)COc2ccccc2)cc1

Procedure:
(-)-Methyl-4-[2-(2-hydroxy-3-phenoxypropylamino)ethoxy]phenoxyacetate (44.0 g) (the same starting material as in Example 2) and 2-methoxyethylamine (30 ml) were heated together on a steam-bath for 24 hours. The mixture was cooled and evaporated under reduced pressure to give an oily residue. This was dissolved in dichloromethane (200 ml) and treated with a solution of ether saturated with hydrogen chloride. The solvent was evaporated and the residual solid crystallised from a mixture of methanol and ethyl acetate to give (S)-4-[2-(2-hydroxy-3-phenoxypropylamino)ethoxy]-N-(2-methoxyethyl)phenoxyacetamide hydrochloride (39.2 g), m.p. 171°-3° C.; αS =-10.7° (c=1.0; methanol); microanalysis: found C, 58.1; H, 7.0; N, 6.0; Cl, 7.9%; required for C22H31ClN2O6 : C, 58.1; H, 6.9; N, 6.2; Cl 7.8%: NMR (DMSO-d6) 3.1(m,1H,CHCH2NH); 3.24(s,3 H,OCH3); 3.24-3.45(m,7H,CHCH2NHCH2 ; NHCH2CH2OCH3): 4.0(m,2H, ArOCH2CHOH): 4.2-4.35(m,3H,CHOH; CH2CH2OAr): 5.95(d,1H,OH); 6.85-7.05(m,7H,Ar); 7.3(m,2H,Ar); 8.15(t,1H, CONHCH2): 9.16 and 9.35 (broad peaks, 2H, NH2+).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][C:8]([O:16][CH3:17])=[C:9]([O:14][CH3:15])[CH:10]=2)[CH:5]=1.C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>C(Cl)Cl>[CH3:25][S:26]([O:1][CH2:2][CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][C:8]([O:16][CH3:17])=[C:9]([O:14][CH3:15])[CH:10]=2)[CH:5]=1)(=[O:28])=[O:27]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc2ccc(CCO)cc2cc1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2ccc(CCOS(C)(=O)=O)cc2cc1OC
Temperature: 3 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
To 5.03 g (0.0216 mole) of 2-(2-hydroxyethyl)-6,7dimethoxynaphthalene in 75 mL of methylene chloride, cooled in an ice bath, was added 6 mL (0.043 mole) of triethylamine followed by 2.2 mL (0.028 mole) of methanesulfonyl chloride. The reaction mixture was stirred at 3° C. for 1 hour and then was washed with 1N hydrochloric acid, 5% sodium bicarbonate solution. The organic layer was dried and concentrated under reduced pressure to give 2-(2-methanesulfonyloxyethyl)-6,7-dimethoxynaphthalene, which was used without purification. A mixture of this mesylate, 5.5 g (0.019 mole) of 2,4-dihydroxy-3-propylbenzoic acid phenylmethyl ester, 0.7 mL of TDA-1 and 5.4 g (0.039 mole) of potassium carbonate in 180 mL of toluene was stirred at reflux for 18 hours. The reaction mixture was washed with water, dried and concentrated under reduced pressure to a solid which was recrystallized from methylene chloride-methanol-water, to give 8.6g (89% yield), mp 112°-113° C., of 2-hydroxy-4-[2-(6,7-dimethoxy-2-naphthalenyl)ethoxy]-3-propylbenzoic acid phenylmethyl ester.
Reaction SMILES: C12N(C3C=NC4C(=CC=CC=4)N=3)CC1CCNC2.[CH:19]12[CH2:25][NH:24][CH:23]1[CH2:22][N:21]([C:26]([C:28]1[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=[CH:30][C:29]=1[O:38][CH2:39][CH3:40])=[O:27])[CH2:20]2.Cl[C:42]1[N:47]=[C:46]([O:48][CH3:49])[CH:45]=[C:44]([O:50][CH3:51])[N:43]=1>>[CH3:51][O:50][C:44]1[CH:45]=[C:46]([O:48][CH3:49])[N:47]=[C:42]([N:24]2[CH2:25][CH:19]3[CH:23]2[CH2:22][N:21]([C:26]([C:28]2[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:31]=[CH:30][C:29]=2[O:38][CH2:39][CH3:40])=[O:27])[CH2:20]3)[N:43]=1
Reactant: COc1cc(OC)nc(Cl)n1
Reactant: CCOc1ccc2ccccc2c1C(=O)N1CC2CNC2C1
Agent: c1ccc2nc(N3CC4CCNCC43)cnc2c1
Product: CCOc1ccc2ccccc2c1C(=O)N1CC2CN(c3nc(OC)cc(OC)n3)C2C1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 2, Step A, using Intermediate 24 and 2-chloro-4,6-dimethoxypyrimidine. MS (ESI) mass calcd. for C24H26N4O4, 434.5; m/z found, 435.2 [M+H]+.
Reaction SMILES: [CH2:1](O)[C:2]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:4]([O:5][CH3:6])[CH:3]=1.C[Si](Cl)(C)C.C(=[N:25][C:26]1[N:27]=[CH:28][NH:29][C:30]=1[C:31]([NH2:33])=[O:32])C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.CS(C)=O>[NH2:25][C:26]1[N:27]=[CH:28][N:29]([CH2:1][C:2]2[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:4]([O:5][CH3:6])[CH:3]=2)[C:30]=1[C:31]([NH2:33])=[O:32]
Reactant: COc1ccc(CO)cc1OC
Reactant: NC(=O)c1[nH]cnc1N=Cc1ccccc1
Agent: C[Si](C)(C)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COc1ccc(Cn2cnc(N)c2C(N)=O)cc1OC
Yield: 62.6 %

Procedure:
A dimethyl sulfoxide solution of 4.29 ml (30 mmol) veratryl alcohol (3,4-dimethoxybenzyl alcohol) was treated in 22.86 ml (180 mmol) trimethylsilyl chloride at room temperature for 1 hour. The resulting product was dissolved in ethyl acetate, washed with distilled water and saturated brine, and dried over anhydrous magnesium sulfate. After concentration under vacuum, the resulting residue was reacted with 2.14 g (10 mmol) of 4-benzylideneamino-5-imidazole carboxamide and 5.52 (40 mmol) of potassium carbonate in the same manner as in Reference Example 2 to obtain 1.73 g of 4-amino-1-(3,4-dimethoxybenzyl)-5-imidazolecarboxamide (yield 63%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([NH:12][C:13]([O:15][CH3:16])=[O:14])[C:9]([OH:11])=[O:10].N[C:18](C1C=CC=CC=1)(C)C(O)=O>>[CH3:16][O:15][C:13]([NH:12][C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=1)([CH3:18])[C:9]([OH:11])=[O:10])=[O:14]
Reactant: CC(N)(C(=O)O)c1ccccc1
Reactant: COC(=O)NC(C(=O)O)c1ccccc1F
Product: COC(=O)NC(C)(C(=O)O)c1ccccc1

Procedure:
2-Methoxycarbonylamino-2-phenyl-propionic acid was prepared using the procedure used to prepare (2-Fluoro-phenyl)-methoxycarbonylamino-acetic acid using 2-Amino-2-phenyl-propionic acid. LCMS-ESI+: calc'd for C11H13NO4: 223.08 (M+); Found: 223.96 (M+H+)
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:9]([O:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:8][CH:7]=[CH:6][N:5]2[CH:18]=1.C(Cl)(Cl)Cl.Cl.[N:24]([O-])=[O:25].[Na+]>O>[CH3:1][C:2]1[N:3]=[C:4]2[C:9]([O:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:8][CH:7]=[CH:6][N:5]2[C:18]=1[N:24]=[O:25]
Reactant: O=N[O-]
Reactant: Cc1cn2cccc(OCc3ccccc3)c2n1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1nc2c(OCc3ccccc3)cccn2c1N=O
Temperature: 25 °C

Procedure:
To a stirred mixture of 10.0 g (42.2 mmol) of 2-methyl-8-(phenylmethoxy)imidazo[1,2-a]pyridine, 150 ml of water and 150 ml of chloroform is added cautiously (EXOTHERM) 179.5 ml (2.15 moles) of concentrated hydrochloric acid and the resultant mixture is heated to an internal temperature of approximately 55° C. To this stirred and heated mixture is added at a rate of approximately 7 ml/minute a solution of of 151 g (2.11 moles) sodium nitrite (97%) in 660 ml of water to produce a vigorous, but manageable, reflux. When the addition is complete,the reaction mixture is allowed to cool to room temperature. The lower (CHCl3) layer is drawn off and the aqueous layer extracted with three--150 ml portions of chloroform. The combined chloroform extracts arewashed with two--450 ml volumes of 2.4 M sodium carbonate solution, then with a single 500 ml portion of saturated aqueous sodium chloride. The extracts are concentrated in vacuo (rotary evaporator, 45°) to lessthan one-half the original volume, dried over anhydrous sodium sulfate and evaporated to a viscous oil. Chromatography of the oil on silica gel, eluting with chloroform/ethyl acetate (1/1) yields the title compound as acrystalline solid, mp 147.5°-149.5° C. (dec).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[CH3:14][N:15]1[C:19]([CH3:20])=[C:18]([C:21]2[CH:22]=[C:23]([CH2:27]O)[CH:24]=[CH:25][CH:26]=2)[C:17]([CH3:29])=[N:16]1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.CCCCCC>[CH3:14][N:15]1[C:19]([CH3:20])=[C:18]([C:21]2[CH:22]=[C:23]([CH:24]=[CH:25][CH:26]=2)[CH2:27][O:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=2)[C:17]([CH3:29])=[N:16]1
Reactant: COC(=O)CCc1ccc(O)cc1
Reactant: Cc1nn(C)c(C)c1-c1cccc(CO)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: COC(=O)CCc1ccc(OCc2cccc(-c3c(C)nn(C)c3C)c2)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 53.6 %

Procedure:
A solution of methyl 3-(4-hydroxyphenyl)propanoate (0.541 g, 3.00 mmol), [3-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl]methanol (0.433 g, 2.00 mmol) and tributylphosphine (0.747 mL, 3.00 mmol) in toluene (30 mL) was stirred under ice-cooling, and 1,1′-(azodicarbonyl)dipiperidine (0.757 g, 3.00 mmol) was added by small portions. The mixture was allowed to warm to room temperature and the mixture was stirred for 22 hr. Hexane (15 mL) was added to the reaction mixture. The precipitated insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30%-70% ethyl acetate/hexane) to give the title compound (0.406 g, yield 54%) as a pale-yellow oil.
Reaction SMILES: FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.O[CH2:17][CH2:18][CH2:19][N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([C:29]2[C:30](=[O:45])[NH:31][C:32](=[O:44])[C:33]=2[C:34]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[N:36]([CH3:43])[CH:35]=2)=[CH:21]1.[CH:46]1([NH2:49])[CH2:48][CH2:47]1>C(Cl)Cl.C1COCC1>[CH:46]1([NH:49][CH2:17][CH2:18][CH2:19][N:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]([C:29]3[C:30](=[O:45])[NH:31][C:32](=[O:44])[C:33]=3[C:34]3[C:42]4[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=4)[N:36]([CH3:43])[CH:35]=3)=[CH:21]2)[CH2:48][CH2:47]1
Reactant: Cn1cc(C2=C(c3cn(CCCO)c4ccccc34)C(=O)NC2=O)c2ccccc21
Reactant: NC1CC1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cn1cc(C2=C(c3cn(CCCNC4CC4)c4ccccc34)C(=O)NC2=O)c2ccccc21
Reaction time: 2 h
Yield: 63.9 %

Procedure:
To a 0° C. solution of trifluoromethanesulfonic acid anhydride (188 mg, 0.67 mmol) in dry methylene chloride (15 mL) was added a solution of 3-[1-(3-hydroxy-propyl)-1H-indol-3-yl)-4(1-methyl-1H-indol-3-yl)-pyrrole-2,5-dione (100 mg, 0.25 mmol) in THF (10 mL). After 2 hours, cyclopropylamine (200 μl, 5 mmol) was added and stirring continued over night. The reaction mixture was quenched with water. The organic phase was separated, washed with water (3×), dried, and evaporated. The residual red oil was purified by flash chromatography on silica gel eluting with a methylene chloride/ethanol gradient (98:2-95:5). Evaporation of the eluting solvent gave the title compound (70 mg, 64% yield).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[NH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:11][O:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[C:14]=1[C:15](Cl)=[O:16]>C1C=CC=CC=1>[CH3:2][C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:15](=[O:16])[C:14]2[C:18]([O:22][CH3:23])=[CH:19][CH:20]=[CH:21][C:13]=2[O:12][CH3:11])[NH:7][N:6]=1)([CH3:4])[CH3:3]
Reactant: COc1cccc(OC)c1C(=O)Cl
Reactant: CC(C)(C)c1cc(N)[nH]n1
Solvent: c1ccccc1
Product: COc1cccc(OC)c1C(=O)Nc1cc(C(C)(C)C)n[nH]1
Yield: 18.2 %

Procedure:
To a stirred solution of 1.39 g of 3-tert.-butyl-5-amino-1H-pyrazole in 50 ml of benzene were added in one portion 2.01 g of 2,6-dimethoxybenzoyl chloride. The reaction mixture was heated at reflux for sixteen hours. The reaction mixture was then cooled, filtered, and the solvent was removed from the filtrate by evaporation. The residue was crystallized from ethyl acetate to provide 550 mg of N-[3-(1,1-dimethylethyl)-1H-pyrazol-5-yl]-2,6-dimethoxybenzamide.