Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-])=O)=[CH:8][CH:9]=2)[N:4]([S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:3]=1.O.[Sn](Cl)Cl>C(O)C.O>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([NH2:11])=[CH:8][CH:9]=2)[N:4]([S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:3]=1
Reactant: O=[N+]([O-])c1ccc2c(Br)cn(S(=O)(=O)c3ccccc3)c2c1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: Nc1ccc2c(Br)cn(S(=O)(=O)c3ccccc3)c2c1
Yield: 91 %

Procedure:
To a slurry of 3-bromo-6-nitro-1-(phenylsulfonyl)-1H-indole (2.80 g, 7.35 mmol) in ethanol (73.5 mL) was added a solution of tin (II) chloride monohydrate (6.63 g, 29.4 mmol) in water (11.0 mL) at 30° C. Once the addition was complete, the reaction was heated to reflux for 3.5 h, then quenched with 2.0 N sodium hydroxide to a pH of 8. The remaining slurry was diluted with ethyl acetate (100 mL), and the aqueous layer was removed and filtered. The organic phase was washed with 2.0 N sodium hydroxide (2×100 mL), and the combined aqueous layers were extracted with ethyl acetate (3×200 mL). The combined organic phases were concentrated to give a tacky, orange solid for 3-bromo-1-(phenylsulfonyl)-1H-indol-6-amine (2.35 g, 6.69 mmol, 91%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[N:6][C:7]=1Cl.[CH2:10]([O:12][C:13](=[O:22])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1)[CH3:11].C(N(CC)C(C)C)(C)C>C(O)CCC>[CH2:10]([O:12][C:13](=[O:22])[CH2:14][C:15]1[CH:16]=[CH:17][C:18]([NH:21][C:7]2[C:2]([Cl:1])=[C:3]([NH2:9])[N:4]=[CH:5][N:6]=2)=[CH:19][CH:20]=1)[CH3:11]
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: Nc1ncnc(Cl)c1Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)Cc1ccc(Nc2ncnc(N)c2Cl)cc1
Temperature: 115 °C
Yield: 65.3 %

Procedure:
To a vial with stirbar were added 5,6-dichloro-pyrimidin-4-ylamine (1.4 g, 8.537 mmol, 1.0 eq), (4-amino-phenyl)-acetic acid ethyl ester (4.3 g, 23.993 mmol, 2.8 eq), N,N-diisopropylethylamine (4.5 ml, 25.611 mmol, 3.0 eq), dissolved in n-butanol (100 ml). The reaction suspension was flushed with nitrogen and heated to 115° C. for 8 days. The mixture was concentrated in vacuo, dissolved in EtOAc, washed with water (2×) and brine (1×), dried over sodium sulfate, and concentrated in vacuo. The crude mixture was purified using Biotage column chromatography eluting from 30-70 EtOAc/hexanes. Fractions containing the desired product were combined and concentrated under reduced pressure to afford (4-(6-amino-5-chloro-pyrimidin-4-ylamino)-phenyl)-acetic acid ethyl ester (1.71 g, 49% yield) as white crystals. MS: m/z=307 [M+H]+. 1H-NMR (DMSO-d6) δ 8.41 (s, 1H), 7.93 (s, 1H), 7.55 (d, 2H), 7.19 (d, 2H), 6.76 (bs, 2H), 4.11 (q, 2H), 1.21 (t, 3H).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([Cl:10])[C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.[CH:11](OCC)(OCC)OCC>O>[Br:1][C:2]1[N:3]=[C:4]([Cl:10])[C:5]2[N:6]([CH:11]=[N:9][N:8]=2)[CH:7]=1
Reactant: NNc1ncc(Br)nc1Cl
Reactant: CCOC(OCC)OCC
Solvent: O
Product: Clc1nc(Br)cn2cnnc12
Temperature: 130 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
A 50 mL round bottom flask was charged with 5-bromo-3-chloro-2-hydrazinylpyrazine (1.24 g, 5.5 mmol) and triethyl orthoformate (20 mL). The resulting mixture was stirred at 130° C. for 2 h. Reaction progress was monitored by TLC (EtOAc/petroleum ether=1:2). Work-up: the reaction mixture was diluted with water and extracted with EtOAc (50 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was further purified by flash column chromatography on silica gel with 30% EtOAc in petroleum ether, to afford 1.12 g (87%) of the product as a red solid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([O:10][C:11]2[C:16]([F:17])=[CH:15][C:14]([NH:18][C:19]([C:21]3([C:24]([OH:26])=O)[CH2:23][CH2:22]3)=[O:20])=[C:13]([F:27])[CH:12]=2)[CH:7]=[CH:6][N:5]=1)(=[O:3])[NH2:2].[F:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1.O.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>O1CCCC1>[NH2:2][C:1]([C:4]1[CH:9]=[C:8]([O:10][C:11]2[C:16]([F:17])=[CH:15][C:14]([NH:18][C:19]([C:21]3([C:24]([NH:33][C:32]4[CH:34]=[CH:35][C:29]([F:28])=[CH:30][CH:31]=4)=[O:26])[CH2:23][CH2:22]3)=[O:20])=[C:13]([F:27])[CH:12]=2)[CH:7]=[CH:6][N:5]=1)=[O:3]
Reactant: Nc1ccc(F)cc1
Reactant: NC(=O)c1cc(Oc2cc(F)c(NC(=O)C3(C(=O)O)CC3)cc2F)ccn1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)c1cc(Oc2cc(F)c(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1
Temperature: 25 °C
Reaction time: 23 h

Procedure:
To a suspension of 1-[4-(2-carbamoylpyridin-4-yl)oxy-2,5-difluorophenylaminocarbonyl]cyclopropanecarboxylic acid (100 mg) and 4-fluoroaniline (0.051 ml) in tetrahydrofuran (4 ml) was added 4-(4,6-dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (157 mg), followed by stirring at room temperature 23 hr. The reaction mixture was partitioned between ethyl acetate and an aqueous solution of sodium hydrogencarbonate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; heptane:ethyl acetate=1:2, ethyl acetate, then ethyl acetate:methanol=10:1), and fractions containing the target compound were concentrated under reduced pressure. The residue was dried under reduced pressure to provide the titled compound as a white solid (133.5 mg, quant.).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH2:19][O:20][CH3:21])=[C:15]([OH:22])[CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[F:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33]Cl>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH2:19][O:20][CH3:21])=[C:15]([O:22][CH2:33][C:32]1[CH:35]=[CH:36][CH:37]=[C:30]([F:29])[CH:31]=1)[CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2[nH]c3cccc(O)c3c2c1COC
Reactant: Fc1cccc(CCl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)c1ncc2[nH]c3cccc(OCc4cccc(F)c4)c3c2c1COC
Yield: 40.9 %

Procedure:
Under a nitrogen atmosphere, 0.3 g of 5-hydroxy-4-methoxymethyl-β-carboline-3-carboxylic acid ethyl ester is refluxed for 4 hours in 60 ml of ethanol with 0.3 g of potassium carbonate and 0.174 g of 3-fluorobenzyl chloride. After filtration and concentration under vacuum, the residue is chromatographed over silica gel (methylene chloride +ethanol/1000+25), thus obtaining 0.167 g of 5-(3-fluorobenzyloxy)-4-methoxymethyl-β-carboline-3-carboxylic acid ethyl ester, mp 188.0° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][NH2:15])=[CH:10][N:9]=2)[CH:5]=[CH:4][N:3]=1.[N:16]1[CH:21]=[CH:20][N:19]=[CH:18][C:17]=1[C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][NH:15][C:26](=[O:27])[C:25]3[CH:24]=[CH:23][C:22]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][N:16]=4)=[CH:30][CH:29]=3)=[CH:10][N:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cc(-c2ccc(CN)cn2)ccn1
Reactant: O=C(O)c1ccc(-c2cnccn2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(-c2ccc(CNC(=O)c3ccc(-c4cnccn4)cc3)cn2)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of (2′-methyl-[2,4′-bipyridin]-5-yl)methanamine 18-2 (10.0 mg, 0.05 mmol), 4-(pyrazin-2-yl)benzoic acid 18-3 (10.0 mg, 0.05 mmol), and HATU (23 mg, 0.06 mmol) were added N,N-diisopropylethylamine (DIEA, 17 μL, 0.1 mmol) and DMF (0.5 mL). The solution was stirred overnight at room temperature and was subjected directly to reverse phase preparative HPLC to yield N-42′-methyl-[2,4′-bipyridin]-5-yl)methyl)-4-(pyrazin-2-yl)benzamide 18 as a white powder. MS m/z 382.2 (M+1). 1H NMR 400 MHz (CDCl3) δ 9.06 (d, 1H), 8.73 (d, 1H), 8.66 (dd, 1H), 8.59 (d, 1H), 8.56 (d, 1H), 8.15-8.08 (m, 2H), 8.00-7.91 (m, 2H), 7.86 (dd, 1H), 7.80-7.73 (m, 2H), 7.65 (dd, 1H), 6.90 (t, 1H), 4.76 (d, 2H), 2.64 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C([Li])CCC.[S:19](Cl)([Cl:22])(=[O:21])=[O:20]>CCOCC.C(OCC)(=O)C>[C:3]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]([S:19]([Cl:22])(=[O:21])=[O:20])=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: Brc1ccccc1-c1ccccc1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: O=S(=O)(Cl)c1ccccc1-c1ccccc1
Temperature: -78 °C
Yield: 51.4 %

Procedure:
2-Bromobiphenyl (2.33 g, 10 mmol) was dissolved in ether (10 ml) and cooled to −78° C. n-Butyllithium (2.5 M solution in hexane, 4.8 ml, 12 mmol) was added dropwise under constant stirring and an argon atmosphere. The resultant reaction mixture was stirred at −70° C. to −60° C. for 1 h. The reaction mixture was cooled to −78° C. and sulfuryl chloride (0.88 ml, 11 mmol) was added dropwise. After addition, the reaction mixture was allowed to attain ambient temperature slowly and stirred for 1 h. The reaction mixture was diluted with ethyl acetate (50 ml), washed with water and the organic layer dried over anhydrous MgSO4. Removal of the solvent under reduced pressure gave a crude product, which was purified by column chromatography, using hexane followed by 5% ethyl acetate in hexane as eluent, to give 2-biphenylsulfonyl chloride as a solid (1.3 g, 51% yield).
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[C:7]1([C:13]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)(O)[CH:14]=[CH2:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[H-].[Na+].[OH:25][C:26]1[CH:27]=[C:28]([CH:33]=[CH:34][CH:35]=1)[C:29]([O:31][CH3:32])=[O:30]>ClCCl.CN(C)C=O>[N:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:13]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:14][CH2:15][O:25][C:26]2[CH:27]=[C:28]([CH:33]=[CH:34][CH:35]=2)[C:29]([O:31][CH3:32])=[O:30])[CH:18]=1
Reactant: C=CC(O)(c1ccccc1)c1cccnc1
Reactant: COC(=O)c1cccc(O)c1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(OCC=C(c2ccccc2)c2cccnc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.5 %

Procedure:
Phosphorus pentachloride (3.0 g, 14.2 mmoles) was suspended in dichloromethane (4 ml). To the suspension was added dropwise a solution of 1-phenyl-1-(3-pyridyl)-2-propen-1-ol (2.0 g, 9.5 mmoles) in dichloromethane (20 ml) at 0° C., then the mixture was stirred for one hour at room temperature, followed by washing with water, saturated aqueous solution of sodium hydrogen carbonate in the order. The organic layer is dried (magnesium sulfate), and concentrated to about 20 ml at a temperature not exceeding 30° C. The solution was further dried with molecular sieves 4A. This solution was named as (a) solution. Separately, sodium hydride (400 mg, 10 mmoles) is suspended in dimethylformamide (5 ml). To the suspension was added dropwise methyl metahydroxybenzoate (1.37 g, 9.0 mmoles) dissolved in dimethylformamide (5 ml). The mixture was stirred for 30 minutes at 0° C., to which was added dropwise the (a) solution, followed by stirring at room temperature for 1.5 hours. The reaction mixture was poured in ice-water, which is subjected to extraction with ethyl acetate, washed with water and dried (magnesium sulfate), followed by removing the solvent by evaporation under reduced pressure. The residue was subjected to silica-gel column chromatography, using ether-ethyl acetate (7:3) as eluant to yield methyl 3-[3-(3-pyridyl)-3-phenyl-2-propenyloxy]benzoate (If-56) (3.0 g, 92%).
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=1)([CH2:6][OH:7])[CH2:4][OH:5].C1CCCCC=1>[Pd].O>[NH2:15][C:12]1[CH:11]=[CH:10][C:9]([NH:8][C:3]([CH2:4][OH:5])([CH2:6][OH:7])[CH2:2][OH:1])=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1ccc(NC(CO)(CO)CO)cc1
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: O
Product: Nc1ccc(NC(CO)(CO)CO)cc1
Yield: 58.1 %

Procedure:
7.3 g (0.03 mol) of 2-hydroxymethyl-2-(4-nitrophenylamino)propane-1,3-diol (5) were placed in a mixture of alcohol, water, and cyclohexene in proportions of 30 ml/15 ml/3 ml. 3 g of 10% Pd/C catalyst were added and the mixture was refluxed for 2 hours until decolorized. The medium was filtered while hot and the catalyst was washed with alcohol. The filtrate was concentrated to dryness and then taken up in 10 ml of ethanol, and the precipitate formed was filtered off and washed with alcohol and then with isopropyl ether. After drying, 3.7 g of a white powder were obtained, the elemental analysis of which gave the following results:
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.[C:13]([OH:23])(=O)[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=1.C(N(CC)CC)C.[NH2:31][CH2:32][CH2:33][NH:34][C:35]1[C:44]([C:45]#[N:46])=[CH:43][C:42]2[C:37](=[CH:38][C:39]([CH3:48])=[CH:40][C:41]=2[CH3:47])[N:36]=1>C(Cl)Cl>[C:45]([C:44]1[C:35]([NH:34][CH2:33][CH2:32][NH:31][C:13](=[O:23])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)=[N:36][C:37]2[C:42]([CH:43]=1)=[C:41]([CH3:47])[CH:40]=[C:39]([CH3:48])[CH:38]=2)#[N:46]
Reactant: COc1cccc(C(=O)O)c1
Reactant: Cc1cc(C)c2cc(C#N)c(NCCN)nc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc(C(=O)NCCNc2nc3cc(C)cc(C)c3cc2C#N)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73 %

Procedure:
EDC hydrochloride (0.192 g, 1 mmol), m-anisic acid (0.152 g, 1 mmol) and triethylamine (0.14 mL, 2.5 mmol) were dissolved in dry DCM (10 mL). The reaction was stirred at room temperature for 30 min. Carbonitrile 4 (0.201 g, 1 mmol) dissolved in 5 mL dry DCM was added dropwise to the solution and reaction stirred for 18 h. The reaction was diluted with DCM (50 mL) and washed with 1M NaHSO4 (aq, 2×100 mL). Organics were dried over Na2SO4, filtered and solvent was removed under reduced pressure. The crude product was then purified by flash chromatography (4:1 hexane:ethyl acetate mobile phase) to produce a light yellow solid (Compound 22) in 73% yield. 1H NMR (400 MHz, CDCl3) δ 8.35 (s, 1H), 8.13 (s, 1H), 7.32 (s, 1H), 7.28 (s, 1H), 7.20 (d, J=7.5, 1H), 7.13 (t, J=7.8, 1H), 6.98 (s, 1H), 6.95 (d, J=8.1, 1H), 5.82 (s, 1H), 3.91 (q, J=5.3, 2H), 3.79-3.68 (m, 5H), 2.55 (s, 3H), 2.42 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 168.10, 159.87, 155.10, 144.27, 140.97, 136.27, 135.41, 129.42, 127.13, 124.48, 119.35, 119.23, 117.72, 116.87, 112.46, 94.30, 55.49, 43.39, 41.25, 29.92, 22.21, 18.57. IR (neat): 3380, 3357, 2957, 2925, 2217, 1605, 1583, 1535, 1258. ESI-LCMS m/z [M+H]+=375.18.
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]#[N:10])=[N:7][C:6](Cl)=[C:5]([Cl:12])[N:4]=1)#[N:2].[CH:13]([OH:16])([CH3:15])[CH3:14]>>[C:9]([C:8]1[C:3]([C:1]#[N:2])=[N:4][C:5]([Cl:12])=[C:6]([O:16][CH:13]([CH3:15])[CH3:14])[N:7]=1)#[N:10]
Reactant: CC(C)O
Reactant: N#Cc1nc(Cl)c(Cl)nc1C#N
Product: CC(C)Oc1nc(C#N)c(C#N)nc1Cl
Yield: 45 %

Procedure:
Isopropanol (50 ml) was added to 1.99 g (0.01 mole) of 2,3-dicyano-5,6-dichloropyrazine, and the mixture was refluxed for 10 hours. After the reaction, the isopropanol was distilled off under reduced pressure. The crude product obtained (1.14 g) was chromatographed on a column of silica gel using benzene-n-hexane as an eluent to afford 1.00 g (yield 45%) of 2,3-dicyano-5-chloro-6-isopropoxypyrazine.
Reaction SMILES: Cl[CH2:2][C:3]#[N:4].[CH2:5]([NH2:13])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH2:5]([NH:13][CH2:2][C:3]#[N:4])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: N#CCCl
Reactant: NCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#CCNCCc1ccccc1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
Chloro-acetonitrile (1.5) eq was added to a solution of phenethylamine (1 eq) and K2CO3 (2 eq) in CH3CN. The mixture was stirred at 60° C. for 4 hrs. After completion of the reaction, the mixture was filtered and the filtrate was concentrated under reduced pressure. Purification by flash chromatography gave the expected compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:26]2[C:31]([CH3:32])=[CH:30][C:29]([OH:33])=[CH:28][C:27]=2[CH3:34])=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.Cl.Cl.Cl[CH2:38][C:39]1[CH:40]=[N:41][N:42]([CH3:44])[CH:43]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:34][C:27]1[CH:28]=[C:29]([O:33][CH2:38][C:39]2[CH:40]=[N:41][N:42]([CH3:44])[CH:43]=2)[CH:30]=[C:31]([CH3:32])[C:26]=1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[C:10]2[C:6]=1[CH2:7][CH2:8][C@H:9]2[O:11][C:12]1[CH:25]=[CH:24][C:15]2[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=2[CH:13]=1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(O)cc5C)ccc(F)c43)ccc21
Reactant: Cn1cc(CCl)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(OCc6cnn(C)c6)cc5C)ccc(F)c43)ccc21
Temperature: 70 °C
Reaction time: 72 h

Procedure:
Methyl 2-((S)-6-((R)-7-fluoro-4-(4-hydroxy-2,6-dimethylphenyl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate (Intermediate 28-29) (46.3 mg) and 4-(chloromethyl)-1-methyl-1H-pyrazole dihydrochloride (61.1 mg) were suspended in dimethylformamide (1.8 mL) and potassium carbonate (124.4 mg) was added. The reaction mixture was shaken for 24 h at 60° C. and 72 h at 70° C. Another portion of 4-(chloromethyl)-1-methyl-1H-pyrazole dihydrochloride (124.4 mg) and potassium carbonate (124.4 mg) was added and the mixture was shaken again for 24 h at 120° C. and than directly chromatographed by HPLC on reversed phase. The product fractions are collected and lyophilized to give the title compound. Yield: 10.1 mg; LC (method 23): tR=2.06 min; Mass spectrum (ESI+): m/z=557 [M+H]+.
Reaction SMILES: [CH2:1]([CH:4]([CH2:7][OH:8])[CH2:5][OH:6])[CH2:2][CH3:3].[CH:9]([C@@H:11]1[CH2:16][O:15][C@@H:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[CH2:13][O:12]1)=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>O>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([C@H:14]2[CH2:13][O:12][C@H:11]([C@H:9]3[O:8][CH2:7][C@H:4]([CH2:1][CH2:2][CH3:3])[CH2:5][O:6]3)[CH2:16][O:15]2)=[CH:18][CH:19]=1
Reactant: COc1ccc([C@H]2CO[C@H](C=O)CO2)cc1
Reactant: CCCC(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCC[C@H]1CO[C@H]([C@@H]2CO[C@@H](c3ccc(OC)cc3)CO2)OC1

Procedure:
A mixture of 1.2 g. 2-propylpropan-1,3-diol, 2.2 g. trans-5-formyl-2-p-methoxyphenyl-1,4-dioxane (obtainable by reaction of 1,1-ethylenedioxypropan-2,3-diol with p-methoxystyrene oxide and hydrolysis), 0.01 g. p-toluene sulphonic acid and 15 ml. toluene is boiled on a water separator for 3 hours, cooled, washed with water and evaporated. One obtains trans-2-p-methoxyphenyl-5-(trans-5-propyl-1,3-dioxan-2-yl)-1,4-dioxane.
Reaction SMILES: [CH3:1][CH:2]([CH3:20])[CH2:3][CH2:4][C:5]([NH:7][N:8]1[C:12](=[O:13])[C:11]2([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[NH:10][C:9]1=[O:19])=[O:6].[CH3:21][S:22](Cl)(=[O:24])=[O:23]>N1C=CC=CC=1>[CH3:21][S:22]([N:16]1[CH2:15][CH2:14][C:11]2([NH:10][C:9](=[O:19])[N:8]([NH:7][C:5](=[O:6])[CH2:4][CH2:3][CH:2]([CH3:20])[CH3:1])[C:12]2=[O:13])[CH2:18][CH2:17]1)(=[O:24])=[O:23]
Reactant: CC(C)CCC(=O)NN1C(=O)NC2(CCNCC2)C1=O
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CC(C)CCC(=O)NN1C(=O)NC2(CCN(S(C)(=O)=O)CC2)C1=O

Procedure:
A solution of 0.514 g of 2(R)-[1(S)-tert-butoxycarbonyl)-4-phenylbutyl]-4-methyl-N-[2,4-dioxo-1,3,8-triazaspiro[4.5]decan-3-yl]valeramide in 10 ml of dry pyridine was cooled to 0° C. with stirring and 0.13 ml of methanesulphonyl chloride added. The mixture was allowed to return to room temperature and was stirred for 2 days. The solvent was evaporated and the residue partitioned between ethyl acetate and dilute hydrochloric acid. The ethyl acetate layer was washed successively with water and saturated sodium chloride solution, dried over anhydrous magnesium sulphate and the solvent evaporated. The residue was purified by flash chromatography using 5% methanol in dichloromethane for the elution. There was obtained 0.322 g of 2(R)-[1(S)-tert-butoxycarbonyl)-4-phenylbutyl]-N-[8-(methanesulphonyl)-2,4-dioxo-1,3,8-triazaspiro[4.5]decan-3-yl]-4-methylvaleramide in the form of a white solid.
Reaction SMILES: [C:1]([O:7][C:8]1[CH:16]=[CH:15][C:14]([Br:17])=[C:13]([CH3:18])[C:9]=1[C:10]([OH:12])=O)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH3:31])[CH:24]=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>ClCCl>[Br:17][C:14]1[CH:15]=[CH:16][C:8]([O:7][C:1](=[O:6])[C:2]([CH3:3])([CH3:4])[CH3:5])=[C:9]([C:13]=1[CH3:18])[C:10]([C:22]1[C:23]([CH3:31])=[CH:24][C:25]([O:29][CH3:30])=[C:26]([O:27][CH3:28])[C:21]=1[O:20][CH3:19])=[O:12]
Reactant: Cc1c(Br)ccc(OC(=O)C(C)(C)C)c1C(=O)O
Reactant: COc1cc(C)cc(OC)c1OC
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClCCl
Product: COc1cc(C)c(C(=O)c2c(OC(=O)C(C)(C)C)ccc(Br)c2C)c(OC)c1OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 50A (6.3 g, 20 mmol), 3,4,5-trimethoxytoluene (3.83 g; 21 mmol), P2O5 (12.0 g) and dichloromethane (100 ml) is stirred at room temperature for 16 hours. Subsequently, the dichloromethane is distilled off and the residue is diluted with water and ethyl acetate. The organic phase is washed with water and concentrated. The residue is purified by flash chromatography with petrol ethers/ethyl acetate (9:1 v/v) as eluent yielding the pure product as white crystals, 5.58 g, (58.2%).
Reaction SMILES: Br[C:2]1[C:6]([CH3:7])=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14]C)=[CH:10][CH:9]=2)[S:4][C:3]=1[CH:16]1[O:20]CCO1.C[O:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[C:25]([CH3:32])[CH:24]=1>>[OH:22][C:23]1[CH:28]=[CH:27][C:26]([C:2]2[C:6]([CH3:7])=[C:5]([C:8]3[CH:9]=[CH:10][C:11]([OH:14])=[CH:12][CH:13]=3)[S:4][C:3]=2[CH:16]=[O:20])=[C:25]([CH3:32])[CH:24]=1
Reactant: COc1ccc(-c2sc(C3OCCO3)c(Br)c2C)cc1
Reactant: COc1ccc(B(O)O)c(C)c1
Product: Cc1cc(O)ccc1-c1c(C=O)sc(-c2ccc(O)cc2)c1C
Yield: 57.5 %

Procedure:
Starting from 2-[3-bromo-5-(4-methoxyphenyl)-4-methylthien-2-yl]-1,3-dioxolane (1.1 g, 3.0 mmol, made in Example 1, Step 1) and substituting 4-methoxy-2-methylphenylboronic acid (0.55 g, 3.3 mmol) in place of 3-methoxyphenylboronic acid (Step 2), the title compound (0.56 g, 90%, m.p. 244-47° C.) was synthesized in essentially the same manner as described in Example 1, Steps 2-4.
Reaction SMILES: [Br:1]Br.[Cl:3][CH2:4][CH2:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8]>ClCCl>[Br:1][CH:6]([CH2:5][CH2:4][Cl:3])[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8]
Reactant: O=C(CCCCl)c1ccccc1
Reactant: BrBr
Solvent: ClCCl
Product: O=C(c1ccccc1)C(Br)CCCl
Reaction time: 0.25 h

Procedure:
Bromine (10 g.) was added dropwise to a stirred solution of 4-chlorobutyrophenone (9.7 g.) in dichloromethane (25 ml.), and the mixture was stirred for a further 15 minutes, then evaporated to dryness under reduced pressure. The residue was dissolved in ethyl acetate, and the solution was washed twice with water then with brine, dried and evaporated to dryness to give α-bromo-4-chlorobutyrophenone as an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[F:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19]Cl)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[F:1][C:2]1[CH:3]=[C:4]([O:11][CH2:19][C:16]2[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: Fc1ccc(CCl)cc1
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=[N+]([O-])c1ccc(OCc2ccc(F)cc2)cc1F
Temperature: 70 °C
Yield: 18.6 %

Procedure:
A stirred mixture of 10.0 g (0.063 mole) of 3-fluoro-4-nitrophenol, 17.0 g (0.090 mole) of 4-fluorophenylmethyl chloride, and 12.42 g (0.090 mole) of anhydrous potassium carbonate in 80 mL of methyl ethyl ketone was heated at 70° C. for approximately 17 hours. The reaction mixture was then cooled and filtered and the filtrate evaporated under reduced pressure, leaving 3.10 g of 4-fluorophenylmethyl 3-fluoro-4-nitrophenyl ether as a solid; m.p. 90°-91° C.