Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[CH:9][CH:10]=2)[CH:7]=1.[C:11]1([C:17]#[CH:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[C:11]1([C:17]#[C:18][C:2]2[CH:3]=[N:4][C:5]3[N:6]([N:8]=[CH:9][CH:10]=3)[CH:7]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C#Cc1ccccc1
Reactant: Brc1cnc2ccnn2c1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C(#Cc1cnc2ccnn2c1)c1ccccc1
Temperature: 65 °C
Reaction time: 2 h

Procedure:
Bis-(triphenylphosphine)-palladium(II)dichloride (27 mg, 0.04 mmol) was dissolved in 1 ml of THF. 6-Bromo-pyrazolo[1,5-a]pyrimidine (150 mg, 0.76 mmol) and phenylacetylene (130 μl, 1.21 mmol) were added at room temperature. Triethylamine (310 μl, 2.3 mmol), triphenylphosphine (6 mg, 0.023 mmol) and copper(I) iodide (4 mg, 0.023 mmol) were added and the mixture was stirred for 2 hours at 65° C. The reaction mixture was cooled and extracted with saturated NaHCO3 solution and two times with a small volume of dichloromethane. The crude product was purified by flash chromatography by directly loading the dichloromethane layers onto a silica gel column and eluting with heptane:ethyl acetate 100:0→50:50. The desired compound was obtained as a yellow solid (150 mg, 90% yield), MS: m/e=220.3 (M+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[N:12]=[N:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[F:8].[F:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][C:29]=1[Sn](CCCC)(CCCC)CCCC>>[F:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[N:12]=[N:13][CH:14]=2)=[CH:3][C:2]=1[C:29]1[CH:28]=[CH:27][N:26]=[CH:25][C:24]=1[F:23]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccncc1F
Reactant: COc1ccc(-c2nncc(-c3ccc(F)c(Br)c3)n2)cc1
Product: COc1ccc(-c2nncc(-c3ccc(F)c(-c4ccncc4F)c3)n2)cc1

Procedure:
5-(3-Bromo-4-fluorophenyl)-3-(4-methoxyphenyl)-[1,2,4]triazine (from Example 9 below) (150 mg, 0.42 mmol) was coupled to 3-fluoro-4-tributylstannylpyridine (170 mg, 0.43 mmol) using the method of Example 6 to give 5-[4-fluoro-3-(3-fluoro-pyridin-4-yl)phenyl]-3-(4-methoxyphenyl)-[1,2,4]triazine, crystallised from hot toluene (70 mg): δH (400 MHz, d6-DMSO) 3.88 (3H, s), 7.16 (2H, d, J 8.9 Hz), 7.69-7.77 (2H, m), 8.53 (2H, d, J 8.9 Hz), 8.63-8.67 (3H, m), 8.79 (1H, m), 10.05 (1H, s); m/z (ES+) 377.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[C:8]([CH3:15])([CH3:14])[CH2:7][CH2:6]2.[Br:16]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:16][CH:6]1[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:9](=[O:13])[C:8]([CH3:15])([CH3:14])[CH2:7]1
Reactant: COc1ccc2c(c1)CCC(C)(C)C2=O
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc2c(c1)C(Br)CC(C)(C)C2=O
Temperature: 25 °C
Yield: 85.5 %

Procedure:
To a mixture of 6-methoxy-2,2-dimethyl-3,4-dihydronaphthalen-1(2H)-one (3.30 g, 16.2 mmol) and 1-bromopyrrolidine-2,5-dione (2.88 g, 16.2 mmol) in 50 mL of CCl4, was added AIBN (0.265 g, 1.62 mmol). The mixture was heated to reflux for three hours. The reaction was cooled to RT and the reaction was quenched with water (25 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine, dried over MgSO4 and filtered. The solvent was evaporated and the residue was purified by column chromatography (0-50% EtOAc/Hexane to provide the title compound as a white solid (3.92 g, 86% yield). MS m/z: 284.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([N+:12]([O-])=O)[C:3]=1[N:15]1[C:19]([N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[N:18][C:17]([C:25]([CH3:28])([CH3:27])[CH3:26])=[N:16]1.O.[OH-].[Na+]>CO.Cl>[NH2:12][C:4]1[CH:5]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:7]=[C:2]([Cl:1])[C:3]=1[N:15]1[C:19]([N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[N:18][C:17]([C:25]([CH3:27])([CH3:26])[CH3:28])=[N:16]1
Reactant: CCN(CC)c1nc(C(C)(C)C)nn1-c1c(Cl)cc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCN(CC)c1nc(C(C)(C)C)nn1-c1c(N)cc(C(F)(F)F)cc1Cl
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 46.7 %

Procedure:
1-(2-Chloro-6-nitro-4-trifluoromethylphenyl)-3-tertiary-butyl-5-diethylamino-1,2,4-triazole (0.6g) was dissolved in methanol (20ml) and the solution warmed to 50° C. A solution of stannous chloride dihydrate (2.3g) in concentrated hydrochloric acid (20ml) was added with vigorous stirring. The reaction mixture was allowed to cool, then stirred at room temperature for 30 minutes and poured into water. The solution was basified to pH 8 with 2N sodium hydroxide solution, and then extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulphate and the solvent evaporated under reduced pressure to afford a pale yellow oil which crystallised on standing. Recrystallisation from hexane gave 1-(2-amino-6-chloro-4-trifluoromethylphenyl)-3-tertiary-butyl-5-diethylamino-1,2,4-triazole (260mg).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:13])=[C:6]([CH:8]2[O:12]CCO2)[CH:7]=1.C([Li])CCC.CON(C)[C:22](=[O:24])[CH3:23]>>[C:22]([C:2]1[CH:3]=[CH:4][C:5]([F:13])=[C:6]([CH:7]=1)[CH:8]=[O:12])(=[O:24])[CH3:23]
Reactant: CON(C)C(C)=O
Reactant: Fc1ccc(Br)cc1C1OCCO1
Agent: [Li]CCCC
Product: CC(=O)c1ccc(F)c(C=O)c1
Temperature: -40 °C
Reaction time: 0.42 h

Procedure:
2-(5-bromo-2-fluorophenyl)-1,3-dioxolane (5.2 g, 21.2 mmol) is taken up in dry, preservative-free THF (30 mL) and the solution is cooled to −40° C. under N2. A 1.6 M solution of n-butyllithium in hexanes (13.2 mL, 1 eq) is added via syringe and the solution is stirred for 25 minutes @ −40° C. The lithiated substrate is added dropwise via cannula to a −40° C. solution of N-methoxy-N-methylacetamide (2.36 mL, 22.2 mmol, Aldrich) in 10 mL of dry, preservative-free THF. The solution is warmed to RT with stirring for 1 hour. The solution is poured into a flask containing 1.0M HCl (100 mL) and heated to 65° C. with vigorous stirring overnight. Upon cooling the oily product is extracted into EtOAc (200 mL) and the organic layer is washed with water and brine (200 mL each). The organic layer is dried over Na2SO4 and filtered. The solvent is removed by rotary evaporation and the product is purified on a Biotage Flash 75 L (800 g silica) cartridge using 30% MTBE in heptane as eluent. The product containing fractions are pooled and the solvent is removed by rotary evaporation. The product is dried under vacuum yielding an oily yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([CH2:8][CH2:9][NH2:10])=[N:6][CH:7]=1.C(N(CC)CC)C.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23]>C1COCC1>[Br:1][C:2]1[CH:3]=[N:4][C:5]([CH2:8][CH2:9][NH:10][C:22](=[O:23])[C:21]2[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=2[C:19]([F:18])([F:29])[F:30])=[N:6][CH:7]=1
Reactant: NCCc1ncc(Br)cn1
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NCCc1ncc(Br)cn1)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.4 %

Procedure:
To 0.06 g of 2-(5-bromopyrimidin-2-yl)ethanamine (3.0 mmol) and triethylamine (0.03 g, 1.0 equivalent) in THF (5 ml), at room temperature whilst stirring, was added the 2-trifluoromethyl benzoyl chloride (0.062 g, 1.0 equivalent) and the mixture was left to stir at room temperature overnight. The solvent was removed by evaporation in vacuo and saturated sodium bicarbonate (10 mls) was added. The mixture was extracted with dichloromethane and the organic phase was collected, dried over MgSO4, and evaporated in vacuo to give the crude product which was purified by chromatography on silica using 1:1 heptane/ethyl acetate to yield to 0.036 g of N-[2-(5-bromopyrimidin-2-yl)ethyl]-2-(trifluoromethyl)benzamide (Compound A-1) (32%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:30]=[CH:31][CH:32]=1)[O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-])=O)[CH:22]=3)=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)([O-])=O.O.NN>COCCO>[NH2:27][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=1)[O:20][C:17]1[CH:16]=[CH:15][C:14]([C:11]2[CH:10]=[CH:9][C:8]([O:7][C:6]3[CH:30]=[CH:31][CH:32]=[C:4]([NH2:1])[CH:5]=3)=[CH:13][CH:12]=2)=[CH:19][CH:18]=1
Reactant: O=[N+]([O-])c1cccc(Oc2ccc(-c3ccc(Oc4cccc([N+](=O)[O-])c4)cc3)cc2)c1
Agent: NN
Solvent: COCCO
Solvent: O
Product: Nc1cccc(Oc2ccc(-c3ccc(Oc4cccc(N)c4)cc3)cc2)c1
Reaction time: 0.5 h
Yield: 85 %

Procedure:
In the next step, a 1 1 glass reaction vessel was charged with 100 grams (0.23 mol) of crude 4,4'-bis(3-nitrophenoxy)biphenyl, 10 grams of active carbon, 1 grams of ferric chloride hexahydrate and 500 ml of 2-methoxyethanol. The mixture was stirred for 30 minutes under reflux and then added dropwise with 46 grams (0.92 mol) of hydrazine hydrate during 3 hours at 70°-80° C. The reaction was terminated by stirring for 5 hours at 70°-80° C. after ending the dropwise addition. The reaction mixture was cooled, filtered to remove the catalyst and poured into 500 ml of water. The separated crystals were filtered, added with 48 grams of 35% hydrochloric acid and 540 ml of 50% isopropyl alcohol and warmed. The solution thus obtained was allowed to cool. The separated 4,4'-bis(3-aminophenoxy)biphenyl hydrochloride was filtered, added with 540 ml of 50% isopropyl alcohol and warmed. The solution thus obtained was added with 5 grams of active carbon, filtered and neutralized with aqueous ammonia. The separated crystals were filtered, washed with water and dried to give 72.0 grams (85% yield) of 4,4'-bis(3-aminophenoxy)biphenyl as colorless crystals having a melting point of 144°-146° C. The purity was 99.6% according to high-speed liquid chromatography.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:12][CH:11]2[C:13]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=3[CH3:28])[CH2:17][CH2:16]2)=[O:14])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I-].[Na+].[C:31]1([N:37]=[C:38]=[O:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>O1CCCC1.C(OCC)(=O)C>[C:1]1([S:7]([N:10]2[CH2:12][CH:11]([C:13]([N:15]3[CH2:16][CH2:17][N:18]([C:21]4[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=4[CH3:28])[CH2:19][CH2:20]3)=[O:14])[N:37]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:38]2=[O:39])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(C)c(N2CCN(C(=O)C3CN3S(=O)(=O)c3ccccc3)CC2)c1
Reactant: O=C=Nc1ccccc1
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(C)c(N2CCN(C(=O)C3CN(S(=O)(=O)c4ccccc4)C(=O)N3c3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.1 %

Procedure:
To a solution of (RS)-(1-benzenesulfonyl-aziridin-2-yl)-[4-(2,5-dimethyl-phenyl)-piperazin-1-yl]-methanone (0.084 g) in tetrahydrofuran (2 ml) were added sodium iodide (0.035 g) and phenylisocyanate (0.038 g). The mixture was stirred for 3 h at room temperature. The mixture was diluted with ethyl acetate and washed with water, 1% aqueous Na2S2O3 solution and again with water. The organic phase was dried, filtered and evaporated. The product was purified by chromatography (SiO2, cyclohexane/ethyl acetate 4:1=>1:1) to give (RS)-1-benzenesulfonyl-4-[4-(2,5-dimethyl-phenyl)-piperazine-1-carbonyl]-3-phenyl-imidazolidin-2-one (0.071 g) as a colorless solid. MS: 519.3 ([M+H]+)
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[N:19]([C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:18]=[N:17][N:16]=2)=[CH:5][CH:4]=1.[CH2:39]([C:43]1[NH:44][C:45]2[CH:51]=[C:50]([N:52]3[C:57](=[O:58])[CH2:56][C:55]([CH3:60])([CH3:59])[CH2:54][C:53]3=[O:61])[CH:49]=[CH:48][C:46]=2[N:47]=1)[CH2:40][CH2:41][CH3:42].CC(C)([O-])C.[K+].O>CS(C)=O>[CH2:39]([C:43]1[N:44]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:15]3[N:19]([C:20]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[N:18]=[N:17][N:16]=3)=[CH:5][CH:4]=2)[C:45]2[CH:51]=[C:50]([N:52]3[C:53](=[O:61])[CH2:54][C:55]([CH3:60])([CH3:59])[CH2:56][C:57]3=[O:58])[CH:49]=[CH:48][C:46]=2[N:47]=1)[CH2:40][CH2:41][CH3:42]
Reactant: CCCCc1nc2ccc(N3C(=O)CC(C)(C)CC3=O)cc2[nH]1
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCCCc1nc2ccc(N3C(=O)CC(C)(C)CC3=O)cc2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1.8 g (3.3 mMol) of 4'-bromomethyl-2-(1-triphenylmethyl-tetrazol-5-yl)-biphenyl are added to a solution of 1.04 g (3.3 mMol) of 2-n-butyl-5-(3,3-dimethylglutarimido)-benzimidazole and 425 mg (3.8 mMol) of potassium tert.-butoxide in 25 ml of dimethylsulphoxide. The mixture is stirred for 3 hours at ambient temperature, then stirred into 150 ml of water, extracted three times with 30 ml of ethyl acetate, then the organic extracts are dried and concentrated by evaporation. The residue obtained is purified by column chromatography (300 g of silica gel; eluant:ethyl acetate/petroleum ether (2:1)).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]([OH:19])=O)=[CH:14][CH:15]=3)[C:10]([C:20]([CH:22]3[C:24]([CH3:26])([CH3:25])[C:23]3([CH3:28])[CH3:27])=[O:21])=[CH:9]2)[CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:41]([NH2:48])[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47]>CCOC(C)=O.C1COCC1>[CH2:41]([NH:48][C:17]([C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([CH2:7][CH:4]1[CH2:3][CH2:2][O:1][CH2:6][CH2:5]1)[CH:9]=[C:10]2[C:20]([CH:22]1[C:23]([CH3:27])([CH3:28])[C:24]1([CH3:25])[CH3:26])=[O:21])=[O:19])[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47]
Reactant: CC1(C)C(C(=O)c2cn(CC3CCOCC3)c3ccc(C(=O)O)cc23)C1(C)C
Reactant: CCCCCCCN
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCCCCNC(=O)c1ccc2c(c1)c(C(=O)C1C(C)(C)C1(C)C)cn2CC1CCOCC1
Yield: 20 %

Procedure:
A mixture 1-(tetrahydro-2H-pyran-4-ylmethyl)-3-[(2,2,3,3-tetramethylcyclopropyl)carbonyl]-1H-indole-5-carboxylic acid (0.10 g, 0.26 mmol, the minor product of Example 114 B), 1,1′-carbonyldimidazole (55 mg, 0.34 mmol) and heptylamine (50 μL, 0.34 mmol) in 4 mL of EtOAc and 3 mL of THF was processed as described in Example 93 to provide the title compound (25 mg, 0.052 mmol, 20% yield). 1H NMR (MeOH-d4, 300 MHz) δ ppm 0.87-0.95 (m, 3H), 1.34 (s, 12H), 1.37-1.43 (m, 7H), 1.43-1.51 (m, 6H), 1.58-1.71 (m, 2H), 2.13-2.27 (m, 1H), 2.18 (s, 1H), 3.32-3.37 (m, 2H), 3.40 (t, J=7.1 Hz, 2H), 3.87-3.97 (m, 2H), 4.19 (d, J=7.1 Hz, 2H), 7.58 (d, J=8.8 Hz, 1H), 7.75 (dd, J=8.6, 1.9 Hz, 1H), 8.16 (s, 1H), 8.77 (d, J=1.7 Hz, 1H); MS (DCI/NH3) m/z 481 (M+H)+; Anal. Calculated for C30H44N2O3.0.2H2O: C, 74.40; H, 9.24; N, 5.78. Found: C, 74.43; H, 9.00; N, 5.81.
Reaction SMILES: C(OC(=O)C)(=O)C.[F:8][C:9]1[C:10]([NH:18][CH3:19])=[C:11]([C:15](=[O:17])[CH3:16])[CH:12]=[CH:13][CH:14]=1.[CH:20]([OH:22])=O>>[C:15]([C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([F:8])[C:10]=1[N:18]([CH3:19])[CH:20]=[O:22])(=[O:17])[CH3:16]
Reactant: O=CO
Reactant: CNc1c(F)cccc1C(C)=O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)c1cccc(F)c1N(C)C=O
Temperature: 25 °C
Reaction time: 2.25 h

Procedure:
A mixture of acetic anhydride (27 ml) and formic acid (18.4 ml) was stirred at 50° for 135 minutes and then cooled to ambient temperature. 3'-Fluoro-2' (methylamino)acetophenone (20.48 g) was then added and the solution stirred overnight. Excess acetic formic anhydride was removed under reduced pressure at 30° and the residue then cooled to 5°. Water (92 ml) followed by aqueous sodium hydroxide (specific gravity 1.5) were then added dropwise to pH 7 whilst maintaining the temperature below 5°. The mixture was extracted with dichloromethane (3×35 ml) and the combined extracts were washed with saturated aqueous sodium carbonate (50 ml) then aqueous sodium chloride (6M, 50 ml) and dried over magnesium sulphate to give a solution of 2'-acetyl-6'-fluoro-N-methylformanilide.
Reaction SMILES: Cl.[C:2]([NH2:10])(=[NH:9])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[Na].[CH3:12][O:13][C:14](=[O:23])[C:15]([CH:18](OC)OC)=[CH:16]O.O>CN(C=O)C>[CH3:12][O:13][C:14]([C:15]1[CH:16]=[N:9][C:2]([C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)=[N:10][CH:18]=1)=[O:23]
Reactant: N=C(N)c1ccncc1
Reactant: COC(=O)C(=CO)C(OC)OC
Agent: Cl
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cnc(-c2ccncc2)nc1
Temperature: 100 °C
Yield: 87.8 %

Procedure:
To a solution of isonicotinamidine hydrochloride (1 g, 6.35 mmol) in anhydrous DMF (12 mL) is added sodium salt of 2-dimethoxymethyl-3-hydroxy-acrylic acid methyl ester (1.46 g, 7.36 mmol) and the reaction mixture is heated at 100° C. under nitrogen for 1 h. The reaction is cooled to room temperature and water (48 mL) is added. The precipitate is collected by filtration, washed with water and vacuum dried to afford 2-pyridin-4-yl-pyrimidine-5-carboxylic acid methyl ester (1.2 g, 88%). MS: 216 (M+H); 1H NMR (300 MHz, CD3OD): δ 4.00 (s, 3H), 8.44 (d, 2H), 8.73 (d, 2H), 9.38 (s, 2H).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6](P(OCC)(OCC)=O)[F:7])=[O:5].C([Li])CCC.CCCCCC.[CH2:27]([O:34][C:35]1[CH:42]=[CH:41][C:38]([CH:39]=O)=[CH:37][CH:36]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:27]([O:34][C:35]1[CH:36]=[CH:37][C:38](/[CH:39]=[C:6](\[F:7])/[C:4]([O:3][CH2:2][CH3:1])=[O:5])=[CH:41][CH:42]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CCOC(=O)C(F)P(=O)(OCC)OCC
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)/C(F)=C/c1ccc(OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80.8 %

Procedure:
A solution of triethyl 2-fluoro-2-phosphonoacetate (4.90 g, 20.2 mmol) in tetrahydrofuran (40 mL) was stirred under a nitrogen atmosphere at 0° C., and 1.6 M n-butyl lithium/hexane solution (13.1 mL, 21.0 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 30 min and a solution of 4-benzyloxybenzaldehyde (4.29 g, 20.2 mmol) in tetrahydrofuran (20 mL) was added dropwise. The obtained mixture was stirred at room temperature for 3 hr and ice-cooled aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=3:97-20:80) to give the title compound (4.90 g, yield 81%) as a yellow oil.
Reaction SMILES: [CH2:1]([NH:7][S:8]([C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[C:13]([N+:18]([O-:20])=[O:19])[C:12]=1Cl)(=[O:10])=[O:9])[C@@H:2]1[O:6][CH2:5][CH2:4][CH2:3]1.[H-].[Na+].[OH2:24]>>[CH2:1]([NH:7][S:8]([C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[C:13]([N+:18]([O-:20])=[O:19])[C:12]=1[OH:24])(=[O:10])=[O:9])[C@@H:2]1[O:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)NC[C@H]2CCCO2)c1Cl
Reactant: O
Agent: [H-]
Agent: [Na+]
Product: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)NC[C@H]2CCCO2)c1O
Yield: 62.3 %

Procedure:
Following the general hydrolysis procedure outlined in example 15, N-((2R)-tetrahydrofurfuryl)-2,6dichloro-3-nitrobenzenesulfonamide (1.17 g, 3.29 mmol), 80% NaH (303 mg, 10.1 mmol) and water (0.063 mL, 3.49 mmol) were reacted to form the desired product (690 mg, 63%). EI-MS m/z 335(M-H)−.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[CH2:25][C:9]3([CH2:24][C:11]4([CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]4)[CH2:10]3)[O:8][C:5]2=[CH:6][N:7]=1.[CH3:26][S:27]([CH2:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1)(=[O:29])=[O:28]>>[CH3:26][S:27]([CH2:30][C:31]1[CH:36]=[CH:35][C:34]([C:2]2[CH:3]=[C:4]3[CH2:25][C:9]4([CH2:24][C:11]5([CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH2:16]5)[CH2:10]4)[O:8][C:5]3=[CH:6][N:7]=2)=[CH:33][CH:32]=1)(=[O:28])=[O:29]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC1(Cc3cc(Cl)ncc3O1)C2
Reactant: CS(=O)(=O)Cc1ccc(B(O)O)cc1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC1(Cc3cc(-c4ccc(CS(C)(=O)=O)cc4)ncc3O1)C2

Procedure:
The title compound is prepared from 5-chloro-1″-tert-butoxycarbonyl-dispiro[2,3-dihydrofuro[2,3-c]pyridine-2,1′-cyclobutane-3′,4″-piperidine] and 4-methylsulfonylmethyl-phenylboronic acid following a procedure analogous to that described for Example 1; the reaction is conducted in a microwave oven at 140° C. LC (method 3): tR=0.95 min; Mass spectrum (ESI+): m/z=499 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:29])[CH:5]=[C:6]([Cl:28])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:23]([S:24][CH:25]([CH3:27])[CH3:26])=[N:22][N:21]=[N:20]2)=[CH:15][CH:14]=1.[Cl:30][C:31](Cl)([Cl:35])[CH2:32][CH2:33]Cl.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[Cl:28][C:6]1[CH:5]=[C:4]([O:29][CH2:33][CH:32]=[C:31]([Cl:35])[Cl:30])[CH:3]=[C:2]([Cl:1])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([N:19]2[C:23]([S:24][CH:25]([CH3:27])[CH3:26])=[N:22][N:21]=[N:20]2)=[CH:17][CH:18]=1
Reactant: CC(C)Sc1nnnn1-c1ccc(OCCCOc2c(Cl)cc(O)cc2Cl)cc1
Reactant: ClCCC(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)Sc1nnnn1-c1ccc(OCCCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)cc1

Procedure:
900 mg of 3,5-dichloro-4-{3-[4-(5-isopropylsulfanyl-tetrazol-1-yl)-phenoxy]-propoxy}-phenol, 720 mg of 1,1,1,3-tetrachloropropane, 691 mg of potassium carbonate and 10 mg of potassium iodide are stirred for 48 hours at 60° C. in 30 ml of acetone. The reaction mixture is filtered and the filtrate is concentrated. Purification over silica gel yields the title compound (compound 1.20).
Reaction SMILES: ClC(Cl)(Cl)C(=N)O[CH:5]([C:7]1[C:15]2[N:14]=[CH:13][N:12]([CH2:16][CH3:17])[C:11]=2[CH:10]=[C:9]([C:18]([F:21])([F:20])[F:19])[CH:8]=1)[CH3:6].[F:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2([CH2:45][OH:46])[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]2)=[CH:28][CH:27]=1.ClC(Cl)C.C1CCCCC1>>[CH2:16]([N:12]1[C:11]2[CH:10]=[C:9]([C:18]([F:21])([F:19])[F:20])[CH:8]=[C:7]([CH:5]([O:46][CH2:45][C:32]3([C:29]4[CH:28]=[CH:27][C:26]([F:25])=[CH:31][CH:30]=4)[CH2:33][CH2:34][N:35]([C:38]([O:40][C:41]([CH3:42])([CH3:43])[CH3:44])=[O:39])[CH2:36][CH2:37]3)[CH3:6])[C:15]=2[N:14]=[CH:13]1)[CH3:17]
Reactant: CCn1cnc2c(C(C)OC(=N)C(Cl)(Cl)Cl)cc(C(F)(F)F)cc21
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(c2ccc(F)cc2)CC1
Solvent: CC(Cl)Cl
Solvent: C1CCCCC1
Product: CCn1cnc2c(C(C)OCC3(c4ccc(F)cc4)CCN(C(=O)OC(C)(C)C)CC3)cc(C(F)(F)F)cc21
Temperature: 0 °C

Procedure:
(±)-(1-(1-Ethyl-6-(trifluoromethyl)-1H-benzo[d]imidazol-4-yl)ethyl 2,2,2-trichloroacetimidate (670 mg, 1.7 mmol) and tert-butyl 4-(4-fluorophenyl)-4-(hydroxymethyl)piperidine-1-carboxylate (772 mg, 2.5 mmol) were combined in a dichloroethane/cyclohexane mixture (4:2, 6 mL) and cooled to 0° C. The reaction mixture was treated with tetrafluoroboric acid-diethyl ether complex (91 μL, 0.67 mmol), and subsequent processing including extractive work up and purification were carried out as described in example 8 to give 281 mg (30.7%) as white foam-like solid. 1H-NMR (500 MHz, CHLOROFORM-D) δ ppm 7.97 (s, 1 H), 7.54 (s, 1 H), 7.20-7.33 (m, 3 H), 7.00 (t, J=8.7 Hz, 2 H), 5.10 (q, J=6.6 Hz, 1 H), 4.17-4.30 (m, 2 H), 3.56-3.78 (m, 2 H), 3.24-3.40 (m, 2 H), 2.93-3.12 (m, 2 H), 2.02-2.21 (m, 2 H), 1.80-1.99 (m, 2 H), 1.56 (t, 3 H), 1.37-1.47 (m, 12 H). 550.40 (MH)+.