Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16](=O)[CH2:15][CH2:14][CH2:13]3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([C:25]#[N:26])(C)C>[I-].[Zn+2].[I-].CCOCC>[C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16]([C:25]#[N:26])=[CH:15][CH2:14][CH2:13]3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[Si](C)(C)C#N
Reactant: O=C1CCCc2cc(S(=O)(=O)c3ccccc3)ccc21
Agent: [I-]
Agent: [Zn+2]
Solvent: CCOCC
Product: N#CC1=CCCc2cc(S(=O)(=O)c3ccccc3)ccc21
Reaction time: 15 h
Yield: 44 %

Procedure:
6-Benzenesulfonyl-3,4-dihydro-2H-naphthalen-1-one from Preparation 1 above (4.0 g, 14 mmol), trimethylsilyl cyanide (10.0 g, 100 mmol) and Zinc Iodide (0.25 g) were combined and stirred under nitrogen for 15 hours. The reaction mixture was then diluted by addition of 200 mL of Et2O, washed with cold water, and the organic layer was dried (MgSO4) and evaporated under reduced pressure to an oil. The oil was dissolved in 250 mL of toluene, and 0.5 g of paratoluene sulfonic acid was added. The reaction mixture was refluxed for three hours, cooled, and the solvent was removed under reduced pressure. The crude product was eluted through silica under medium pressure with 5% EtOAc in hexanes to yield 1.8 g (6.1 mmol, 44%) of (racemic) 6-benzenesulfonyl-3,4-dihydro-naphthalene-1-carbonitrile as an oil. MS: 296 (M+H)+.′
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:19]=[CH:18][C:7]([CH2:8][CH:9]([C:14]([O:16][CH3:17])=[O:15])[C:10]([O:12][CH3:13])=[O:11])=[CH:6][C:5]=1[CH2:20][OH:21])[CH3:2].[F:22][C:23]([F:34])([F:33])[C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1>>[CH2:1]([O:3][C:4]1[CH:19]=[CH:18][C:7]([CH2:8][CH:9]([C:14]([O:16][CH3:17])=[O:15])[C:10]([O:12][CH3:13])=[O:11])=[CH:6][C:5]=1[CH2:20][O:21][C:31]([NH:30][C:27]1[CH:26]=[CH:25][C:24]([C:23]([F:22])([F:33])[F:34])=[CH:29][CH:28]=1)=[O:32])[CH3:2]
Reactant: CCOc1ccc(CC(C(=O)OC)C(=O)OC)cc1CO
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Product: CCOc1ccc(CC(C(=O)OC)C(=O)OC)cc1COC(=O)Nc1ccc(C(F)(F)F)cc1

Procedure:
Using dimethyl 2-[4-ethoxy-3-(hydroxymethyl)benzyl]-malonate and α,α,α-trifluoro-p-tolylisocyanate, the title compound was obtained in the same manner as described in Example 192b).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH:4]([NH:7][C:8]1[S:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=2)[N:12]=1)[CH2:5][OH:6].C(N(CC)CC)C.Cl[C:29](Cl)([O:31]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[Br:19][C:16]1[CH:17]=[CH:18][C:13]([C:11]2[N:12]=[C:8]([N:7]3[C@H:4]([C:3]([O:2][CH3:1])=[O:20])[CH2:5][O:6][C:29]3=[O:31])[S:9][CH:10]=2)=[CH:14][CH:15]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COC(=O)C(CO)Nc1nc(-c2ccc(Br)cc2)cs1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1COC(=O)N1c1nc(-c2ccc(Br)cc2)cs1
Temperature: 0 °C
Reaction time: 1 h
Yield: 43.2 %

Procedure:
2-[4-(4-Bromophenyl)-1,3-thiazol-2-ylamino]-3-hydroxy-propionic acid methyl ester (1.1 g, 3.08 mmol), prepared in the previous step, was dissolved in 40 mL of methylene chloride and triethylamine (4.3 mL, 30.8 mmol) was added. The mixture was cooled to 0° C. and triphosgene (2.3 g, 7.7 mmol) was added. The mixture was stirred for 1 h and then diluted with methylene chloride, washed with saturated NaHCO3, water, and brine, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. Flash chromatography (gradient 2% acetone/hexane to 15% acetone/hexane) afforded the title compound (510 mg, 44%) as a white solid. mp 165-167° C. HRMS: calcd for C14H, BrN2O4S+H+, 382.96956; found (ESI, [M+H]+), 382.9718. Analytical HPLC: retention time 9.9 min, 210-370 nm the Xterra® RP18 column, 3.5μ, 150×4.6 mm 40° C. 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min, 1.2 mL/min 5 μL injection.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][C:3]=1[F:9].[CH3:10][C:11]([O:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][C:27]#[CH:28])=[CH:19][C:18]=1[CH3:29])([CH3:15])[C:12]([OH:14])=[O:13]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:28]#[C:27][CH2:26][CH2:25][CH2:24][O:23][C:20]2[CH:21]=[CH:22][C:17]([O:16][C:11]([CH3:15])([CH3:10])[C:12]([OH:14])=[O:13])=[C:18]([CH3:29])[CH:19]=2)=[CH:4][C:3]=1[F:9]
Reactant: C#CCCCOc1ccc(OC(C)(C)C(=O)O)c(C)c1
Reactant: Fc1cc(I)ccc1Cl
Product: Cc1cc(OCCCC#Cc2ccc(Cl)c(F)c2)ccc1OC(C)(C)C(=O)O

Procedure:
In analogy to the procedure described in example 24E], 1-chloro-2-fluoro-4-iodobenzene and 2-methyl-2-(2-methyl-4-pent-4-ynyloxy-phenoxy)-propionic acid (example 26B]), followed by purification described in example 26A] yielded the title compound as off-white powder, mp. 106-107° C., dec.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8](Br)[C:7]([O:11][CH3:12])=[N:6][CH:5]=1.[F:14][C:15]([F:26])([F:25])[C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1.C(=O)(O)[O-].[Na+].C1(C)C=CC=CC=1>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.O>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([C:15]([F:26])([F:25])[F:14])[CH:21]=2)[C:7]([O:11][CH3:12])=[N:6][CH:5]=1
Reactant: COC(=O)c1cnc(OC)c(Br)c1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
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: Cc1ccccc1
Solvent: O
Product: COC(=O)c1cnc(OC)c(-c2cccc(C(F)(F)F)c2)c1
Yield: 107.6 %

Procedure:
5-Bromo-6-methoxy-nicotinic acid methyl ester (1.03 g, 4.18 mmol), 3-trifluoromethylbenzeneboronic acid (0.795 g, 4.19 mmol), tetrakis(triphenylphosphine)palladium(0) (24 mg, 0.021 mmol) and sodium bicarbonate (1.05 g, 12.5 mmol) were partitioned between toluene (10 ml) and water (10 ml) under argon and stirred in reflux for 1 h. The material was partitioned between ethyl acetate and water, the combined organic extracts were dried over sodium chloride, filtered over a small plug of silica and evaporated to dryness. The solid material was titured with methanol, filtered and dried in vacuo to yield the title compound (1.4 g) sufficiently pure for further synthesis.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1Br.[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][CH:11]=1>>[C:2]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:7]=[CH:6][C:5]([NH:9][C:10]2[C:11]([NH:9][C:10]3[CH:11]=[CH:12][C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:14][CH:15]=3)=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:4][CH:3]=1
Reactant: Brc1ccccc1Br
Reactant: Nc1ccc(-c2ccccc2)cc1
Product: c1ccc(-c2ccc(Nc3ccccc3Nc3ccc(-c4ccccc4)cc3)cc2)cc1
Yield: 78.8 %

Procedure:
The synthesis is carried out in accordance with the general procedure in accordance with Example 2 from 56.6 g (240 mmol) of 1,2-dibromobenzene and 85.4 g (505 mmol) of 4-aminobiphenyl. The precipitated solid is recrystallised from toluene/acetonitrile (5:1), and the residue is washed with MeOH, giving 78 g (189 mmol) of a crystalline solid. The overall yield is 80%.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=2[CH:6]=1.[C:13]1(=[O:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.O>CCOCC>[OH:19][C:13]1([C:2]2[S:3][C:4]3[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=3[CH:6]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=C1CCCCC1
Reactant: COc1ccc2cc(Br)sc2c1
Solvent: CCOCC
Solvent: O
Product: COc1ccc2cc(C3(O)CCCCC3)sc2c1
Yield: 41.7 %

Procedure:
To Mg (0.22 g, 9.05 mmol) under argon in Et2O (20 ml) was added dropwise a solution of bromide (4) (2.00 g, 8.23 mmol) in Et2O (20 ml). The mixture was refluxed for 2 h, a solution of cyclohexanone (1.00 ml, 9.87 mmol) in Et2O (5 ml) was added and the mixture was refluxed for 2 h. It was poured into iced water. The solution was extracted with ethyl acetate, dried over Na2SO4, filtered, and concentrated under vacuum to give 8.00 g as an oil. Triturating from diisopropyl ether afforded 2-(1-hydroxycyclohexyl)-6-methoxybenzothiophene as a white powder (0.90 g, 65%).
Reaction SMILES: [OH-:1].[Na+].[NH2:3][CH2:4][C:5]12[CH2:12][N:11]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:10][CH:9]1[CH2:8][CH2:7][O:6]2>O.C(O)(C)(C)C>[CH2:13]([N:11]1[CH2:12][C:5]2([CH2:4][NH:3][C:7]([O:6][C:5]([CH3:12])([CH3:9])[CH3:4])=[O:1])[CH:9]([CH2:8][CH2:7][O:6]2)[CH2:10]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: [OH-]
Reactant: NCC12CN(Cc3ccccc3)CC1CCO2
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)NCC12CN(Cc3ccccc3)CC1CCO2
Temperature: 25 °C
Reaction time: 15 h

Procedure:
2 g of NaOH in 45 ml of water are added to 10.4 g (44.7 mmol) of 1-aminomethyl-7-benzyl-2-oxa-7-azabicyclo[3.3.0]octane in 56 ml of tert-butanol, and 10.2 g (47 mmol) of di-tert-butyl pyrodicarbonate are then added dropwise. The mixture is stirred at room temperature for 15 hours, and then extraction with chloroform, drying over potassium carbonate, concentration and distillation are carried out.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[Cl:13])[O:5][CH2:6][C:7](=O)[CH3:8].Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]Br.C(N(C(C)C)C(C)C)C>C(O)C>[Cl:13][C:12]1[C:2]([N:1]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:3][C:4]2[O:5][CH:6]=[C:7]([CH3:8])[C:10]=2[CH:11]=1
Reactant: CC(=O)COc1ccc(Cl)c(N)c1
Reactant: BrCCCCCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1coc2cc(N3CCCCC3)c(Cl)cc12

Procedure:
A mixture of 9.98 g (50 mmole) of 1-(3-amino-4-chlorophenoxy)-2-propanone, 22.9 g (0.10 mole) of 1,5-dibromopentane, 12.9 g (0.10 mole) of N-ethyldiisopropylamine and 60 ml of ethanol is boiled under reflux for 18 hours. The residue obtained after concentration by evaporation in vacuo is taken up in methylene chloride and washed twice with dilute sodium bicarbonate solution. The organic phase is dried, concentrated by evaporation and the crude product is taken up in 250 ml of ethanol, 40 ml of concentrated hydrochloric acid are added and the whole is boiled under reflux for 30 hours. The ethanol is concentrated in a vacuum rotary evaporator and the residue is diluted with ice-water, rendered alkaline with 6N sodium hydroxide solution and extracted with methylene chloride. The organic phases are washed with water, combined, dried over sodium sulphate and concentrated in a vacuum rotary evaporator. Chromatography over silica gel using chloroform as eluant yields 5-chloro-3-methyl-6-(piperidin-1-yl)-benzofuran which, after recrystallisation from petroleum ether, melts at 82°-84°.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][NH:5][CH2:6][CH2:7]Cl.[NH2:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[CH:13]2.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[NH:15]1[C:16]2[C:12](=[CH:11][C:10]([N:9]3[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]3)=[CH:18][CH:17]=2)[CH:13]=[CH:14]1
Reactant: Nc1ccc2[nH]ccc2c1
Reactant: ClCCNCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: c1cc2cc(N3CCNCC3)ccc2[nH]1
Yield: 18.5 %

Procedure:
Bis(2-chloroethyl)amine hydrochloride (3.60 g, 20.2 mmol) was added to a suspension of 5-aminoindole (2.53 g, 19.1 mmol) in ethanol (30 ml) and the mixture heated at reflux for 16 h. The mixture was allowed to cool, sodium carbonate (2.14 g, 20.2 mmol) was added and the reaction mixture heated at reflux for 8 h. The mixture was allowed to cool, filtered and the filtrate evaporated. The residue was dissolved in 1M hydrochloric acid (100 ml) and extracted with dichloromethane (2×50 ml). The aqueous phase was made basic with 4M sodium hydroxide (30 ml) and extracted with ethyl acetate (2×100ml). The extracts were washed with brine (100 ml), combined and dried (MgSO4). The residue from evaporation of the extracts was purified by flash chromatography, eluting with dichloromethane/methanol/ammonia, to give 1-(5-indolyl)piperazine (0.71 g, 18%), as a cream solid; δH (DMSO-d6) 2.94 (4H, m, 2×piperzinyl CH2), 3.00 (4H, m, 2×piperazinyl CH2), 6.29 (1H, m, 3-H), 6.84 (1H, dd, J 9.0,2.0 Hz, 6-H), 7.00 (1H, d, J 2.0 Hz, 2-H), 7.24 (2H, m, 4-H, 7-H), and 10.82 (1H, br s, NH).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:22]=2[NH2:28])[CH:18]=[CH:19][CH:20]=1>>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:22]=2[NH:28][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH3:12])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: COc1cccc(-c2ccc(C)cc2N)c1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Product: COc1cccc(-c2ccc(C)cc2Nc2ccnc3nc(C)ccc23)c1

Procedure:
The product from Example 1d (0.065 g, 0.36 mmol) was reacted with the product from Example 217b (0.072 g, 0.34 mmol) for 96 h at 100° C. following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing a trifluoroacetic acid salt (0.102 gm, 64%). 1H NMR (300 MHz, DMSO-d6) ppm: 2.43 (s, 3 H) 2.72 (s, 3 H) 3.62 (s, 3 H) 6.29 (d, J=7.35 Hz, 1 H) 6.77 (dd, J=7.91, 2.02 Hz, 1 H) 6.87-7.00 (m, 2 H) 7.17 (t, J=7.91 Hz, 1 H) 7.36 (s, 1 H) 7.41-7.46 (m, 1 H) 7.51-7.56 (m, 1 H) 7.75 (d, J=8.46 Hz, 1 H) 8.32 (d, J=7.35 Hz, 1 H) 8.91 (d, J=8.82 Hz, 1 H) 11.99-12.22 (s, 1 H); MS (ESI+) m/z 356.0 (M+H)+; (ESI−) m/z 354.0 (M−H)−.
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[N:18]=[C:19]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[C:20]3[N:26]=[CH:25][N:24]=[C:23]([SH:27])[C:21]=3[N:22]=2)[CH2:13][CH2:12]1)=[O:10]>[OH-].[Na+]>[CH2:1]([S:27][C:23]1[C:21]2[N:22]=[C:17]([N:14]3[CH2:15][CH2:16][N:11]([CH:9]=[O:10])[CH2:12][CH2:13]3)[N:18]=[C:19]([N:28]3[CH2:29][CH2:30][O:31][CH2:32][CH2:33]3)[C:20]=2[N:26]=[CH:25][N:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1ccccc1
Reactant: O=CN1CCN(c2nc(N3CCOCC3)c3ncnc(S)c3n2)CC1
Agent: [Na+]
Agent: [OH-]
Product: O=CN1CCN(c2nc(N3CCOCC3)c3ncnc(SCc4ccccc4)c3n2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.7 ml (0.006 mol) of benzyl chloride were added dropwise to a solution of 1.8 gm (0.005 mol) of 2-(N-formylpiperazino)-8-mercapto-4-morpholino-pyrimido-[5,4-d]-pyrimidine (m.p.: 250°-255° C.) in about 60 ml of 0.1N sodium hydroxide. After stirring the mixture at room temperature for one hour, the precipitated reaction product was suction-filtered off, washed with water and dried.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[C:8]3[CH:18]=[C:17]([CH:19]=C)[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1.ClCCl.C[OH:27]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[C:8]3[CH:18]=[C:17]([CH:19]=[O:27])[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1
Reactant: CO
Reactant: C=Cc1cnc2c(c1)C(=O)N(C)c1ccc(Cl)nc1N2CC
Solvent: ClCCl
Product: CCN1c2ncc(C=O)cc2C(=O)N(C)c2ccc(Cl)nc21
Temperature: -78 °C
Yield: 81 %

Procedure:
The 2-chloro-5,11-dihydro-11-ethyl-5-methyl-8-vinyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (2.34 g, 7.43 mmol) was dissolved in 1:1 dichloromethane/methanol (40 mL) and cooled to -78° C. This solution was then saturated with ozone and a stream ozone was bubbled through for 10 minutes while stirring. The mixture was warmed to ambient temperature and quenched with excess dimethylsulfide. The mixture was then concentrated and the resulting residue was purified by flash chromatography (gradient of hexanes to 1:1 hexanes/ethyl acetate) to give the title compound (1.9 g, 81%), m.p. 199°-201° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@@H:17]([CH3:28])[CH2:16]1)(=[O:14])=[O:13].[C:29](=O)([O-])[O-].[K+].[K+].CB1OB(C)OB(C)O1>O1CCOCC1.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>[CH3:28][C@H:17]1[CH2:16][N:15]([S:12]([C:3]2[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=2[CH3:29])(=[O:14])=[O:13])[CH2:20][CH2:19][N:18]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]
Reactant: C[C@H]1CN(S(=O)(=O)c2cc(C(F)(F)F)ccc2Br)CCN1C(=O)OC(C)(C)C
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CB1OB(C)OB(C)O1
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ccc(C(F)(F)F)cc1S(=O)(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](C)C1
Temperature: 100 °C

Procedure:
1,1-dimethylethyl (2S)-4-{[2-bromo-5-(trifluoromethyl)phenyl]sulfonyl}-2-methyl-1-piperazinecarboxylate (may be prepared as described in Description 25) (2.5 g, 5.13 mmol), potassium carbonate (1.134 g, 8.21 mmol) in 1,4-dioxane (80 ml) were stirred for 5 min then trimethylboroxin (1.142 ml, 8.21 mmol) and Pd(PPh3)4 (0.593 g, 0.513 mmol) were added and the reaction mixture heated at 100° C. for 1.5 h. Further trimethylboroxin (0.5 mL) was added and the reaction heated for 30 min before it was allowed to cool overnight.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([NH:10][CH3:11])[C:7]([C:12]([F:15])([F:14])[F:13])=[CH:6][C:5]=1[NH2:16].[C:18](Cl)(=[O:20])[CH3:19]>O1CCOCC1>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([N:10]([C:18](=[O:20])[CH3:19])[CH3:11])[C:7]([C:12]([F:14])([F:13])[F:15])=[CH:6][C:5]=1[NH2:16]
Reactant: CC(=O)Cl
Reactant: CNc1cc(C(=O)OC)c(N)cc1C(F)(F)F
Solvent: C1COCCO1
Product: COC(=O)c1cc(N(C)C(C)=O)c(C(F)(F)F)cc1N
Temperature: 80 °C
Reaction time: 2 h
Yield: 12.8 %

Procedure:
2-Amino-5-methylamino-4-trifluoromethyl-benzoic acid methyl ester (26 mg, 0.96 mmoles) is dissolved in dioxane and after addition of acetyl chloride (54 μL, 1 eq.) the mixture is stirred for 2 h (TLC control) at 80° C. Acetyl chloride (0.9 eq.) is then added and stirring continued for 18 hours at 80° C. The mixture is evaporated to dryness. The residue is dissolved in dichloromethane, filtrated, evaporated and dried under HV. The crude product is purified by flash-chromatography (gradient hexane to ethyl acetate, silicagel) to yield 5-(acetyl-methyl-amino)-2-amino-4-trifluoromethyl-benzoic acid methyl ester as a yellow solid (36 mg, 12.8% yield) (MH+291, Rt 5.0 min.). The other monoacetyl derivative (50 mg) and the diacetyl derivative (92 mg) are also isolated.
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:7])[CH:4]([OH:6])[CH3:5].[Cl:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12](Cl)=[O:13].CCOCC>C1COCC1>[Cl:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([O:1][N:2]=[C:3]([NH2:7])[CH:4]([OH:6])[CH3:5])=[O:13]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: CC(O)C(N)=NO
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(O)C(N)=NOC(=O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6.45 g crude N′,2-dihydroxypropanimidamide was cooled on an ice-bath with 23.5 mL DEA in THF (200 mL). To this slurry 21.94 g 3-chlorobenzoyl chloride was added. The mixture was warmed to r.t. and stirred for 2 h. Addition of Et2O (200 mL), washing with sat. aq. NH4Cl and re-extraction of the aq. layer gave after combining and concentration of the org. layers followed by drying in vacuo 27.24 g of crude title compound, which was used directly in the next step for 1-[5-(3-chlorophenyl)-[1,2,4]oxadiazol-3-yl]ethanol. LC-MS (M++1): 243
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9]([NH:11][C:12]3[C:13]([O:18][C@H:19]4[CH2:23][CH2:22][O:21][CH2:20]4)=[N:14][CH:15]=[CH:16][CH:17]=3)=[N:8][CH:7]=[N:6][C:5]=2[S:4][C:3]=1[C:24]([OH:26])=O.[NH3:27]>>[CH3:1][C:2]1[C:10]2[C:9]([NH:11][C:12]3[C:13]([O:18][C@@H:19]4[CH2:23][CH2:22][O:21][CH2:20]4)=[N:14][CH:15]=[CH:16][CH:17]=3)=[N:8][CH:7]=[N:6][C:5]=2[S:4][C:3]=1[C:24]([NH2:27])=[O:26]
Reactant: Cc1c(C(=O)O)sc2ncnc(Nc3cccnc3O[C@H]3CCOC3)c12
Reactant: N
Product: Cc1c(C(N)=O)sc2ncnc(Nc3cccnc3O[C@@H]3CCOC3)c12

Procedure:
Prepared analogously to example 10.4 from 5-methyl-4-{2-[(S)-(tetrahydro-furan-3-yl)oxy]-pyridin-3-ylamino}-thieno[2,3-d]pyrimidine-6-carboxylic acid and ammonia.
Reaction SMILES: [Si:1]([N:8]1[CH:11]([CH2:12][CH:13]([OH:15])[CH3:14])[CH2:10][C:9]1=[O:16])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C=CC=CC=1.[C:23](Cl)(=[O:25])[CH3:24]>C(Cl)Cl>[Si:1]([N:8]1[CH:11]([CH2:12][CH:13]([O:15][C:23](=[O:25])[CH3:24])[CH3:14])[CH2:10][C:9]1=[O:16])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CC(O)CC1CC(=O)N1[Si](C)(C)C(C)(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OC(C)CC1CC(=O)N1[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1-(t-butyldimethylsilyl)-4-(2-hydroxypropyl)-2-azetidinone (2.46 g) is dissolved in 20 ml CH2Cl2 cooled to 0° and treated with 0.90 g pyridine and 0.080 g of acetyl chloride (added dropwise). The reaction mixture is stirred at 0° for 15 min, allowed to warm to r.t. during the next 15 min and then worked up by dilution with CH2Cl2 and washing with water, drying and evaporating. The residue on chromatography on silica gel gives 1-(t-butyldimethylsilyl)-4-(2-acetoxypropyl)-2-azetidinone.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:25]([CH3:38])=[C:26]([CH3:37])[C:27]4[O:31][C:30]([CH3:33])([CH3:32])[CH:29]([OH:34])[C:28]=4[C:35]=3[CH3:36])[CH2:20][CH2:19]2)=[CH:14][CH:13]=1>CCCCCC.C(OCC)(=O)C>[CH3:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([N:18]2[CH2:19][CH2:20][N:21]([C:24]3[C:25]([CH3:38])=[C:26]([CH3:37])[C:27]4[O:31][C:30]([CH3:33])([CH3:32])[CH:29]([O:34][CH2:3][C:4]5[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=5)[C:28]=4[C:35]=3[CH3:36])[CH2:22][CH2:23]2)=[CH:16][CH:17]=1
Reactant: ClCc1ccccn1
Reactant: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(O)C(C)(C)O4)CC2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(OCc3ccccn3)C(C)(C)O4)CC2)cc1
Yield: 86 %

Procedure:
Using 2-chloromethylpyridine hydrochloride and 5-(4-(4-methoxyphenyl)piperazin-1-yl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-ol obtained in Reference Example 18, the title compound was synthesized in the same manner as in Example 74. Yield 86%. mp. 120–121° C. (hexane-ethyl acetate). 1H-NMR (CDCl3) δ: 1.37 (3H, s), 1.59 (3H, s), 2.09 (3H, s), 2.25 (3H, s), 2.28 (3H, s), 3.05–3.28 (8H, m), 3.79 (3H, s), 4.67 (2H, s), 4.75 (1H, s), 6.86 (2H, d, J=9.2 Hz), 6.97 (2H, d, J=9.2 Hz), 7.15–7.21 (1H, m), 7.48 (1H, d, J=7.6 Hz), 7.68 (1H, t, J=7.6 Hz), 8.52 (1H, d, J=4.4 Hz).