Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B.O1CCCC1.[Cl:7][C:8]1[C:9]([Cl:17])=[N:10][CH:11]=[C:12]([CH:16]=1)[C:13](O)=[O:14]>O1CCCC1>[Cl:17][C:9]1[C:8]([Cl:7])=[CH:16][C:12]([CH2:13][OH:14])=[CH:11][N:10]=1
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1
Agent: B
Solvent: C1CCOC1
Product: OCc1cnc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 44.2 %

Procedure:
Borane-tetrahydrofuran complex (1M solution in tetrahydrofuran, 52 ml) was added to a stirred solution of 5,6-dichloronicotinic acid (2 g) in tetrahydrofuran (60 ml) over 20 minutes at 0° C. The reaction mixture was allowed to warm to room temperature over 90 minutes and then cooled to 0° C. and quenched with water (100 ml). The solution was saturated with solid sodium chloride and extracted with ethyl acetate and the combined organic extracts were dried and concentrated in vacuo. The residue was triturated with dichloromethane-50% ethyl acetate and the solid by-product was removed by filtration. The filtrate was concentrated in vacuo and purified by column chromatography using isohexane/ethyl acetate (1:1 v/v) as eluent to yield the product as a white solid (820 mg, 45%). NMR: δ 4.55 (d, 2H), 5.5 (t, 1H), 8.0 (m, 1H), 8.3 (m, 1H); m/z 178.1 (M+H+).
Reaction SMILES: Cl.[C:2]1([C:8]([CH:10]([NH2:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=O)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]([C:24]([O:26][CH3:27])=[O:25])#[C:19][C:20]([O:22][CH3:23])=[O:21].C([O-])(=O)C.[Na+].Cl.[Na]>O.CO>[C:2]1([C:8]2[C:18]([C:24]([O:26][CH3:27])=[O:25])=[C:19]([C:20]([O:22][CH3:23])=[O:21])[NH:17][C:10]=2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(C(=O)c1ccccc1)c1ccccc1
Reactant: COC(=O)C#CC(=O)OC
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1[nH]c(-c2ccccc2)c(-c2ccccc2)c1C(=O)OC
Reaction time: 2 h
Yield: 63 %

Procedure:
In a 2 l RB 3-neck flask with mechanical stirrer and condenser was placed 76.7 g (0.31 mole) of desyl amine hydrochloride [Pschorr et al, Chem. Ber., 35, 2740 (1902)], 750 ml methanol, 88 g (0.62 mole) dimethyl acetylenedicarboxylate (freshly distilled) and 61 g (0.75 mole) anhydrous sodium acetate. The mixture was heated at reflux for two hours. Then another 44 g (0.31 mole) of dimethyl acetylenedicarboxylate was added, and heating continued another two hours. While the reaction mixture was still at reflux, concentrated hydrochloric acid (~60 ml, to pH~2) was added dropwise. The mixture was heated at reflux another hour, then poured into 2 l water containing 200 ml 10% sodium bicarbonate solution. With stirring, more sodium bicarbonte was added until the solution was neutral. The gummy solid which precipitated was collected and washed with water. Trituration of this gummy material with ~500 ml of 50% aqueous ethanol gave a tan powdery solid, which was recrystallized from ~85% aqueous ethanol to give 65.5 g (63%) of white crystals, m.p. 191°-2° [Lit. m.p. 185°-7°; J. B. Hendrickson et al, J. Am. Chem. Soc., 86, 107 (1964)].
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].C(=O)([O-])[O-].[K+].[K+].[N:17]1([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>CC#N>[N+:8]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[N:20]1[CH2:19][CH2:18][N:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:22][CH2:21]1)([O-:10])=[O:9]
Reactant: CCOC(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1cnccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)N1CCN(c2ccncc2[N+](=O)[O-])CC1
Temperature: 23 °C
Reaction time: 16 h
Yield: 73.6 %

Procedure:
A solution of technical grade 3-nitropyridone (25 g, 177 mmol) (contains about 20% 3,5-dinitropyridone by weight) in 150 mL of phosphorous oxychloride was heated at 90° C. for 2 h. The excess phosphorous oxychloride was removed by distillation and the remaining oil poured into ice/water. The aqueous solution was extracted with five 300 mL portions of CH2Cl2. The CH2Cl2 extracts were dried (MgSO4), filtered and concentrated in vacuo to yield 26.7 g of crude 4-chloro-3-nitropyridine. To a solution of the crude 4-chloro-3-nitropyridine (26.7 g) in 200 mL of MeCN was added potassium carbonate (25.7 g, 186 mmol) and ethyl 1-piperazinecarboxylate (27.2 mL, 186 mmol). The reaction mixture was stirred at 23° C. for 16 h and then concentrated in vacuo. The mixture was diluted with ethyl acetate (1 L), and the organic solution was washed with water, dried (brine, MgSO4), filtered and concentrated in vacuo to a solid mass. Silica gel chromatography of the mixture gave ethyl 4-(3-nitro-4-pyridinyl)-1-piperazinecarboxylate (34.73 g, 73%): mp 101°-103° C., and ethyl 4-(3,5-dinitro-4-pyridinyl)-1-piperazinecarboxylate (7.07 g, 22%): mp 165°-167° C. Anal. Calcd for C12H16N4O4 : C, 51.42; H, 5.75; N, 19.99. Found: C, 51.26; H, 5.69; N, 19.91. Anal. Calcd for C12H15N5O6 : C, 44.31; H, 4.65; N, 21.53. Found: C, 44.51; H, 4.65; N, 21.36.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@H:3]([NH:6][C:7]([C:9]23[CH2:18][CH:13]4[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]4)[CH2:10]2)[CH2:16]3)=[O:8])[CH2:2]1.C1(C)C=CC(S(O[CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[F:37])(=O)=O)=CC=1>>[F:37][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[CH2:30][CH2:29][N:1]1[CH2:5][CH2:4][C@H:3]([NH:6][C:7]([C:9]23[CH2:18][CH:13]4[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]4)[CH2:10]2)[CH2:16]3)=[O:8])[CH2:2]1
Reactant: O=C(N[C@H]1CCNC1)C12CC3CC(CC(C3)C1)C2
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccccc2F)cc1
Product: O=C(N[C@H]1CCN(CCc2ccccc2F)C1)C12CC3CC(CC(C3)C1)C2
Yield: 29.6 %

Procedure:
(S)-N-(Pyrrolidin-3-yl)-1-adamantanecarboxamide (0.5 g) and 2-(2-fluorophenyl)ethyl p-toluenesulfonate (0.59 g) were reacted under the same conditions as in Example 6 to give (S)-N-(1-(2-(2-fluorophenyl)ethyl)pyrrolidin-3-yl)-1-adamantanecarboxamide (0.22 g), melting point 106-108° C.
Reaction SMILES: B(F)(F)F.[C:5](O)(=[O:7])[CH3:6].[O:9]([C@H:16]([CH3:21])[C:17]([O:19][CH3:20])=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])(=O)C.[Na+]>>[C:5]([C:13]1[CH:14]=[CH:15][C:10]([O:9][C@H:16]([CH3:21])[C:17]([O:19][CH3:20])=[O:18])=[CH:11][CH:12]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)O
Reactant: COC(=O)[C@@H](C)Oc1ccccc1
Agent: CC(=O)[O-]
Agent: FB(F)F
Agent: [Na+]
Product: COC(=O)[C@@H](C)Oc1ccc(C(C)=O)cc1
Temperature: 80 °C
Reaction time: 7 h
Yield: 83.7 %

Procedure:
67 g (1 mol) of boron trifluoride were passed into 60 g (1 mol) of acetic acid. The mixture was heated to 45°-50° C., and 36 g (0.2 mol) of methyl (R)-2-phenoxypropionate were added. After stirring at 45°-50° C. for 7 hours, the temperature was raised to 80° C. for 1 h and the mixture was then stirred into 800 ml of 25% by weight aqueous sodium acetate solution. The product was extracted with 200 ml of ethyl acetate and, after concentration of the organic phase, purified by vacuum distillation. Yield: 83.7% (94-95% enantiomeric excess).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=2)[NH2:12])[CH:3]=1.[C:16]([O:20][C:21]([NH:23][C:24]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=S)=[O:22])([CH3:19])([CH3:18])[CH3:17].C(N(C(C)C)CC)(C)C.[I-].C[N+]1C=CC=CC=1Cl>ClCCl>[C:30]([O:29][C:27]([NH:26][C:24]([NH:23][C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:22])=[N:12][C:11]1[CH:13]=[CH:14][CH:15]=[C:9]([O:8][C:4]2[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][N:5]=2)[CH:10]=1)=[O:28])([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)OC(=O)NC(=S)NC(=O)OC(C)(C)C
Reactant: Cc1ccnc(Oc2cccc(N)c2)c1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccnc(Oc2cccc(N=C(NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c2)c1
Reaction time: 16 h
Yield: 77.5 %

Procedure:
To a suspension of 3-(4-methylpyridin-2-yloxy)aniline (264 mg), N,N′-bis(tert-butoxycarbonyl)thiourea (474 mg) and diisopropylethyl-amine (0.529 ml) in dichloromethane (13.2 ml) was added 1-methyl-2-chloropyridinium iodide (438 mg), and the mixture was stirred for 16 hours. The mixture was diluted with dichloromethane, washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 25 g, n-hexane:ethyl acetate 4:1) to give N,N′-bis(tert-butoxycarbonyl)-N″-(3-(4-methylpyridin-2-yloxy)phenyl)-guanidine (452 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16](Br)[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:21][C:22]1([CH3:41])[CH2:31][CH2:30][CH2:29][C:28]2[CH:27]=[C:26](B3OC(C)(C)C(C)(C)O3)[CH:25]=[CH:24][C:23]1=2.O.O.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>COCCO.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:26]3[CH:25]=[CH:24][C:23]4[C:22]([CH3:41])([CH3:21])[CH2:31][CH2:30][CH2:29][C:28]=4[CH:27]=3)[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)CCCc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(Br)n2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(-c3ccc4c(c3)CCCC4(C)C)n2)CC1

Procedure:
500 mg (1.46 mmol) of 4-(6-bromopyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester, 460 mg (1.61 mmol) of 2-(5,5-dimethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane and 620 mg (2.92 mmol) of tripotassium phosphate trihydrate are suspended in 10 ml of ethylene glycol monomethyl ether, degassed a number of times, and 82 mg (0.04 mmol) of bis(triphenylphosphine)palladium(II) dichloride are added under nitrogen atmosphere. The reaction mixture is treated in an ultrasound bath for 10 min, subsequently irradiated in the microwave at 100° C. for 90 min, 50 ml of water and 50 ml of ethyl acetate are added, and the mixture is filtered. The residue is discarded. The organic phase of the filtrate is separated off, and the aqueous phase is extracted three times with ethyl acetate. The combined organic phases are dried over Na2SO4 and evaporated. The crude product is purified by means of flash chromatography on silica gel.
Reaction SMILES: Cl.C(OC(=O)[NH:8][CH2:9][C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[O:17][CH2:18][C:19]1[NH:20][CH2:21][CH2:22][N:23]=1)(C)(C)C>CCOCC.CO>[Cl:16][C:14]1[CH:13]=[CH:12][C:11]([O:17][CH2:18][C:19]2[NH:23][CH2:22][CH2:21][N:20]=2)=[C:10]([CH:15]=1)[CH2:9][NH2:8]
Reactant: CC(C)(C)OC(=O)NCc1cc(Cl)ccc1OCC1=NCCN1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: NCc1cc(Cl)ccc1OCC1=NCCN1
Reaction time: 8 h
Yield: 73.7 %

Procedure:
A solution of 30% HCl in ether (0.5 mL) was added to a solution of [5-chloro-2-(4,5-dihydro-1H-imidazol-2-ylmethoxy)benzyl]-carbamic acid tert-butyl ester (146 mg, 0.43 mmol) in methanol (5 mL). After stirring overnight, the mixture was concentrated and triturated from ether, filtered, washed with ether and dried to afford 76 mg of the title compound as a colorless solid. 1H NMR (400 MHz, CD3OD) δ 7.4 (m, 2H); 7.04 (m, 1H); 4.91 (s, 2H); 4.12 (s, 2H); 4.00 (s, 2H); 3.79 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:17])[CH:10]([CH3:16])[C:11]([O:13]CC)=[O:12]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:17])[CH:10]([CH3:16])[C:11]([OH:13])=[O:12]
Reactant: CCOC(=O)C(C)C(=O)Nc1ccccc1Cl
Solvent: C1CCOC1
Product: CC(C(=O)O)C(=O)Nc1ccccc1Cl

Procedure:
The acid was prepared according to Procedure B using ethyl 3-(2-chlorophenylamino)-2-methyl-3-oxopropanoate (1.8 g, 7.04 mmol) in THF (7.0 mL) to give 3-(2-chlorophenylamino)-2-methyl-3-oxopropanoic acid. Mass Spectrum (ESI) m/e=228.1 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH3:20].[CH3:21][S:22](Cl)(=[O:24])=[O:23]>>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([CH3:20])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][S:22]([CH3:21])(=[O:24])=[O:23])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: Cc1nc2c(N)nc3ccccc3c2n1CCCCN
Reactant: CS(=O)(=O)Cl
Product: Cc1nc2c(N)nc3ccccc3c2n1CCCCNS(C)(=O)=O
Yield: 12.4 %

Procedure:
Using the general method of Example 232, 1-(4-aminobutyl)-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine (1.00 g, 3.7 mmol) was reacted with methanesulfonyl chloride (0.46 mL, 5.9 mmol) to provide 0.16 g of N-[4-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]methanesulfonamide as an off white solid, m.p. 229.4–230.5° C. Analysis: Calculated for C16H21N5O2S.0.25H2O: % C, 54.60; % H, 6.16; % N, 19.90. Found: % C, 54.80; % H, 6.24; % N, 19.58.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[N:11][C:12]=2[NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[C:17]([Cl:29])[CH:16]=2)[NH:7][N:6]=1.[NH:30]([CH2:34][CH2:35][OH:36])[CH2:31][CH2:32][OH:33]>>[Cl:29][C:17]1[CH:16]=[C:15]([NH:14][C:12]2[N:11]=[CH:10][N:9]=[C:8]3[NH:7][N:6]=[C:5]([O:4][CH2:3][CH2:2][N:30]([CH2:34][CH2:35][OH:36])[CH2:31][CH2:32][OH:33])[C:13]=23)[CH:20]=[CH:19][C:18]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: ClCCOc1n[nH]c2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Reactant: OCCNCCO
Product: OCCN(CCO)CCOc1n[nH]c2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Yield: 18 %

Procedure:
The procedure described in Example 23 was repeated using 3-(2-chloroethoxy)-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine and diethanolamine to give the title compound in 18% yield; NMR Spectrum: 2.66 (t, 4H), 2.98 (t, 2H), 3.44-3.48 (m, 4H), 4.35 (t, 2H), 4.43 (t, 2H), 5.28 (s, 2H), 7.23 (d, 1H), 7.37 (t, 1H), 7.57-7.60 (m, 2H), 7.87 (t, 1H), 7.94 (d, 1H), 8.29 (s, 1H), 8.44 (s, 1H), 8.59 (d, 1H); Mass Spectrum: 500 (MH+).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH3:16])[N:8]=[CH:9][C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:5])C.[OH-].[Na+].Cl>>[CH2:14]([O:13][C:11]([C:10]1[CH:9]=[N:8][N:7]([CH3:16])[C:6]=1[C:4]([OH:5])=[O:3])=[O:12])[CH3:15]
Reactant: CCOC(=O)c1cnn(C)c1C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)c1cnn(C)c1C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(This compound was prepared in close analogy to the method of Perez et al., Spanish patent appl. ES 493459.) 2-Methyl-2H-pyrazole-3,4-dicarboxylic acid diethyl ester (2.06 g, 9.1 mmol) was suspended in a NaOH solution (0.5M in water, 20 ml, 10 mmol) and heated to reflux (30 min). If the conversion was incomplete after this time, as indicated by HPLC control, small amounts of NaOH were added in 30 min intervals. The reaction mixture was cooled, and HCl was added, and stirred for an additional 30 min (r.t.). The precipitate was filtered, washed (water, small amount) and dried under vacuum. The title compound was obtained as a white solid (1.27 g, 70%), and was used in the next step without further purification. MS (m/e)=198 [M+H+].
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16](=O)[CH3:17])=[CH:12][CH:11]=2)[N:3]=[CH:2]1.Cl.[NH2:20][OH:21].[OH-].[Na+].C(O)C>O>[NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16](=[N:20][OH:21])[CH3:17])=[CH:12][CH:11]=2)[N:3]=[CH:2]1
Reactant: CC(=O)c1ccc(OCCCc2c[nH]cn2)cc1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(=NO)c1ccc(OCCCc2c[nH]cn2)cc1

Procedure:
1.2 mmol of (4-(3-(1H-imidazol-4-yl)propyloxy)phenyl)ethanone (Example 78), 2.4 mmol of hydroxylamine hydrochloride and 4.8 mmol of NaOH are heated under reflux in 10 ml of water and 10 ml of ethanol for 7 hours. The mixture is concentrated under reduced pressure and alkalized with saturated K2CO3 solution, and the crude product is filtered off and washed with water. The product is crystallized as hydrogen maleate from diethyl ether and ethanol.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([Cl:11])[CH:10]=1)[C:7](=[O:12])[N:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1)[CH2:5]2.[CH3:25][Si:26]([CH3:31])([CH3:30])[CH2:27][C:28]#C>C(NC(C)C)(C)C.ClCCl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:11][C:9]1[CH:10]=[C:2]([C:28]#[C:27][Si:26]([CH3:31])([CH3:30])[CH3:25])[CH:3]=[C:4]2[C:8]=1[C:7](=[O:12])[N:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1)[CH2:5]2
Reactant: C#CC[Si](C)(C)C
Reactant: O=C1c2c(Cl)cc(Br)cc2CN1Cc1ccc(OC(F)(F)F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: C[Si](C)(C)C#Cc1cc(Cl)c2c(c1)CN(Cc1ccc(OC(F)(F)F)cc1)C2=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 45.7 %

Procedure:
A mixture of 5-bromo-7-chloro-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.210 g, 0.5 mmol), PdCl2(PPh3)2 (0.019 g, 0.05 mmol), and CuI (0.010 g, 0.05 mmol) in diisopropyl amine (4 mL) was treated with trimethyl-prop-2-ynyl-silane (0.141 mL, 1 mmol) and stirred at ambient temperature for 16 h. The reaction mixture diluted with dichloromethane (20 mL) filtered and concentrated. Silica gel column chromatography using 3:1 hexane-ethyl acetate afforded 7-chloro-2-(4-trifluoromethoxy-benzyl)-5-trimethylsilanylethynyl-2,3-dihydro-isoindol-1-one (0.100 g, 46%). GC-MS: 437 (M)+, 356 (M-81)+.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:29]#[C:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:8][C:9]=1[N:10]1[C@H:15]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:14][O:13][C@@:12]([CH2:23][CH:24]([OH:27])[CH2:25][OH:26])([CH3:22])[C:11]1=[O:28])=[O:4].CO.O.O[Li].O>C1COCC1>[CH:16]1([C@H:15]2[N:10]([C:9]3[CH:8]=[C:7]([C:29]#[C:30][C:31]([CH3:34])([CH3:33])[CH3:32])[S:6][C:5]=3[C:3]([OH:4])=[O:2])[C:11](=[O:28])[C@:12]([CH2:23][CH:24]([OH:27])[CH2:25][OH:26])([CH3:22])[O:13][CH2:14]2)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N1C(=O)[C@@](C)(CC(O)CO)OC[C@H]1C1CCCCC1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)(C)C#Cc1cc(N2C(=O)[C@@](C)(CC(O)CO)OC[C@H]2C2CCCCC2)c(C(=O)O)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.7 %

Procedure:
3-[(2R,5R)-5-Cyclohexyl-2-(2,3-dihydroxy-propyl)-2-methyl-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl ester from the previous step was dissolved in 4.0 ml of THF and 0.3 mL of solution was taken out for the reaction. To the stirred solution was added THF (0.3 mL), MeOH (0.3 mL), water (0.3 mL), and LiOH.H2O (25.6 mg, 0.61 mmol, 10.0 equiv) and the resulting solution was stirred at room temperature for 30 minutes. The reaction was quenched by addition of 3.0 N HCl aqueous solution until pH=5. To the solution was then added EtOAc and the phases were separated. The aqueous layer was extracted by EtOAc. The organic layers were combined, dried (over Na2SO4) and concentrated. The residue was purified by HPLC (0.1% NH4OH, MeCN/H2O, 10%-90%) to give product (11 mg, 37.7% yield) as white solid. MS: 478 [M−H+].
Reaction SMILES: [Br-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=2)C=CC=CC=1.C([Li])CCC.[CH3:41][O:42][C:43]1[CH:44]=[C:45]([CH:48]=[CH:49][C:50]=1[O:51][CH3:52])[CH:46]=O>C1COCC1.CCCCCC.C(OCC)(=O)C>[CH3:41][O:42][C:43]1[CH:44]=[C:45]([CH2:46][CH2:9][CH2:10][CH2:11][C:12]2[CH:13]=[C:14]([O:22][CH3:23])[C:15]([O:20][CH3:21])=[C:16]([O:18][CH3:19])[CH:17]=2)[CH:48]=[CH:49][C:50]=1[O:51][CH3:52]
Reactant: COc1cc(CCC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc(OC)c1OC
Reactant: COc1ccc(C=O)cc1OC
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(CCCCc2cc(OC)c(OC)c(OC)c2)cc1OC
Reaction time: 1 h
Yield: 50.8 %

Procedure:
Suspended in 15 ml of THF were 1.23 g (2.2 mmol) of triphenyl[3-(3,4,5-trimethoxyphenyl)propyl]phosphonium bromide. The suspension was added with 1.4 ml (1.57M, 2.2 mmol) of butyl lithium in hexane under ice cooling, followed by stirring for one hour. The reaction mixture was further added with 365 mg (2.2 mmol) of 3,4-dimethoxybenzaldehyde, followed by stirring at room temperature for 21 hours. After the reaction mixture was dissolved in 30 ml of ethyl acetate, the resulting solution was washed with water and then with saturated NaCl. The organic layer was then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The oil thus obtained (1.31 g) was purified by column chromatography (silica gel: "MERCK #9385", 30 g, eluent: 1:4 mixed solvent of ethyl acetate and hexane), whereby 403 mg of the title compound were obtained as colorless oil. The oil was immediately dissolved in 10 ml of ethyl acetate, followed by the addition of 10 mg of a 10% palladium-carbon catalyst. The resulting suspension was stirred at room temperature for 35 hours under a hydrogen atmosphere of 1 atm. Insoluble matter was removed by filtration and the filtrate was concentrated. The concentrate was purified by column chromatography (silica gel: "MERCK #9385", 10 g, eluent: 1:4 mixed solvent of ethyl acetate and hexane), whereby 198 mq of the title compound were obtained as a colorless solid (25%)
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([Cl:17])[CH:3]=1.[CH3:18][O:19][C:20]1[N:25]=[CH:24][C:23](B(O)O)=[CH:22][N:21]=1>>[Cl:17][C:4]1[CH:3]=[C:2]([C:23]2[CH:22]=[N:21][C:20]([O:19][CH3:18])=[N:25][CH:24]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: Cc1c2n(c3c(Br)cc(Cl)cc13)CCNC2=O
Reactant: COc1ncc(B(O)O)cn1
Product: COc1ncc(-c2cc(Cl)cc3c(C)c4n(c23)CCNC4=O)cn1

Procedure:
The title compound, white solid (68 mg, 79%), MS (ISP) m/z=343.5 [(M+H)+], mp 270.5° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-chloro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 12) (78.4 mg, 0.25 mmol) and commercially available 2-methoxypyrimidin-5-ylboronic acid (50.0 mg, 0.325 mmol).
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C:8]([C:10]1[S:11][C:12]([S:32][CH3:33])=[C:13]([S:15]([C:18]2[CH:19]=[C:20]([C:24]3[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][C:25]=3[NH2:31])[CH:21]=[CH:22][CH:23]=2)(=[O:17])=[O:16])[CH:14]=1)=[NH:9])([CH3:4])([CH3:3])[CH3:2].[CH2:35]([O:37][C:38](=[O:44])[CH2:39][CH2:40][C:41](Cl)=[O:42])[CH3:36].C1COCC1>CCOC(C)=O>[CH2:35]([O:37][C:38](=[O:44])[CH2:39][CH2:40][C:41]([NH:31][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]([CH3:30])[C:24]=1[C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([S:15]([C:13]2[CH:14]=[C:10]([C:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:34])=[NH:9])[S:11][C:12]=2[S:32][CH3:33])(=[O:17])=[O:16])[CH:19]=1)=[O:42])[CH3:36]
Reactant: CCOC(=O)CCC(=O)Cl
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2N)c1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)CCC(=O)Nc1cccc(C)c1-c1cccc(S(=O)(=O)c2cc(C(=N)NC(=O)OC(C)(C)C)sc2SC)c1
Temperature: 50 °C

Procedure:
{[4-(2′-Amino-6′-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (38.5 mg, 0.07 mmol, Example 25: step c) and 3-chlorocarbonyl-propionic acid ethyl ester (13 μL, 0.09 mmol) were dissolved into THF (1 mL) and heated to 50° C. for one hour. The reaction was dissolved into EtOAc and washed with brine. The combined organic layers were dried, (MgSO4) and the solvents were removed in vacuo. Purification by preparative TLC (30% EtOAc/hexanes) yielded the title compound. ESI-MS (m/z): Calcd. for C30H35N3O7S3: 646.2 (M+1); found: 645.8.
Reaction SMILES: Cl[CH:2]([CH2:7][C:8]([F:11])([F:10])[F:9])[C:3]([F:6])([F:5])[F:4].C1S(=O)(=O)CCC1.[F-].[K+]>>[F:4][C:3]([F:6])([F:5])[CH:2]=[CH:7][C:8]([F:11])([F:10])[F:9]
Reactant: FC(F)(F)CC(Cl)C(F)(F)F
Agent: [F-]
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Product: FC(F)(F)C=CC(F)(F)F

Procedure:
200 g of 2-chloro-1,1,1,4,4,4-hexafluorobutane were added dropwise to a mixture of 195 ml of distilled tetramethylene sulphone and 87 g of dried potassium fluoride at 190° C. and the 1,1,1,4,4,4-hexafluorobut-2-ene which formed was continuously distilled off. 135 g of 1,1,1,4,4,4-hexafluorobut-2-ene were obtained.