Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[H-].[Na+].[CH2:20](Br)[CH:21]=[CH2:22]>CN(C)C=O.[Cl-].[Na+]>[CH2:22]([O:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:21]=[CH2:20]
Reactant: C=CCBr
Reactant: CCCCCCCCCCCCCCCCO
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOCCCCCCCCCCCCCCCC
Temperature: 50 °C
Yield: 49.6 %

Procedure:
n-Hexadecanol (24.2 g, 0.1 mol) was added to a suspension of sodium hydride (9.6 g of a 50% dispersion in mineral oil, 0.2 mol) in dimethylformamide (200 ml) and heated to 50° C. for 30 minutes. Allyl bromide (24.2 g, 0.2 mol) was then added and the mixture heated to 90° C. for 5 hours. The reaction was cooled, diluted with a solution of saturated sodium chloride (300 ml), and extracted with ether (2×300 ml). The combined ether extracts were washed with a saturated solution of sodium chloride (200 ml), filtered, dried over magnesium sulfate, treated with activated charcoal, filtered, and evaporated under reduced pressure to an oil. The resulting oil was purified by absorbing it on silica gel, placing the silica gel in a sintered glass filter, and eluting the product off with hexane (7×200 ml) followed by toluene (4×200 ml). Concentration yielded the pure ether (14 g, 50% yield): NMR (CDCl3) 3.40 (t, 2, --CH2 --O--CH2CH=CH2), 3.92 (d, 2, --O--CH2CH=CH2), 4.95-5.38 (m, 2, =CH2) and 5.58-6.20 (m, 1, --CH=CH2).
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[CH3:6][O:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[N:16]=C(C)C=[CH:13]2.IC>O1CCCC1>[CH2:3]([C:2]1[CH:1]=[CH:13][C:12]2[C:17](=[C:8]([O:7][CH3:6])[CH:9]=[CH:10][CH:11]=2)[N:16]=1)[CH3:4]
Reactant: COc1cccc2ccc(C)nc12
Reactant: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: CCc1ccc2cccc(OC)c2n1
Temperature: -60 °C
Reaction time: 0.25 h

Procedure:
n-Butyllithium (1 ml, 1.6M in hexanes) was added dropwise to a stirred solution of 8-methoxy-2-methylquinoline (0.25 g) in tetrahydrofuran (4 ml) at -60° C. under an inert atmosphere. The resulting red solution was stirred at -60° C. for 15 minutes, and then warmed to -40° C. Iodomethane (0.27 ml) was then added dropwise and the reaction warmed slowly to room temperature with continued stirring for 12 hours. The reaction was quenched with brine (50 ml) and extracted with dichloromethane (2×5ml). The organic phases were combined, dried over magnesium sulphate and preadsorbed onto silica. Purification was achieved by column chromatography eluting with ethyl acetate to afford the title compound as a pale yellow solid (0.16 g).
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]([CH2:8][N:9]2[CH:13]=[N:12][N:11]=[N:10]2)=[CH:6][CH:5]=1)([O-])=O.C(O)C>[C].[Pd].O1CCCC1>[NH2:1][C:4]1[CH:15]=[CH:14][C:7]([CH2:8][N:9]2[CH:13]=[N:12][N:11]=[N:10]2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(Cn2cnnn2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1ccc(Cn2cnnn2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 71 %

Procedure:
A mixture of 1-(4-nitrobenzyl)-1H-tetrazole (5 g), 10% palladium carbon (500 mg), ethanol (100 ml) and tetrahydrofuran (100 ml) was stirred under a hydrogen atmosphere at room temperature for 4 hrs. Palladium carbon was removed from the reaction mixture by filtration, and the filtrate was concentrated. Recrystallization of the residue from ethyl acetate-hexane gave 1-(4-aminobenzyl)-1H-tetrazole (3.03 g, 71%) as yellow prism crystals. melting point: 138-140° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[S:20][C:16]=3[C:15]([Br:25])=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)=[CH:4][C:3]=1[OH:26].[C:27]([O:32]C)(=[O:31])[C@@H:28]([CH3:30])O.BrBr>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[S:20][C:16]=3[C:15]([Br:25])=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)=[CH:4][C:3]=1[O:26][C@H:28]([CH3:30])[C:27]([OH:32])=[O:31]
Reactant: Oc1cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)ccc1Br
Reactant: COC(=O)[C@@H](C)O
Agent: BrBr
Product: C[C@@H](Oc1cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)ccc1Br)C(=O)O

Procedure:
Prepared from of 2-bromo-5-(6-bromo-benzo[b]naphtho[2,3-d]thiophen- 11-yl)-phenol (Example 68) and commercially available (R)-lactic acid, methyl ester. White solid: mp 133-134.5° C.: MS (-ESI): [M-H]-, 2 bromine isotope pattern 553, 555, 557; Anal. Calc. for C25H16Br2O3S: C, 53.98, H, 2.90, N, 0.00. Found: C, 53.18, H, 2.82, N, 0.04.
Reaction SMILES: [N:1]1([CH:5]2[CH2:10][CH2:9][N:8]([CH2:11][C:12]3[S:13][C:14]4[N:15]=[C:16]([Cl:27])[N:17]=[C:18]([N:21]5[CH2:26][CH2:25][O:24][CH2:23][CH2:22]5)[C:19]=4[N:20]=3)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.N1CCC(N2CC[O:37][CH2:36]C2)CC1>>[Cl:27][C:16]1[N:17]=[C:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:19]2[N:20]=[C:12]([CH2:11][N:8]3[CH2:9][CH2:10][CH:5]([N:1]4[CH2:4][CH2:3][O:37][CH2:36][CH2:2]4)[CH2:6][CH2:7]3)[S:13][C:14]=2[N:15]=1
Reactant: C1CC(N2CCOCC2)CCN1
Reactant: Clc1nc(N2CCOCC2)c2nc(CN3CCC(N4CCC4)CC3)sc2n1
Product: Clc1nc(N2CCOCC2)c2nc(CN3CCC(N4CCOCC4)CC3)sc2n1

Procedure:
Prepared according to the method used in the preparation of 2-(4-azetidin-1-ylpiperidin-1-ylmethyl)-5-chloro-7-morpholin-4-ylthiazolo[5,4-d]pyrimidine using 4-piperidin-4-ylmorpholine in place of 4-azetidin-1-ylpiperidine. The title compound was obtained as a white solid (104 mg, 67%).
Reaction SMILES: [CH3:1][C:2]([OH:10])([C:4]#[C:5][C:6]([CH3:9])(O)[CH3:7])[CH3:3].[OH2:11]>OS(O)(=O)=O>[CH3:3][C:2]1([CH3:1])[C:4](=[O:11])[CH2:5][C:6]([CH3:7])([CH3:9])[O:10]1
Reactant: O
Reactant: CC(C)(O)C#CC(C)(C)O
Agent: O=S(=O)(O)O
Product: CC1(C)CC(=O)C(C)(C)O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
Mercuric oxide (600 mg) was dissolved in 200 mL of water containing 2 mL of concentrated H2SO4. Solid 2,5-dimethyl-3-hexyne-2,5-diol (50.0 g, 352 mmol) was added and the solution was heated until the homogeneous solution turned cloudy. Heating was stopped and the flask was stirred in a room temperature water bath for 30 min. The solution was distilled and 250 mL of distillate was collected (more H2O was added). The biphasic material was taken up into ether, separated, washed with brine, dried over MgSO , filtered, evaporated and distilled (~150° C.) to give 44.5 g (89%) of dihydro-2,2,5,5-tetramethyl-3(2H)-furanone as a water-white oil. Dihydro-2,2,5,5-tetramethyl-3(2H)furanone (32.1 g, 226 mmol) in 50 mL of ether was added dropwise to a suspension of sodium hydride (18.1 g of 60%, 453 mmol) in 400 mL of ether containing two drops of ethanol and 36.5 mL (453 mmol) of ethyl formate stirred at 0° C. After stirring overnight at room temperature, the reaction mixture was taken up into water, washed with additional ether, acidified with 6N HCl and extracted into ether. The combined ether layers were washed with water and brine, dried over MgSO4, decolorized with charcoal, filtered through celite and evaporated. The solid residue was recrystallized from a small volume of ether and a large quantity of hexanes. The solid was isolated by filtration and dried to give 30.4 g (79%) of 4-hydroxymethylene-dihydro-2,2,5,5-tetramethyl-3(2H)-furanone as an off-white solid. Ethylenediamine (1.15 mL, 17.4 mmol) was added to a solution of 4-hydroxymethylene-dihydro-2,2,5,5-tetramethyl-3(2H)furanone (5.9 g, 34.7 mmol) in 40 mL of THF. This solution was refluxed for one hour. The solvents were evaporated under high vacuum with moderate heating. The solid residue was slurried in 50 mL of cold ether and filtered to give 5.3 g (76%) of off-white solid. Recrystallization from 50 mL of THF followed by drying at 70° C. (1 Torr) for 6 hours gave 4.0 g of 1,2-bis[dihydro-2,2,5,5-tetramethy13(2H)furanone-4-methyleneamino]ethane as a white solid: Anal. Calc'd for C20H32N2O4 : C, 65.93; H, 8.79; N, 7.69. Found: C, 65.68; H, 8.90; N, 7.65.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([Cl:15])=[CH:5][C:6]=1[CH:7]1[CH2:12][C:11](=[O:13])[CH2:10][C:9](=[O:14])[CH2:8]1.C1(N=C=NC2CCCCC2)CCCCC1.[C:31](O)(=[O:33])[CH3:32].Cl>CN(C)C1C=CN=CC=1.CN(C)C=O.O>[Cl:1][C:2]1[S:3][C:4]([Cl:15])=[CH:5][C:6]=1[CH:7]1[CH2:12][C:11](=[O:13])[C:10](=[C:31]([OH:33])[CH3:32])[C:9](=[O:14])[CH2:8]1
Reactant: CC(=O)O
Reactant: O=C1CC(=O)CC(c2cc(Cl)sc2Cl)C1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CC(O)=C1C(=O)CC(c2cc(Cl)sc2Cl)CC1=O
Temperature: 25 °C
Reaction time: 13 h
Yield: 70.2 %

Procedure:
To a solution of 5-(2,5-dichlorothiophen-3-yl)cyclohexane-1,3-dione (3.07 g), 4-dimethylaminopyridine (2.14 g) and dicyclohexylcarbodiimide (3.13 g) in dimethylformamide (10 ml) was added acetic acid (1.26 g), and the mixture was stirred at room temperature for 13 hours. To the mixture were added water (30 ml) and 2N hydrochloric acid (10 ml), and the mixture was extracted with ethyl acetate. The organic layer was extracted with 0.5N sodium hydroxide solution, and to the aqueous layer was added 2N hydrochloric acid to make the solution acidic. The solution was extracted with ethyl acetate, and the organic layer was washed with water. Under reduced pressure, the solvent was evaporated, and the residue was recrystallized from ethyl acetate-hexane to give 5-(2,5-dichlorothiophen-3-yl)-2-(1-hydroxyethylidene)cyclohexane-1,3-dione (2.5 g) as yellow crystals.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].P(Cl)(Cl)(Cl)=O.[Cl:14][CH2:15][C:16](Cl)=[O:17]>O>[Cl:14][CH2:15][C:16]([C:6]1[CH:5]=[C:3]([OH:4])[C:1](=[CH:8][CH:7]=1)[OH:2])=[O:17]
Reactant: Oc1ccccc1O
Reactant: O=C(Cl)CCl
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: O=C(CCl)c1ccc(O)c(O)c1
Temperature: 125 °C
Yield: 65 %

Procedure:
Similar to the procedures of R. W. Schayer (J. Am. Chem. Soc. 74, 2441 [1952]) and N. Levin et al. (J. Org. Chem. 7, 408-415 [1942]), but without an additional solvent, a mixture of 100 g catechol, 750 g (450 ml) of phosphorus oxychloride and 206 g (145 ml) of chloracetyl chloride was stirred at reflux temperature (ca. 125° C.) in an argon atmosphere for 4.5 hours. Then most of the volatiles were distilled off at 80° C. (bath temperature) and, finally, under reduced pressure. To the nearly intractable dark mass were added at ca 80° C. 200 ml of water upon which the mixture became stirabel again. 600 ml of cold (0° C.) water were added in portions to control the exothermic reaction. When all of the water was added and the exothermic reaction had ceased the mixture was stirred for 2 hours under reflux. Upon stirring over night without further heating 125 g of crude product precipitated as dark brown crystals with a purity of about 90% (yield ca. 65%).
Reaction SMILES: CC1(C)C[O:6][C:5]([CH2:14][S:15][C@H:16]2[C:19](=[O:20])[N:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@@H:17]2[C:27]2[CH:37]=[CH:36][C:30]([O:31][CH2:32][C:33]([OH:35])=O)=[CH:29][CH:28]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)OC1.CN1CCOCC1.Cl.[NH2:47][CH2:48][C:49]([NH:51][C@@H:52]([C:56]([O:58]C(C)(C)C)=[O:57])[CH:53]([CH3:55])[CH3:54])=[O:50].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[BH4-].[Na+]>C(Cl)Cl>[OH:6][CH:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:14][S:15][C@H:16]1[C:19](=[O:20])[N:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@@H:17]1[C:27]1[CH:37]=[CH:36][C:30]([O:31][CH2:32][C:33]([NH:47][CH2:48][C:49]([NH:51][C@@H:52]([C:56]([OH:58])=[O:57])[CH:53]([CH3:54])[CH3:55])=[O:50])=[O:35])=[CH:29][CH:28]=1
Reactant: CC(C)[C@@H](NC(=O)CN)C(=O)OC(C)(C)C
Reactant: CC1(C)COC(CS[C@H]2C(=O)N(c3ccccc3)[C@@H]2c2ccc(OCC(=O)O)cc2)(c2ccccc2)OC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)[C@@H](NC(=O)CNC(=O)COc1ccc([C@@H]2[C@@H](SCC(O)c3ccccc3)C(=O)N2c2ccccc2)cc1)C(=O)O
Reaction time: 0.17 h

Procedure:
[4-((2R,3R)-3-{[(5,5-Dimethyl-2-phenyl-1,3-dioxan-2-yl)methyl]thio}-4-oxo-1-phenylazetidin-2-yl)phenoxy]acetic acid (12.6 mg, 0.024 mmol) and N-methylmorpholine (15 μl, 0.14 mmol) were dissolved in DCM (2 ml). Additional DCM (2 ml), N-methylmorpholine (20 μl, 0.18 mmol) and tert-butyl glycyl-D-valinate hydrochloride, (9.0 mg, 0.034 mmol) were added after 0.5 h and the mixture was stirred for 10 minutes. TBTU (10.5 mg, 0.033 mmol) was added and the mixture was stirred overnight. The formation of the ester was confirmed. M/z: 746.1. The solvent was removed under reduced pressure and the residue was purified with preparative HPLC on a C8 column. A gradient from 20% to 50% MeCN in 0.1 M ammonium acetate buffer was used as eluent. After lyophilisation, the obtained compound was dissolved in DCM (2 ml) and TFA (1 ml) was added. The reaction mixture was stirred for 2.5 h. The hydrolysis of the ester was confirmed. M/z: 604.2. The solvent was removed under reduced pressure. Co-evaporation with toluene was performed to assist the removal of TFA. The residue was dissolved in methanol (2 ml) and sodium borohydride (9.2 mg, 0.24 mmol) was added. After 15 minutes, the solvent was evaporated off and the residue was purified with preparative HPLC on a C8 column. A gradient from 20% to 50% MeCN in 0.1 M ammonium acetate buffer was used as eluent. After lyophilisation, the title compound was obtained as a white solid was (4.0 mg, 28%). H-NMR (400 MHz, DMSO-d6): 0.78 (d, 6H), 1.95-2.04 (m, 1H), 2.83-2.97 (m, 2H), 3.76 (d, 2H), 3.89-3.95 (m, 1H), 4.26 (d, 0.5H), 4.30 (d, 0.5H), 4.51 (s, 2H), 4.67-4.75 (m, 1H), 5.01 (d, 0.5H), 5.03 (d, 0.5H), 6.98 (d, 2H), 7.03 (t, 1H), 7.17-7.22 (m, 3H), 7.23-7.32 (m, 6H), 7.36 (d, 2H), 7.55-7.65 (m, 1H), 8.29 (t, 1H). M/z: 603.96 (M−H).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:8](=[CH:9][CH:10]=1)[CH:7]([C:11]#[N:12])[CH2:6]2.B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[CH:4]=[C:5]2[C:8](=[CH:9][CH:10]=1)[CH:7]([C:11]#[N:12])[CH2:6]2
Reactant: COc1ccc2c(c1)CC2C#N
Agent: BrB(Br)Br
Solvent: ClCCl
Product: N#CC1Cc2cc(O)ccc21
Temperature: 0 °C
Reaction time: 8 h

Procedure:
68.7 g (431.6 mmol) of 3-methoxybicyclo[4.2.0]octa-1,3,5-triene-7-carbonitrile dissolved in 1500 mL of dichloromethane are brought to 0° C. There are then added, dropwise, over 1 hour 15 minutes, 863 mL of a 1M solution of boron tribromide in dichloromethane (863 mmol/2 eq.). The mixture is then allowed to come back up to ambient temperature overnight. The mixture is brought back to about 0° C. and is poured onto 1 kg of ice. Stirring is carried out for 30 minutes at ambient temperature, the phases are separated and the aqueous phase is extracted again twice with 500 mL of dichloromethane. The combined organic phases are washed with 600 mL of water and then dried over magnesium sulphate. After filtration and concentration, the desired product is obtained.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([NH2:15])[C:13]=1[Cl:14])[C:8]([OH:10])=[O:9])(=[O:4])=[O:3].[CH:16](=O)[C:17]1[O:21][CH:20]=[CH:19][CH:18]=1>O>[CH:16](=[N:15][C:12]1[CH:11]=[C:7]([CH:6]=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[C:13]=1[Cl:14])[C:8]([OH:10])=[O:9])[C:17]1[O:21][CH:20]=[CH:19][CH:18]=1
Reactant: CS(=O)(=O)c1cc(C(=O)O)cc(N)c1Cl
Reactant: O=Cc1ccco1
Solvent: O
Product: CS(=O)(=O)c1cc(C(=O)O)cc(N=Cc2ccco2)c1Cl
Reaction time: 1 h

Procedure:
A mixture of 3-methylsulfonyl-4-chloro-5-aminobenzoic acid (3.0 g.; 0.012 mole) and furfural (50 ml.) is heated to 70°-80° C. on a water bath. The water formed during the reaction is azeotropically distilled with the excess furfural at 15 mm Hg. pressure during a one hour period. The reaction mixture is cooled and triturated with carbon tetrachloride (100 ml.) to yield 3.6 g. (90%) of 3-furfurylideneamino-4-chloro-5-methylsulfonylbenzoic acid which melts at 221° C. and is used in Step E without further purification.
Reaction SMILES: [OH:1][CH2:2][C@H:3]([N:5]1[C:13]2[C:8](=[C:9]([C:16]([F:19])([F:18])[F:17])[C:10]([C:14]#[N:15])=[CH:11][CH:12]=2)[CH:7]=[C:6]1[CH3:20])[CH3:4].[F:21][C:22]1[N:27]=[CH:26][C:25](O)=[CH:24][CH:23]=1>>[F:21][C:22]1[N:27]=[CH:26][C:25]([O:1][CH2:2][C@H:3]([N:5]2[C:13]3[C:8](=[C:9]([C:16]([F:19])([F:17])[F:18])[C:10]([C:14]#[N:15])=[CH:11][CH:12]=3)[CH:7]=[C:6]2[CH3:20])[CH3:4])=[CH:24][CH:23]=1
Reactant: Oc1ccc(F)nc1
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1[C@H](C)CO
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1[C@H](C)COc1ccc(F)nc1

Procedure:
Synthesized as described in Example 139C using 1-[(1R)-2-hydroxy-1-methylethyl]-2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 329) and 6-fluoro-3-pyridinol: MS (ES) m/z 378 (M+1).
Reaction SMILES: C([Mg]Br)C.[Cl:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=1)[O:9][CH2:10][C:11]#[CH:12].[C-]#N.Br[CH2:19][C:20]#[C:21][CH2:22][C:23]#[CH:24]>CCOCC.O1CCCC1>[Cl:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=1)[O:9][CH2:10][C:11]#[C:12][CH2:19][C:20]#[C:21][CH2:22][C:23]#[CH:24]
Reactant: C#CCC#CCBr
Reactant: C#CCOc1cccc(Cl)c1
Agent: CC[Mg]Br
Agent: [C-]#N
Solvent: C1CCOC1
Solvent: CCOCC
Product: C#CCC#CCC#CCOc1cccc(Cl)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
21.76 ml (9.8 g, 0.735 mmol) of a 3.38N solution of ethylmagnesium bromide in ether was added dropwise, under argon to a cold (0°-5° C.) solution of 11.66 g (0.7 mol) of 3-(m-chlorophenoxy)-1-propyne [I. Iway, et al., Chem. Pharm. Bull., 11, 1042 (1963)] in 80 ml of anhydrous tetrahydrofuran. The rate was monitoredto maintain a temperature of 0° C. Thereafter, the reaction mixture was stirred for 1 hour further at 0°-5° C. Then, 31.35 mg ofcuprous cyanide were added and the mixtured stirred 20 minutes more. Then asolution of 5.5 g (0.035 mol) of 1-bromo-2,5-hexadiyne in 20 ml of anhydrous tetrahydrofuran was added dropwise to the mixture as the temperature was maintained at between 0°-5° C. Then the reaction was stirred at room temperature for 3 additional hours and quenched with 200 ml of 1N sulfuric acid and ice. After extraction with ether (3×200 ml), the combined organic extracts were concentrated invacuo to a small volume, and washed several times with EDTA and water, dried over sodium sulfate and evaporated in vacuo. The residue was purified by column chromatography on 350 g of silica gel, using hexane as eluant, and the product crystallized from methylene chloride-hexane, to yield 9-(m-chlorophenoxy)-1,4,7-nonatriyne, as an oil. The product was stored in dry ice.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](/[CH:10]=[CH:11]/[C:12]([OH:14])=O)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[CH3:15][NH:16][CH3:17].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4](/[CH:10]=[CH:11]/[C:12]([N:16]([CH3:17])[CH3:15])=[O:14])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: CNC
Reactant: COc1ncc(Br)cc1/C=C/C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ncc(Br)cc1/C=C/C(=O)N(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.2 %

Procedure:
To a solution of (2E)-3-(5-bromo-2-methoxypyridin-3-yl)acrylic acid (1.00 g, 3.87 mmol) in DCM (10 mL) were added dimethylamine (2.0 M in THF, 5.80 mmol), DIEA (2.02 mL, 11.6 mmol) and TBTU (1.49 g, 4.65 mmol). The reaction mixture was allowed to stir at rt overnight. The reaction was quenched with water and then the aqueous solution was extracted with DCM. The organic solutions were combined, washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to give (2E)-3-(5-bromo-2-methoxypyridin-3-yl)-N,N-dimethylacrylamide (1.05 g, 95%) as a white solid. LCMS (FA): Rt=1.68 min, m/z=285.1 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[S:16][C:15]3[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:14]=3[C:13]=2[CH3:22])(=[O:11])=[O:10])=[C:4]([C:23]([F:26])([F:25])[F:24])[CH:3]=1.[F:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][N:29]=1>COCCOC.C(O)C.C(=O)([O-])[O-].[Na+].[Na+].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>[F:27][C:28]1[N:29]=[CH:30][C:31]([C:2]2[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]3[S:16][C:15]4[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:14]=4[C:13]=3[CH3:22])(=[O:11])=[O:10])=[C:4]([C:23]([F:26])([F:25])[F:24])[CH:3]=2)=[CH:32][CH:33]=1
Reactant: Cc1c(S(=O)(=O)Nc2ccc(Br)cc2C(F)(F)F)sc2ccc(F)cc12
Reactant: OB(O)c1ccc(F)nc1
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: CCO
Solvent: COCCOC
Product: Cc1c(S(=O)(=O)Nc2ccc(-c3ccc(F)nc3)cc2C(F)(F)F)sc2ccc(F)cc12
Yield: 56.4 %

Procedure:
This compound was prepared in analogy to Example 2 starting from 5-fluoro-3-methyl-benzo[b]thiophene-2-sulfonic acid(4-bromo-2-trifluoromethyl-phenyl)-amide (0.12 g) and 2-fluoropyridine-5-boronic acid (0.072 g) in 1,2-dimethoxyethane (1.5 ml), ethanol (0.32 ml) and 2 M aqueous sodium carbonate solution (1.0 ml) with tetrakis(triphenylphosphine)palladium (0.015 g) to obtain the title compound (0.070 g) as a colorless solid. MS (ISP): 485.3 (M+H)+
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]2[C:14]3[C:15]([S:38][C:10]=2[CH2:9]1)=[N:16][C:17]([CH2:31][N:32]1[CH2:36][CH2:35][CH2:34][C:33]1=[O:37])=[C:18]([Cl:30])[C:19]=3[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=1)C1C=CC=CC=1.[N+](C1C=CC=CC=1)([O-])=O>[Pd].C1(C)C(C)=CC=CC=1>[Cl:30][C:18]1[C:19]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)=[C:14]2[C:11]3[C:10](=[CH:9][N:8]=[CH:13][CH:12]=3)[S:38][C:15]2=[N:16][C:17]=1[CH2:31][N:32]1[CH2:36][CH2:35][CH2:34][C:33]1=[O:37]
Reactant: COc1ccc(-c2c(Cl)c(CN3CCCC3=O)nc3sc4c(c23)CCN(Cc2ccccc2)C4)cc1OC
Agent: [Pd]
Solvent: O=[N+]([O-])c1ccccc1
Solvent: Cc1ccccc1C
Product: COc1ccc(-c2c(Cl)c(CN3CCCC3=O)nc3sc4cnccc4c23)cc1OC
Yield: 10.1 %

Procedure:
A mixture of the compound obtained in Example 28B (3.0 g), palladium on carbon (5%, 5.0 g), nitrobenzene (1.3 g) and xylene (100 ml) was stirred under reflux for 4 hours and the insoluble solid was filtered off. The filtrate was concentrated in vacuo and the residue was chromatographed on SiO2 with ethyl acetate to give 3-chloro-4-(3,4-dimethoxyphenyl)-2-(2-oxopyrrolidin-1-ylmethyl)thieno[2,3-b:5,4-c']dipyridine (0.25 g, 10%) as crystals. Recrystallization from ethyl acetate-hexane give colorless prisms, m.p. 228-230° C.
Reaction SMILES: Cl.[F:2][C:3]([F:14])([F:13])[C:4]1[CH:9]=[CH:8][C:7]([C:10](=[NH:12])[NH2:11])=[CH:6][CH:5]=1.[Cl:15][C:16]([SH:19])(Cl)Cl.[OH-].[Na+]>ClCCl.O>[Cl:15][C:16]1[S:19][N:11]=[C:10]([C:7]2[CH:6]=[CH:5][C:4]([C:3]([F:13])([F:14])[F:2])=[CH:9][CH:8]=2)[N:12]=1
Reactant: N=C(N)c1ccc(C(F)(F)F)cc1
Reactant: SC(Cl)(Cl)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: FC(F)(F)c1ccc(-c2nsc(Cl)n2)cc1
Temperature: 25 °C
Yield: 29.1 %

Procedure:
To a solution of 4-(trifluoromethyl)benzenecarboximidamide hydrochloride (2.60 g, 10.0 mmol) and perchloromethyl mercaptan (1.07 ml, 10.0 mmol) in dichloromethane (10 ml) was added dropwise a solution of sodium hydroxide (1.60 g, 40.0 mmol) in water (4 ml) under ice-cooling. Then, the reaction mixture was stirred under ice-cooling for 1 hour and at room temperature for 1 hour. The organic layer was separated, washed with water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give 770 mg (29.2%) of the desired product as an oil.