Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]=[CH:2]C(=C)C.[CH2:6]([O:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][O:11]1)[C:7]#[CH:8].C(Br)C>CCCCCC>[CH2:6]([O:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][O:11]1)[C:7]#[C:8][CH2:1][CH3:2]
Reactant: C=CC(=C)C
Reactant: C#CCOC1CCCCO1
Solvent: CCCCCC
Solvent: CCBr
Product: CCC#CCOC1CCCCO1
Reaction time: 0.25 h
Yield: 105.3 %

Procedure:
0.89 g (127 mmol) of granulated lithium were added within 5 minutes to 100 ml (4 mol) of liquid ammonia at −38° C. The mixture was stirred until no more lithium floated (after approximately 10 minutes). A dark blue solution of lithium in liquid ammonia was obtained. Isoprene (5.94 g, 86 mmol) was added portion wise within 20 minutes. The reaction mixture was held at −38° C. for about 15 minutes. The end of the formation of Li-amide could be recognized by the de-coloration of the reaction mixture. 11.33 g (70 mmol) of 2-prop-2-ynyloxy-tetrahydropyran were added via a dropping funnel to the reaction mixture at −38° C. within 20 minutes. The reaction mixture was held at −38° C. for about 1 hour. Ethyl bromide 14.0 g (126 mmol) was added via a dropping funnel to the reaction mixture within 20 minutes. The reaction mixture was subsequently stirred for 1 hour. 100 ml n-hexane was added to the reaction mixture and the liquid ammonia was evaporated under normal pressure within 1.5 hours. 50 ml of water was added to the reaction mixture at 22° C., and the mixture was stirred until all salt was dissolved. The water layer was extracted twice with 50 ml n-hexane. The organic layer was dried over 5 g of anhydrous sodium sulfate. The solution was concentrated under reduced pressure (40° C., 60 mbar) and the crude product was analyzed by GC. Crude 2-pent-2-ynyloxy-tetrahydro-pyran (12.4 g) was obtained with a purity of 90.1% (94.3% yield based on 2-prop-2-ynyloxy-tetrahydropyran).
Reaction SMILES: [Mg].Br[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([O:13][CH3:14])[CH:7]=[CH:6]2.[CH2:15]([CH:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1)[CH2:16][CH3:17].Cl>O1CCCC1>[CH3:14][O:13][C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([C:21]3[CH2:22][CH2:23][CH:18]([CH2:15][CH2:16][CH3:17])[CH2:19][CH:20]=3)[CH:4]=2)[CH:9]=1
Reactant: CCCC1CCC(=O)CC1
Reactant: COc1ccc2cc(Br)ccc2c1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCC1CC=C(c2ccc3cc(OC)ccc3c2)CC1
Reaction time: 1 h
Yield: 75.8 %

Procedure:
5.7 g of magnesium was suspended in 12 ml of tetrahydrofuran. To the suspension was then added dropwise a solution of 50 g of 6-bromo-2-methoxynaphthalene in 200 ml of tetrahydrofuran at a rate such that tetrahydrofuran was gently refluxed. The reaction mixture was then further stirred for 1 hour. To the reaction solution was then added dropwise a solution of 30 g of 4-propylcyclohexanone in 120 ml of tetrahydrofuran at room temperature. The reaction mixture was then further stirred for 1 hour. To the reaction solution was then added 200 ml of a 10% hydrochloric acid. The reaction mixture was extracted with 300 ml of toluene, washed with water, saturated aqueous solution of sodium bicarbonate and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was then distilled off. To the residue were then added 230 ml of toluene and 4.0 g of p-toluenesulfonic acid monohydrate. The reaction mixture was then heated under reflux for 3 hour. The reaction solution was allowed to cool to root temperature, washed with water, saturated aqueous solution of sodium bicarbonate and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was then distilled off. The residue was then recrystallized from ethanol to obtain 44.8 g of 2-methoxy-6-(4-propylcyclohexa-1-ene-1-yl)naphthalene.
Reaction SMILES: O[C:2]1([CH3:28])[CH:7]([C:8]([O:10][CH3:11])=[O:9])[CH:6]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[C:5]([C:22]([O:24][CH3:25])=[O:23])=[C:4]([NH:26][CH3:27])[CH2:3]1.S(Cl)(Cl)=O>N1C=CC=CC=1>[CH3:28][C:2]1[CH:7]([C:8]([O:10][CH3:11])=[O:9])[CH:6]([C:12]2[CH:13]=[CH:14][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:16][CH:17]=2)[C:5]([C:22]([O:24][CH3:25])=[O:23])=[C:4]([NH:26][CH3:27])[CH:3]=1
Reactant: CNC1=C(C(=O)OC)C(c2ccc(C(F)(F)F)cc2)C(C(=O)OC)C(C)(O)C1
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: CNC1=C(C(=O)OC)C(c2ccc(C(F)(F)F)cc2)C(C(=O)OC)C(C)=C1
Temperature: 60 °C
Reaction time: 0.17 h

Procedure:
10.0 g (25 mmol) of dimethyl 6-hydroxy-6-methyl-4-methylamino-2-(4-trifluoromethylphenyl)-cyclohex-3-ene-1,3-dicarboxylate (preparation analogous to Example II) are heated to 60° C. in 100 ml of pyridine and treated with 2.5 ml of thionyl chloride. The mixture is stirred at 60° C. for 10 minutes and concentrated, and the residue is taken up in methylene chloride, washed three times with water, dried and concentrated. The residue is grossly purified on 200 g of silica gel (petroleum ether/AcOEt=3:1) and then separated by MPLC (methylene chloride/AcOEt=30:1). Two fractions are obtained. 224 mg (2.3%) of dimethyl 4-methyl-6-methylamino-2-(4-trifluoromethylphenyl)-cyclohexa-3,6-diene-1,3-dicarboxylate (non-polar isomer (2)) crystallize from ether/petroleum ether. From the 2nd fraction, 2.29 g (22%) of the polar isomer, dimethyl 6-methyl-4-methylamino-2-(4-trifluoromethylphenyl)-cyclohexa-3,5-diene-1,3-dicarboxylate (3) are precipitated from AcOEt as the hydrochloride (Rf =0.47 (c)).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH2:28]([C:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][NH:38][C:39]([C:41]2([CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=3[F:54])[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)=[O:40])=[CH:32][CH:31]=1)[CH3:29].[F:55][C:56]1[CH:61]=[CH:60][C:59]([CH2:62][CH2:63][C:64](O)=[O:65])=[CH:58][CH:57]=1.C(N(CC)CC)C>O1CCCC1.C(OCC)C>[CH2:28]([C:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][NH:38][C:39]([C:41]2([CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=3[F:54])[CH2:42][CH2:43][N:44]([C:64](=[O:65])[CH2:63][CH2:62][C:59]3[CH:60]=[CH:61][C:56]([F:55])=[CH:57][CH:58]=3)[CH2:45][CH2:46]2)=[O:40])=[CH:32][CH:31]=1)[CH3:29]
Reactant: O=C(O)CCc1ccc(F)cc1
Reactant: CCc1ccc(CCNC(=O)C2(Cc3ccccc3F)CCNCC2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCc1ccc(CCNC(=O)C2(Cc3ccccc3F)CCN(C(=O)CCc3ccc(F)cc3)CC2)cc1
Yield: 40.3 %

Procedure:
Benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (0.266 g, 0.602 mmol) was added to a solution of 4-(2-fluoro-benzyl)-piperidine-4-carboxylic acid [2-(4-ethyl-phenyl)-ethyl]-amide (0.185 g, 0.502 mmol), 3-(4-fluoro-phenyl)-propionic acid (0.101 g, 0.602 mmol) and triethylamine (0.210 mL, 1.51 mmol) in tetrahydrofuran (5 mL). After 1 h the mixture was diluted with ethyl ether (20 mL), washed with saturated aqueous sodium bicarbonate (20 mL) followed by water (2×10 mL). The organic layer was collected, concentrated under reduced pressure and the crude product purified by column chromatography to give 0.105 g (40 %) of 4-(2-fluoro-benzyl)-1-[3-(4-fluoro-phenyl)-propionyl]-piperidine-4-carboxylic acid [2-(4-ethyl-phenyl)-ethyl]-amide LRMS m/z 519.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[S:8][C:9]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:10][N:11]=2)[O:6]CCO1.[F:19][C:20]([F:33])([F:32])[C:21]1[CH:26]=[CH:25][C:24](/[CH:27]=[CH:28]/[C:29](O)=[O:30])=[CH:23][CH:22]=1>>[C:2]([C:7]1[S:8][C:9]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:29](=[O:30])/[CH:28]=[CH:27]/[C:24]3[CH:23]=[CH:22][C:21]([C:20]([F:32])([F:33])[F:19])=[CH:26][CH:25]=3)[CH:15]=[N:14]2)=[CH:10][N:11]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)/C=C/c1ccc(C(F)(F)F)cc1
Reactant: CC1(c2ncc(Cn3ncc(N)n3)s2)OCCO1
Product: CC(=O)c1ncc(Cn2ncc(NC(=O)/C=C/c3ccc(C(F)(F)F)cc3)n2)s1

Procedure:
Following general procedure A followed by B, starting from 2-[2-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-5-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and (E)-3-(4-trifluoromethyl-phenyl)-acrylic acid.
Reaction SMILES: C([C:3]1[O:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[CH:7]=1)#N.N.[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>>[N:13]1([C:3]2[O:4][C:5]3[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=3[CH:7]=2)[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1
Reactant: C1CNCCN1
Reactant: N#Cc1cc2ccccc2o1
Agent: N
Product: c1ccc2oc(N3CCNCC3)cc2c1

Procedure:
In step 1 of Scheme C, bromophenol n undergoes iodination to form bromo-iodo-phenol o. Phenol compound o is then reacted with cinnamoyl halide p in step 2 to afford phenoxy ester compound g. Compound g undergoes a cyclization in step 3 to form benzofuran compound r. In step 4 compound r is reacted with dimethyl formamide in the presence of phosphorus oxychloride to afford benzofuran-2-carboxaldehyde s. Aldehyde compound s is converted to cyano-benzofuran compound t in step 5 by reaction with aqueous ammonia. In step 6 a Buchwald reaction is carried out by reacting compound t with piperazine compound f to afford piperazinyl benzofuran u. The nitrile group of compound u undergoes oxidation in step 7 to give benzofuran carboxamide compound v. Compound v is then deprotected in step 8 to afford compound w, which is a compound of formula II in accordance with the invention.
Reaction SMILES: [I-].[K+].Br[CH:4]([C:6]1[CH:7]=[C:8]([C:23]([O:25][CH3:26])=[O:24])[CH:9]=[C:10]2[C:15]=1[O:14][C:13]([N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)=[CH:12][C:11]2=[O:22])[CH3:5].[F:27][C:28]1[CH:29]=[C:30]([CH:33]=[C:34]([F:36])[CH:35]=1)[NH:31][CH3:32]>C(Cl)(Cl)Cl.CO>[F:27][C:28]1[CH:29]=[C:30]([N:31]([CH3:32])[CH:4]([C:6]2[CH:7]=[C:8]([C:23]([O:25][CH3:26])=[O:24])[CH:9]=[C:10]3[C:15]=2[O:14][C:13]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[CH:12][C:11]3=[O:22])[CH3:5])[CH:33]=[C:34]([F:36])[CH:35]=1
Reactant: CNc1cc(F)cc(F)c1
Reactant: COC(=O)c1cc(C(C)Br)c2oc(N3CCOCC3)cc(=O)c2c1
Agent: [I-]
Agent: [K+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(C(C)N(C)c2cc(F)cc(F)c2)c2oc(N3CCOCC3)cc(=O)c2c1
Temperature: 25 °C
Yield: 81.2 %

Procedure:
Potassium iodide (1.521 g, 9.16 mmol) was added to a suspension of methyl 8-(1-bromoethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxylate (3.3 g, 8.33 mmol, as described in Example 2.00) and 3,5-difluoro-N-methylaniline (3.58 g, 24.99 mmol) in CHCl3 (16 mL) and MeOH (4 mL). The mixture was stirred at RT over the weekend. The reaction mixture was concentrated to dryness and the resulting dark oil was triturated with diethyl ether to give a solid which was collected by filtration. This solid was suspended in water and pH was adjusted to 6-7 with 2N NaOH. The crude product was filtered and washed with ether, dried and purified by flash chromatography on silica gel eluting with 0 to 10% MeOH in DCM. The solvent was evaporated to dryness to afford methyl 8-(1-((3,5-difluorophenyl)(methyl)amino)ethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxylate (3.1 g, 81%) as a white solid. Mass Spectrum: M+H+ 459.
Reaction SMILES: [OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[F:12][C:13]([F:24])([F:23])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]=[C:21]=[O:22]>>[OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH:4][C:21]([NH:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:13]([F:12])([F:23])[F:24])=[O:22]
Reactant: O=C=Nc1ccccc1C(F)(F)F
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Product: O=C(Nc1ccc([N+](=O)[O-])cc1O)Nc1ccccc1C(F)(F)F
Yield: 52.7 %

Procedure:
N-(2-Hydroxy-4-nitrophenyl)-N'-(2-trifluoromethylphenyl)urea was prepared from 2-hydroxy 4-nitro aniline (154 mg, 1.0 mmol) and 2-trifluoromethyl phenyl isocyanate (1.0 mmol) according to the procedure in General Method B. The product was purified by dilution with methylene chloride and precipitation with hexanes. Filtering afforded the title compound (180 mg, 52%). EI-MS m/z 342(M+H)+
Reaction SMILES: [CH:1]([O:3][CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([CH2:11][OH:12])[CH2:7][CH2:6]1)=[CH2:2].[CH3:13][S:14](Cl)(=[O:16])=[O:15].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:13][S:14]([O:12][CH2:11][CH:8]1[CH2:9][CH2:10][CH:5]([CH2:4][O:3][CH:1]=[CH2:2])[CH2:6][CH2:7]1)(=[O:16])=[O:15]
Reactant: CS(=O)(=O)Cl
Reactant: C=COCC1CCC(CO)CC1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: C=COCC1CCC(COS(C)(=O)=O)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 61.6 %

Procedure:
4-[(Vinyloxy)methyl]cyclohexylmethanol (2.0 g, 0.010 mol) was dissolved in chloroform (20 mL), cooled to 0° C., and then methanesulfonyl chloride (0.85 mL, 0.011 mol) and triethylamine (1.5 mL, 0.011 mol) were added. The reaction was stirred at 0° C. for 2 hours. The reaction was extracted with ethyl acetate, and the extracts were washed with water, brine, and then dried over MgSO4 and concentrated. The product was purified via column chromatography on silica gel (40% ethyl acetate, 60% hexanes), to give 1.53 g of the desired product as a 3:1 mixture of the two diastereomers. 1H NMR (400 MHz, CDCl3): δ 6.36-6.41 (m, 1H), 4.04-4.10 (m, 2H), 3.94-3.96 (m, 2H), 3.39-3.43 (m, 2H), 2.92 (s, 3H), 0.90-1.80 (m, 10H) (major diastereomer).
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[K+].C(S[CH:10]([C:36]1[CH:40]=[CH:39][N:38]([CH2:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])[N:37]=1)[C:11]1[CH2:16][N:15]([C:17]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:14][CH2:13][CH:12]=1)(=O)C>CS(C)=O.C(OCC)(=O)C>[C:1]([S:3][CH:12]1[CH2:13][CH2:14][N:15]([C:17]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:16][C:11]1=[CH:10][C:36]1[CH:40]=[CH:39][N:38]([CH2:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])[N:37]=1)(=[O:4])[CH3:2]
Reactant: CCOC(=O)CCn1ccc(C(SC(C)=O)C2=CCCN(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2)n1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCOC(=O)CCn1ccc(C=C2CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)CCC2SC(C)=O)n1
Temperature: 80 °C
Reaction time: 4 h
Yield: 97.7 %

Procedure:
Potassium thioacetate (5.91 g) was added to a solution of 5-((acetylsulfanyl){1-[2-(ethoxycarbonyl)ethyl]-1H-pyrazol-3-yl}methyl)-1-(triphenylmethyl)-1,2,3,6-tetrahydropyridine (3.00 g), in dimethyl sulfoxide (30 ml). The mixture was stirred at 80° C. for 4 hours. After cooling to room temperature, the mixture was diluted with ethyl acetate, and washed successively with water and a saturated aqueous sodium chloride solution. After the extract was dried over anhydrous sodium sulfate, it was concentrated under reduced pressure, and the residue was purified by silica gel chromatography using ethyl acetate and hexane (1:9 to 2:3) as eluents to afford a crude product of 4-(acetylsulfanyl)-3-({1-[2-(ethoxycarbonyl)ethyl]-1H-pyrazol-3-yl}methylidene)-1-(triphenylmethyl)piperidine (2.93 g) as a mixture of geometric isomers.
Reaction SMILES: [CH:1]1([NH:7][N:8]2[NH:12][CH:11]=[C:10]([C:13]3[N:14]([CH3:21])[C:15]([N+:18]([O-:20])=[O:19])=[CH:16][N:17]=3)[S:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:22](N)[CH2:23]CCCCCC.C1(N)CCCCC1>>[CH2:1]([NH:7][N:8]1[NH:12][CH:11]=[C:10]([C:13]2[N:14]([CH3:21])[C:15]([N+:18]([O-:20])=[O:19])=[CH:16][N:17]=2)[S:9]1)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:22][CH3:23]
Reactant: CCCCCCCCN
Reactant: Cn1c([N+](=O)[O-])cnc1C1=CNN(NC2CCCCC2)S1
Solvent: NC1CCCCC1
Product: CCCCCCCCNN1NC=C(c2ncc([N+](=O)[O-])n2C)S1

Procedure:
The preparation of the above compound is carried out essentially as described for the 2-cyclohexylamino derivative (Example 38), an equivalent of n-octylamine replacing the cyclohexylamine. The crude product is purified by recrystallization from aqueous 2-methoxyethanol and then melts at 130°-132° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([N+:19]([O-])=O)=[N:8][CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=1.O>C(O)(=O)C.[Zn]>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([NH2:19])=[N:8][CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=1
Reactant: COCCOc1cc(Oc2ccccc2)cnc1[N+](=O)[O-]
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: COCCOc1cc(Oc2ccccc2)cnc1N
Temperature: 100 °C
Yield: 76 %

Procedure:
3-(2-Methoxy-ethoxy)-2-nitro-5-phenoxy-pyridine (0.4 mmol) is dissolved in acetic acid (1.3 ml). After addition of water (1.3 ml), zinc powder (6 eq.) is added and the reaction suspension is heated to 100° C. for 3 h. The reaction suspension is cooled to room temperature and filtrated. The filtrate is pored into 3.5% NaOH (30 ml) and extracted with dichloromethane. The combined organic layers are extracted with brine, dried over MgSO4 and the solvent is removed in vacuo. 3-(2-Methoxyethoxy)-5-phenoxy-pyridine-2-ylamine is obtained as brown oil in a yield of 76%. HPLC (method C): 1.43 min; LC-MS (method A): 0.808 min, 261.15 (M+H+).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([C:14]#[C:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[CH:13]=1)[O:10][C:9]([CH3:21])([CH3:20])[CH2:8][C:7]2([CH3:23])[CH3:22])(=O)[CH3:2].C([N-]C(C)C)(C)C.[Li+].P(Cl)(OCC)(OCC)=O>O1CCCC1>[C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([C:14]#[C:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[CH:13]=1)[O:10][C:9]([CH3:21])([CH3:20])[CH2:8][C:7]2([CH3:23])[CH3:22])#[CH:2]
Reactant: CC(=O)c1cc(C#C[Si](C)(C)C)c2c(c1)C(C)(C)CC(C)(C)O2
Agent: CC(C)[N-]C(C)C
Agent: CCOP(=O)(Cl)OCC
Agent: [Li+]
Solvent: C1CCOC1
Product: C#Cc1cc(C#C[Si](C)(C)C)c2c(c1)C(C)(C)CC(C)(C)O2
Temperature: 0 °C
Reaction time: 0.83 h
Yield: 49.7 %

Procedure:
A solution of 6-acetyl-8-trimethylsilanylethynyl-2,2,4,4-tetramethyl chroman (Compound 36, 0.616 g, 1.88 mmol) in anhydrous tetrahydrofuran (3 mL) was cannulated into a stirred, cooled (−78° C.) solution of lithium diisopropyl amide [2.82 mmol in 2 mL of tetrahydrofuran generated from N,N-diisopropyl amine (0.4 mL, 2.82 mmol) and 1.6M solution of n-butyl lithium in hexanes (1.88 mL, 3 mmol)] and the resulting reaction mixture was stirred at the same temperature for 50 min. Diethyl chlorophosphate (0.35 mL, 2.44 mol) was then added and the reaction mixture was allowed to warm to 0° C. over 1.5 h. The reaction mixture was then cannulated into a stirred, cooled (−78° C.) solution of lithium diisopropyl amide [8.46 mmol in 3 mL of tetrahydrofuran generated from N,N-diisopropyl amine (1.2 mL, 8.46 mmol) and 1.6M solution of n-butyl lithium in hexanes (5.64 mL, 9 mmol)]. The reaction mixture was allowed to warm to −30° C. over 2 h. It was then quenched with water and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to a residue that was subjected to flash column chromatography over silica gel (230-400 mesh) using 1-2.5% ethyl acetate in hexane as the eluent to afford the title compound as a white solid (0.29 g, 50%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[C:13]([OH:15])=O.C(Cl)(=O)C(Cl)=O.[CH2:22]([CH2:24][NH2:25])[OH:23].C(N(CC)CC)C.Cl>ClCCl>[OH:23][CH2:22][CH2:24][NH:25][C:13]([C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[CH:12][C:3]=1[O:2][CH3:1])=[O:15]
Reactant: NCCO
Reactant: COc1ccc2ccccc2c1C(=O)O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc2ccccc2c1C(=O)NCCO
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A solution of 2-methoxy-naphthalene-1-carboxylic acid (0.50 g, 2.5 mmol) in anhydrous dichloromethane at 0° C. was treated dropwise with a 2.0 M solution of oxalyl chloride in dichloromethane (1.9 mL, 3.8 mmol). The resulting solution was stirred under a N2 atmosphere at 0° C. for 20 min, then allowed to warm to r.t. and stirred 1 hr. The solution was cooled to 0° C., and ethanolamine (0.3 mL, 5.0 mmol) and triethylamine (1.0 mL, 7.2 mmol) were added. The resulting mixture was stirred at 0° C. for 15 min, then allowed to warm to r.t. and stirred 90 min. The mixture was poured into 1N HCl (20 mL) and extracted with dichloromethane (2×20 mL), and the combined organic layers were washed with saturated NaHCO3 (20 mL) and dried over Na2SO4. The drying agent was filtered off, and the solvent was removed in vacuo to give the title compound as colorless syrup.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][C@@H:12]2[CH3:17])[N:3]=1.CI.[C:20]([O-])([O-])=O.[K+].[K+]>C1COCC1>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:20])=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][C@@H:12]2[CH3:17])[N:3]=1
Reactant: C[C@H]1COCCN1c1nc(Cl)nc2[nH]cnc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: C[C@H]1COCCN1c1nc(Cl)nc2c1ncn2C
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.5 %

Procedure:
A mixture of 2-chloro-6-((S)-3-methylmorpholin-4-yl)-9H-purine (5.3 g, 20.89 mmol), methyl iodide (1.6 mL, 25.70 mmol) and K2CO3 (4.0 g, 28.94 mmol) in THF (100 mL) were stirred at r.t. for 18 h then concentrated in vacuo. The resulting residue was partitioned between EtOAc and H2O, the organic phase washed with brine, then dried (Na2SO4) and concentrated in vacuo affording the title compound (4.84 g, 87%). LCMS (method H): RT 2.74 min [M+H]+ 268.2
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]=[C:6]([O:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=2[CH:12]=[CH:11][CH:10]=1)[CH3:7])[CH3:2].[Br:20]N1C(=O)CCC1=O>ClCCl.N(C(C)(CC(C)C)C#N)=NC(C)(CC(C)C)C#N>[CH2:1]([O:3][C:4](=[O:19])[CH:5]=[C:6]([O:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=2[CH:12]=[CH:11][CH:10]=1)[CH2:7][Br:20])[CH3:2]
Reactant: CCOC(=O)C=C(C)Oc1cccc2c1CCCC2
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)CC(C)(C#N)N=NC(C)(C#N)CC(C)C
Solvent: ClCCl
Product: CCOC(=O)C=C(CBr)Oc1cccc2c1CCCC2
Temperature: 45 °C
Reaction time: 8 h
Yield: 71.1 %

Procedure:
A solution of 3-(5,6,7,8-tetrahydro-naphthalen-1-yloxy)-but-2-enoic acid ethyl ester (0.69 g, 2.65 mmol) in dichloromethane (14 mL) was treated with N-bromosuccinimide (0.50 g, 2.80 mmol) and 2,2′-azobis(2,4-dimethylvaleronitrile) (31.6 mg, 0.12 mmol). The reaction was then warmed to 45° C. where it stirred overnight. At this time, the reaction was diluted with dichloromethane (50 mL) and was washed with water (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL), dried over magnesium sulfate, filtered, rinsed with dichloromethane, and concentrated in vacuo. Purification by Analogix flash chromatography (40 g, 1-10% ethyl acetate/hexanes) afforded impure 4-bromo-3-(5,6,7,8-tetrahydro-naphthalen-1-yloxy)-but-2-enoic acid ethyl ester (638.8 mg, 71%) as a yellow oil. The material was used without further purification.
Reaction SMILES: [Cl-].[Li+].Br[C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[N:9][CH:8]=[CH:7]2.C([Sn](CCCC)(CCCC)[C:19]1[S:23][C:22]([NH:24][C:25](=[O:27])[CH3:26])=[N:21][CH:20]=1)CCC.CN(C=O)C>CCOC(C)=O.O.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>[CH:10]1[C:11]2[C:6](=[CH:5][C:4]([C:19]3[S:23][C:22]([NH:24][C:25](=[O:27])[CH3:26])=[N:21][CH:20]=3)=[CH:13][CH:12]=2)[CH:7]=[CH:8][N:9]=1
Reactant: Brc1ccc2cnccc2c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc(NC(C)=O)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ncc(-c2ccc3cnccc3c2)s1
Temperature: 100 °C
Yield: 93.1 %

Procedure:
To a mixture of lithium chloride (0.295 g, 6.94 mmol) (flame-dried), 6-bromoisoquinoline (0.1805 g, 0.868 mmol), and Pd(PPh3)4 (0.0501 g, 0.0434 mmol) in a microwave reaction vessel, was added a solution of N-(5-(tributylstannyl)thiazol-2-yl)acetamide (0.561 g, 1.30 mmol) in DMF (2.00 mL, 0.868 mmol). The mixture was sealed and heated at 100° C. (oil bath) overnight. After cooling, the mixture (solidified) was diluted with EtOAc and water (2 mL each) and sonicated for 10 minutes. The resulting mixture was filtered, and the solid was washed with water and more EtOAc to provide N-(5-(isoquinolin-6-yl)thiazol-2-yl)acetamide (0.2177 g, 0.808 mmol) as a yellow solid. LCMS (M+H+) 270.3 calc. for C14H12N3OS 270.3; 1H NMR (400 MHz, DMSO-d6) δ ppm 12.32 (br s, 1H), 9.27 (s, 1H), 8.48 (d, J=5.67 Hz, 1H), 8.13-8.15 (m, 3H), 8.06 (d, J=7.20 Hz, 1H), 7.85 (d, J=5.67 Hz, 1H), 2.20 (s, 3H).