Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:20]([OH:22])=O)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.[C:30]1([O:40][C:41](=[O:71])[C@H:42]([CH2:44][CH2:45][CH2:46][N:47]([C:61]([O:63][CH2:64][C:65]2[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=2)=[O:62])[C:48](=[NH:60])[NH:49][C:50]([O:52][CH2:53][C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)=[O:51])[NH2:43])[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][CH:31]=1.C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1>CN(C)C=O.C(N(CC)CC)C>[C:30]1([O:40][C:41](=[O:71])[C@H:42]([CH2:44][CH2:45][CH2:46][N:47]([C:61]([O:63][CH2:64][C:65]2[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=2)=[O:62])[C:48](=[NH:60])[NH:49][C:50]([O:52][CH2:53][C:54]2[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=2)=[O:51])[NH:43][C:20](=[O:22])[C@H:12]([CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:11][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][CH:31]=1
Reactant: N=C(NC(=O)OCc1ccccc1)N(CCC[C@H](N)C(=O)Oc1cccc2ccccc12)C(=O)OCc1ccccc1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: N=C(NC(=O)OCc1ccccc1)N(CCC[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)Oc1cccc2ccccc12)C(=O)OCc1ccccc1
Yield: 43.1 %

Procedure:
In 8 ml of dimethylformamide (DMF) were dissolved 898 mg of benzyloxycarbonyl-L-phenylalanine and 2.05 g of Nδ,Nω -dibenzyloxycarbonyl-L-arginine 1-naphthyl ester trifluoroacetate, and to the resulting solution were added 681 mg of dicyclohexylcarbodiimide (DCC), 405 mg of 1-hydroxybenzotriazole (HOBt) and 304 mg of triethylamine (TEA) with ice-cooling and with stirring, after which the mixture was stirred for 3 hrs at the same temperature. The temperature was elevated to room temperature and the mixture was stirred for a further 24 hrs. After the reaction, the crystals of dicyclohexylurea (DCU) precipitated were removed by filtration, and ethyl acetate was added to the filtrate, after which the mixture was washed with 10% aqueous citric acid solution, saturated sodium bicarbonate solution and saturated sodium chloride solution in this order, dried over anhydrous magnesium sulfate, and thereafter evaporated under reduced pressure to removed the solvent. The white powder thus precipitated was collected and recrystallized from chloroform-diethyl ether to obtain 1.1 g (yield 43%) of benzyloxycarbonyl-L-phenylalanyl-Nδ,Nω -dibenzyloxycarbonyl-L-arginine 1-naphthyl ester, m.p. 125°-130° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=CC=CC=1.[H-].[Na+].[CH3:16][C:17]1([CH3:34])[O:21]C(COS(C2C=CC(C)=CC=2)(=O)=O)C[O:18]1>CN(C)C=O>[CH3:16][C:17]1([CH3:34])[O:21][CH:2]([CH2:1][N:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)[CH2:7][O:18]1
Reactant: Cc1ccc(S(=O)(=O)OCC2COC(C)(C)O2)cc1
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)OCC(CN2CCNCC2)O1
Reaction time: 8 h

Procedure:
A solution of 2.6 ml N-benzylpiperazine in dimethylformamide (30 ml) is treated slowly with sodium hydride (510 mg). To this suspension is added toluene-4-sulfonic acid 2,2-dimethyl-[1,3]dioxolan-4-ylmethyl ester (0.8 g) and the mixture stirred overnight. The reaction mixture is evaporated, the residue is trated with water and the product extracted with ethyl acetate. The organic extract is dried and evaporated. The crude product is purified by flash chromatography on silica gel using heptane/ethyl acetate 1:1 as eluent. The purified intermediate (0.9 g) is dissolved in methanol (30 ml) and hydrogenated over palladium on charcoal (0.3 g). The catalyst is filtered off and the filtrate is evaporated to yield 0.54 g of the title compound as a waxy solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]([C:12](=[O:14])[CH3:13])([CH3:11])[CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:27][C:28]#[N:29].[O-2].[Al+3].[O-2].[O-2].[Al+3]>O1CCCC1>[CH2:1]([O:3][C:4](=[O:15])[C:5]([C:12](=[O:14])[CH2:13][CH2:27][C:28]#[N:29])([CH3:11])[CH2:6][CH:7]=[C:8]([CH3:9])[CH3:10])[CH3:2]
Reactant: CCOC(=O)C(C)(CC=C(C)C)C(C)=O
Reactant: N#CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Al+3]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(CC=C(C)C)C(=O)CCC#N
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
A solution of 2-acetyl-2,5-dimethyl-hex-4-enoic acid ethyl ester (1.0 g, 4.71 mmol) in anhydrous tetrahydro furan (30 mL) was treated with a 1.0 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (5.2 mL, 5.18 mmol) at −78° C. The reaction mixture was stirred at −78° C. for 30 min and was then added via cannula to a solution of bromoacetonitrile (which was stirred for 30 min over basic aluminum oxide, filtered and used fresh in the reaction) in anhydrous tetrahydrofuran (5 mL) cooled to −78° C. The reaction mixture was stirred at −78° C. for 1 h, before it was allowed to warm to 25° C. and quenched by pouring it over ice in a 1.0 M aqueous hydrochloric acid solution. The mixture was extracted with ethyl acetate (3×100 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Further purification by flash column chromatography (ISCO RediSep column, 0 to 40% ethyl acetate in hexanes) afforded the desired product, 2-(3-cyano-propionyl)-2,5-dimethyl-hex-4-enoic acid ethyl ester (0.71 g, 71%), as an oil. 1H NMR (400 MHz, CDCl3) δ: 1.28 (3H, t, J=7.0 Hz), 1.36 (3H, s), 1.63 (3H, s), 1.70 (3H, s), 2.52-2.62 (4H, m), 2.76-2.91 (2H, m), 4.20 (2H, q, J=7.0 Hz), 4.91-4.95 (1H, m). LC-MS (ESI) calcd for C14H21NO3: 251.15, found 252.3 [M+H+].
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9](Cl)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Al+3].[Cl-].[Cl-].[Cl-].[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=1.Cl>C(Cl)(Cl)(Cl)Cl>[CH3:16][O:17][C:18]1[CH:19]=[C:20]([O:24][CH3:25])[CH:21]=[CH:22][C:23]=1[C:9](=[O:10])[CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1cccc(OC)c1
Reactant: O=C(Cl)CCc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(C(=O)CCc2ccccc2)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.2 %

Procedure:
A solution of 45.5 g of 3-phenylpropanoyl chloride in 50 ml of CCl4 is added dropwise to a suspension of 43.2 g of AlCl3 and 37.5 g of 1,3-dimethoxybenzene in 210 ml of CCl4. The reaction mixture is left stirring for 1 hour at r.t. and poured into a mixture of 400 g of ice and 150 ml of concentrated HCl. After 30 minutes of stirring, the resulting mixture is extracted with DCM, the combined organic phases are washed with saturated sodium hydrogen carbonate solution and dried over sodium sulphate and the solvents are evaporated off under vacuum. 66.5 g of oil of the expected product are obtained, which oil is used as it is.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2=[N:7][CH:8]=[C:9]([C:10](=[O:20])[CH2:11][CH:12]([OH:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:4]2[C:3]=1[CH3:21].[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1>[CH3:1][C:2]1[S:6][C:5]2=[N:7][CH:8]=[C:9]([CH:10]([OH:20])[CH2:11][CH:12]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[OH:19])[N:4]2[C:3]=1[CH3:21]
Reactant: Cc1sc2ncc(C(=O)CC(O)c3ccccc3)n2c1C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: Cc1sc2ncc(C(O)CC(O)c3ccccc3)n2c1C

Procedure:
1-(2,3-Dimethylimidazo[2,1-b]thiazol-5-yl)-3-hydroxy-3-phenyl-1-propanone (Formula R-3, X=H), 0.08 g, in toluene (10 mL) was treated with 1M diisobutylaluminum hydride (1.0 mL) and reacted for 1.25 hours. The solution was quenched into 5% citric acid, the mixture was extracted with ethyl acetate and the citric acid solution was neutralized with NaOH. Extraction of product from the neutralized solution gave pure 1-(2,3-Dimethylimidazo[2,1-b]thiazol-5-yl)-3-phenyl-1,3-propanediol (Formula R-4, X=H), 0.04 g, m.p. 152-153° after crystallization from CH2Cl2/CH3CN solution.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15](S(C)=O)[C:14]([F:20])=[CH:13][N:12]=3)=[CH:9][N:8]([S:21]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)(=[O:23])=[O:22])[C:5]2=[N:6][CH:7]=1.[NH2:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH:34]([C:38]([OH:40])=[O:39])[CH:33]1[OH:41].CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:31][CH:32]4[CH2:37][CH2:36][CH2:35][CH:34]([C:38]([OH:40])=[O:39])[CH:33]4[OH:41])[C:14]([F:20])=[CH:13][N:12]=3)=[CH:9][N:8]([S:21]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)(=[O:23])=[O:22])[C:5]2=[N:6][CH:7]=1
Reactant: NC1CCCC(C(=O)O)C1O
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(S(C)=O)n3)c3cc(Cl)cnc32)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(NC4CCCC(C(=O)O)C4O)n3)c3cc(Cl)cnc32)cc1

Procedure:
5-chloro-3-(5-fluoro-4-methylsulfinyl-pyrimidin-2-yl)-1-(p-tolylsulfonyl)-pyrrolo[2,3-b]pyridine, 65a, (0.30 g, 0.64 mmol), 3-amino-2-hydroxy-cyclohexanecarboxylic acid (0.19 g, 0.97 mmol), iPr2NEt (0.45 mL, 2.58 mmol) in DMF (23.2 mL) solution was heated in microwave at 130° C. for 10 min. The solvent of the reaction mixture was removed under reduced pressure and the residue was purified by preparatory HPLC to give 240 mg of 3-[[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]amino]-2-hydroxy-cyclohexanecarboxylic acid, 65b, as a mixture of stereoisomers.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:19][CH2:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[CH:9][C:10]=2[O:12][CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[N:5]=[CH:4][C:3]=1[C:29]#[N:30].[CH3:31][O:32][CH2:33][C:34]#[C:35][C:36]1[CH:42]=[CH:41][C:39]([NH2:40])=[C:38]2[O:43][CH2:44][O:45][C:37]=12.[ClH:46].CN(C)C(=N)N(C)C>C(O)CC.C(OCC)C>[ClH:1].[ClH:46].[C:29]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[NH:40][C:39]1[CH:41]=[CH:42][C:36]([C:35]#[C:34][CH2:33][O:32][CH3:31])=[C:37]3[O:45][CH2:44][O:43][C:38]=13)=[C:10]([O:12][CH:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1)[CH:9]=[C:8]([O:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)[CH:7]=2)#[N:30]
Reactant: COCC#Cc1ccc(N)c2c1OCO2
Reactant: N#Cc1cnc2cc(OCCCN3CCOCC3)cc(OC3CCOCC3)c2c1Cl
Agent: CN(C)C(=N)N(C)C
Agent: Cl
Solvent: CCOCC
Solvent: CCCO
Product: COCC#Cc1ccc(Nc2c(C#N)cnc3cc(OCCCN4CCOCC4)cc(OC4CCOCC4)c23)c2c1OCO2

Procedure:
A mixture of 4-chloro-3-cyano-7-(3-morpholin-4-ylpropoxy)-5-(tetrahydro-2H-pyran-4-yloxy)quinoline (125 mg) and 4-(3-methoxyprop-1-ynyl)-2,3-methylendioxyaniline (179 mg) in 1-propanol (8 ml) was treated with a 11.0M solution of hydrogen chloride in diethyl ether (0.30 ml) then stirred and heated at reflux for 1 hour. The mixture was allowed to cool and neutralised by the addition of tetramethylguanidine (0.10 ml). The resulting solution was evaporated to dryness and the residue was purified by chromatography on a Biotage silica cartridge (20 g) eluting with a gradient of methanol in dichloromethane (1–10%). The fractions containing the product were combined and evaporated. The residue was dissolved in ethanol (8 ml) and treated with 2 equivalents of hydrogen chloride (1.0M in diethyl ether). The title compound was thus obtained as a white solid (130 mg); NMR Spectrum: (DMSOd6, 300K) 1.87 (m, 2H), 2.10 (m, 2H), 2.31 (m, 2H), 3.11 (m, 2H), 3.30 (m, 2H), 3.36 (s, 3H), 3.50 (m, 4H), 3.87 (m, 4H), 3.97 (m, 2H), 4.32 (m, 2H), 4.37 (s, 2H), 5.10 (m, 1H), 6.18 (s, 2H), 1.05 (m, 3H), 7.13 (s, 1H), 8.87 (s, 1H), 10.43 (s, 1H), 11.34 (s, 1H); Mass Spectrum: M+H+ 601.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][N:9]2[C:13]([CH3:15])([CH3:14])[C:12](=[O:16])[N:11]([C:17]3[CH:18]=[CH:19][C:20]([S:50][C:51]([F:54])([F:53])[F:52])=[C:21]([NH:23][C:24](=[O:49])[C@H:25]([NH:32]C(=O)CC4C5C=CC=CC=5C5C4=CC=CC=5)[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:22]=3)[C:10]2=[O:55])[CH:5]=[CH:4][N:3]=1.[NH2:56][C:57]1[CH:58]=[N:59][CH:60]=[CH:61][CH:62]=1.CC1(C)C2C=CC(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=2OC2C1=CC=C(P(C1C=CC=CC=1)C1C=CC=CC=1)C=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:32][C@H:25]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:24]([NH:23][C:21]1[CH:22]=[C:17]([N:11]2[C:12](=[O:16])[C:13]([CH3:14])([CH3:15])[N:9]([CH2:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:56][C:57]4[CH:58]=[N:59][CH:60]=[CH:61][CH:62]=4)[CH:7]=3)[C:10]2=[O:55])[CH:18]=[CH:19][C:20]=1[S:50][C:51]([F:52])([F:54])[F:53])=[O:49]
Reactant: Nc1cccnc1
Reactant: CC1(C)C(=O)N(c2ccc(SC(F)(F)F)c(NC(=O)[C@H](NC(=O)CC3c4ccccc4-c4ccccc43)c3ccccc3)c2)C(=O)N1Cc1ccnc(Cl)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2ccc(P(c3ccccc3)c3ccccc3)cc2Oc2cc(P(c3ccccc3)c3ccccc3)ccc21
Solvent: C1COCCO1
Product: CC1(C)C(=O)N(c2ccc(SC(F)(F)F)c(NC(=O)[C@H](N)c3ccccc3)c2)C(=O)N1Cc1ccnc(Nc2cccnc2)c1
Temperature: 110 °C
Yield: 18.7 %

Procedure:
To a solution of 33 mg of (2R)—N-(5-{3-[(2-chloropyridin-4-yl)methyl]-4,4-dimethyl-2,5-dioxoimidazolidin-1-yl}-2-[(trifluoromethyl)thio]phenyl)-2-[(9H-fluoren-9-ylacetyl)-amino]-2-phenylacetamide obtained in stage e) below in 1 mL of dioxane are successively added, under argon, 14 mg of 3-aminopyridine, 3 mg of (9,9-dimethyl-9H-xanthene-3,6-diyl)bis(diphenylphosphine) (Xantphos), 1.1 mg of palladium acetate and 61 mg of caesium carbonate. The reaction mixture is heated at 110° C. for 3 h, filtered and washed with twice 10 mL of dioxane, and the filtrate is then concentrated under reduced pressure. The residue is purified by HPLC (gradient: water/acetonitrile containing 0.1% formic acid) to give 5 mg of (2R)-2-amino-N-{5-(4,4-dimethyl-2,5-dioxo-3-{[2-(pyridin-3-ylamino)pyridin-4-yl]methyl}imidazolidin-1-yl)-2-[(trifluoromethyl)thio]phenyl}-2-phenylacetamide, the characteristics of which are as follows:
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]([OH:15])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][O:17][CH:18]([O:21][CH3:22])[CH2:19][NH2:20].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:16][O:17][CH:18]([O:21][CH3:22])[CH2:19][NH:20][C:13]([CH:9]1[CH2:10][CH2:11][CH2:12][N:8]1[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:15]
Reactant: COC(CN)OC
Reactant: O=C(O)C1CCCN1Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(CNC(=O)C1CCCN1Cc1ccccc1)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 1-Benzyl-pyrrolidine-2-carboxylic acid (474) (Belokon, Y. N. at al; Tetrahedron Asymmetry 1998, 9, 4249-4252) in CH2Cl2 (20 mL) was added 2,2-dimethoxy-ethylamine (614 mg, 5.84 mmol), EDCI (1.12 g, 5.84 mmol), HOBT (658 mg, 4.87 mmol), and NMM (1.08 mL, 9.8 mmol). The reaction mixture was stirred overnight at 25° C. Saturated aqueous NaHCO3 solution (50 mL) was added. The aqueous layer was extracted with CH2Cl2 (50 mL×3). The combined organic layers was washed with brine (50 mL), dried over Na2SO4, and concentrated by rotary evaporator to give 1-benzyl-pyrrolidine-2-carboxylic acid (2,2-dimethoxy-ethyl)-amide as yellow oil. To 1-benzyl-pyrrolidine-2-carboxylic acid (2,2-dimethoxy-ethyl)-amide was added acetic acid (10 mL) and ammonium acetate (11 g). The reaction mixture was heated to 140° C. overnight. After it was cooled down, it was poured into 100 mL ice-water with stirring. Solid NaHCO3 was added in small portion with stirring to adjust the pH of the solution to 8-9. The aqueous solution was extracted with EtOAc (100 mL×2). The combined organic layers was washed with brine, dried over Na2SO4, and concentrated with rotary evaporator. Compound 475 (110 mg) was isolated by SiO2 chromatography (CH2Cl2/MeOH/NH3: 40:1:0.1 to 20:1:0.1). MS: m/z 228.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.I[C:12]1[S:21][C:15]2[C:16](=[O:20])[O:17][CH2:18][CH2:19][C:14]=2[C:13]=1[CH3:22].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Na+].[Na+].Cl.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>CC#N.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]2[S:21][C:15]3[C:16](=[O:20])[O:17][CH2:18][CH2:19][C:14]=3[C:13]=2[CH3:22])=[CH:4][CH:3]=1
Reactant: Cc1c(I)sc2c1CCOC2=O
Reactant: OB(O)c1ccc(Cl)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Solvent: O
Product: Cc1c(-c2ccc(Cl)cc2)sc2c1CCOC2=O
Temperature: 80 °C
Yield: 86.6 %

Procedure:
Add 4-chlorophenyl boronic acid (215 mg, 1.38 mmol) to a slurry of 2-iodo-3-methyl-4,5-dihydro-thieno[2,3-c]pyran-7-one (135 mg, 0.46 mmol) in CH3CN (2 mL). Add PPh3 (37 mg, 0.14 mmol) followed by 2.0 M Na2CO3 (0.69 mL). Bubble dry argon through the reaction for 15 min. Add Pd(OAc)2 (12 mg, 0.05 mmol) and heat using microwave irradiation to 100° C. for 45 min. Pour the reaction into 1N HCl (50 mL) and extract with EtOAc (3×50 mL). Wash the combined organic extracts with brine (50 mL). Concentrate, dissolve the crude residue in toluene (5 mL) and treat with p-toluenesulfonic acid monohydrate (50 mg, 0.26 mmol). Heat to 80° C. for 8 h. Cool to RT, pour into aqueous NaHCO3 (50 mL) and extract with EtOAc (3×50 mL). Wash the combined extracts with brine (50 mL) and concentrate. Purify the resulting residue using silica gel chromatography (0-50% EtOAc/hexanes) to provide 111 mg (87%) of the desired product.
Reaction SMILES: [N:1]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]1[OH:10])=[N+:2]=[N-:3].[OH-].[Na+].S(OC)(O[CH3:17])(=O)=O>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[N:1]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]1[O:10][CH3:17])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NC1CCCCC1O
Reactant: COS(=O)(=O)OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC1CCCCC1N=[N+]=[N-]
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 58.1 %

Procedure:
The azide (171.8 g, 1.22 mol) and tetrabutylammonium hydrogensulfate (4.2 g, 12.4 mmol) are sequentially added to a solution of methylene chloride (700 ml) and a 50% w/w aqueous solution of sodium hydroxide (129 g in 129 ml of water). The resulting mixture is vigorously stirred for 30 minutes before being cooled to 0° C. Dimethyl sulfate (186 g, 140 ml, 1.48 mol) is added in a dropwise manner to the vigorously stirred solution over a period of one hour, during which time a solid mass forms. This is broken up by addition of a further portion of methylene chloride (150 ml). The reaction mixture is then allowed to warm to room temperature and stirred for 20 hours. TLC analysis indicates a small amount of alcohol still remaining, and thus the reaction is allowed to proceed for an additional 12 hours at 50° C. After cooling to room temperature, the reaction is quenched by addition of concentrated ammonium hydroxide solution (100 ml) and allowed to stir for 45 minutes. The mixture is poured into water (500 ml) and extracted with methylene chloride (2×500 ml). The organic extracts are washed with water (3×500 ml) until the washings are neutral. The extracts are dried over sodium sulfate and the volatiles removed in vacuo. The crude product is passed through a plug of silica eluting with hexanes:ethyl acetate (9:1) to yield 1-azido-2-methoxycyclohexane (110 g, 58%) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[C:6]([B:7]2[O:11][C:10]([CH3:13])([CH3:12])[C:9]([CH3:15])([CH3:14])[O:8]2)=[CH:5][NH:4][N:3]=1.[C:16]([CH:18]=[C:19]1[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20]1)#[N:17].N12CCCN=C1CCCCC2>C(#N)C>[C:16]([CH2:18][C:19]1([N:4]2[CH:5]=[C:6]([B:7]3[O:11][C:10]([CH3:13])([CH3:12])[C:9]([CH3:15])([CH3:14])[O:8]3)[C:2]([CH3:1])=[N:3]2)[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20]1)#[N:17]
Reactant: CC(C)(C)OC(=O)N1CC(=CC#N)C1
Reactant: Cc1n[nH]cc1B1OC(C)(C)C(C)(C)O1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1nn(C2(CC#N)CN(C(=O)OC(C)(C)C)C2)cc1B1OC(C)(C)C(C)(C)O1
Temperature: 60 °C

Procedure:
A mixture of 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.06 g, 5.10 mmol), tert-butyl 3-(cyanomethylene)azetidine-1-carboxylate (1.00 g, 5.15 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.38 mL, 2.6 mmol) in acetonitrile (20 mL) was heated at 60° C. for 2 h. After cooling, the solvent was removed under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluting with ethyl acetate in hexanes (0-60%) to afford the desired product. LCMS cacld. for C16H24BN4O4 (M−55)+: m/z=347.2. Found: 347.1.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5](I)=[CH:4][N:3]=1.[C:10]([C:12]1[CH:13]=[C:14]([O:22][CH3:23])[C:15]([O:20][CH3:21])=[C:16]([O:18][CH3:19])[CH:17]=1)#[CH:11]>>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:11]#[C:10][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:4][N:3]=1
Reactant: Nc1ncc(I)c(N)n1
Reactant: C#Cc1cc(OC)c(OC)c(OC)c1
Product: COc1cc(C#Cc2cnc(N)nc2N)cc(OC)c1OC
Yield: 89.9 %

Procedure:
2,4-Diamino-5-iodopyrimidine (236 mg) was allowed to react with 5-Ethynyl-1,2,3-trimethoxybenzene (384 mg) as per the general procedure to afford 2,4-Diamino-5-(2-(3,4,5-trimethoxyphenyl)ethynyl)pyrimidine as a white powder (270 mg, 90%): Rf=0.28 (9:1, CHCl3:MeOH); mp=202-204° C.; 1H NMR (DMSO-d6) δ 7.94 (s, 1H), 6.90 (s, 2H), 6.37 (s, 2H), 3.79 (s, 6H), 3.67 (s, 3H); 13C NMR (DMSO-d6) δ 163.4, 162.2, 159.4, 159.2, 152.8, 137.6, 118.6, 108.3, 108.2, 94.7, 89.8, 83.4, 60.2, 60.1, 56.0, 55.9; Anal. (C15H16N4O3) C, H, N.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:49])[N:10]([CH2:31][CH2:32][CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[CH:37][CH:36]=1)[CH2:11][CH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([OH:22])[CH:20]=2)[NH:15][C:14]=1[C:23]1[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([CH3:30])[CH:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:50]([N:52]=[C:53]=[O:54])[CH3:51]>>[CH2:1]([O:8][C:9]([N:10]([CH2:31][CH2:32][CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][CH2:42][C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)=[CH:37][CH:36]=1)[CH2:11][CH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:22][C:53](=[O:54])[NH:52][CH2:50][CH3:51])[CH:20]=2)[NH:15][C:14]=1[C:23]1[CH:24]=[C:25]([CH3:30])[CH:26]=[C:27]([CH3:29])[CH:28]=1)=[O:49])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN=C=O
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(O)cc3c2CCN(CCCCc2ccc(OCc3ccccc3)cc2)C(=O)OCc2ccccc2)c1
Product: CCNC(=O)Oc1ccc2[nH]c(-c3cc(C)cc(C)c3)c(CCN(CCCCc3ccc(OCc4ccccc4)cc3)C(=O)OCc3ccccc3)c2c1
Temperature: 25 °C

Procedure:
To a solution of [4-(4-benzyloxyphenyl)-butyl]-[2-[2-(3,5-dimethylphenyl)-5-hydroxy-1H-indol-3-yl]ethyl]carbamic acid benzyl ester (50 mg in 0.5 mL dry tetrahydrofuran) was added 0.035 mL of ethyl isocyanate and the mixture stirred at room temperature. Over the course of 2 weeks, additional ethyl isocyanate was added in portions and the mixture heated to reflux for several days after which time it was cooled to room temperature, concentrated in vacuo and purified by flash chromatography on silica gel (hexane:ethyl acetate, 2:1) to give the title compound (20 mg).