Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C:5]1[N:9]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:12][CH:11]=2)[N:8]=[C:7]([CH3:20])[CH:6]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+].O.[O:28]1CCO[CH2:30][CH2:29]1>>[C:16]([C:13]1[CH:12]=[CH:11][C:10]([N:9]2[C:5]([OH:4])=[C:6]([C:29](=[O:28])[CH3:30])[C:7]([CH3:20])=[N:8]2)=[CH:15][CH:14]=1)([CH3:17])([CH3:18])[CH3:19]
Reactant: CC(=O)Oc1cc(C)nn1-c1ccc(C(C)(C)C)cc1
Reactant: C1COCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC(=O)c1c(C)nn(-c2ccc(C(C)(C)C)cc2)c1O
Yield: 66 %

Procedure:
5-Acetyloxy-1-(4-t-butylphenyl)-3-methyl-1H-pyrazole (4.21 g, 15.5 mmol) in 1,4-dioxane (150 mL) was stirred with potassium carbonate (2.14 g, 15.5 mmol) at 110° C. for 3.5 hours, and after addition of water (50 mL), the organic solvent was removed by distillation. Then, ethyl acetate, water and 6 M hydrochloric acid were added to adjust the aqueous layer to pH 2, and the aqueous layer and the organic layer were separated. The aqueous layer was extracted with ethyl acetate twice, and the organic layer was combined with the extract, washed with saturated aqueous ammonium chloride three times and with saturated aqueous sodium chloride once and dried over anhydrous sodium sulfate and filtered. The solvent was removed by distillation, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=6/1→3/1→1/1) to give 2.77 g of the desired product (66% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([F:11])=[CH:4][C:3]=1[CH3:12].[CH:13]([Mg]Br)=[CH2:14].O>C1COCC1>[Br:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]([F:11])=[C:6]2[C:7]=1[CH:13]=[CH:14][NH:8]2
Reactant: C=C[Mg]Br
Reactant: Cc1cc(F)c([N+](=O)[O-])cc1Br
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(F)c2[nH]ccc2c1Br
Temperature: -78 °C
Reaction time: 2 h
Yield: 16.3 %

Procedure:
To a solution of 1-bromo-4-fluoro-2-methyl-5-nitro-benzene (20 g, 0.086 mol) in THF (250 mL) at −78° C. was added vinylmagnesium bromide (300 ml, 0.3 mol) dropwise, then the mixture was stirred at −78° C. for 2 h. Water was added and the reaction allowed to warm slowly to rt. The mixture was extracted with EtOAc, dried over Na2SO4, and concentrated. The crude product was purified by silica gel column chromatography to afford 4-bromo-7-fluoro-5-methylindole (3.2 g, 16.4%).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[Cl-].[Al+3].[Cl-].[Cl-].[S:10]1[CH:14]=[CH:13][N:12]2[CH:15]=[N:16][CH:17]=[C:11]12.O>ClCCCl>[Cl:1][CH2:2][C:3]([C:17]1[N:16]=[CH:15][N:12]2[CH:13]=[CH:14][S:10][C:11]=12)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: c1cn2cncc2s1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: O
Product: O=C(CCl)c1ncn2ccsc12
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Chloroacetyl chloride (5.97 ml) was added to a solution of 12.5 g of aluminum chloride in 40 ml of 1,2-dichloroethane. The mixture was stirred at room temperature for 20 min. A solution of 1.93 g of imidazo[5,1-b]thiazole in 20 ml of 1,2-dichloroethane was added thereto. The mixture was heated under reflux for 2 hr. Water was added thereto, followed by extraction with dichloromethane. The organic layers were combined together. The combined organic layers were washed with a dilute aqueous sodium hydroxide solution and saturated brine in that order. The solvent was removed by distillation. Isopropyl ether was added to the residue. The resultant powder was collected by filtration to obtain the title compound.
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][N:7]2[CH:15]=[C:14]3[C:9]([CH:10]=[C:11]([C:16]4[CH:17]=[C:18]([CH:26]5[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]5)[N:19]5[C:24]=4[C:23]([NH2:25])=[N:22][CH:21]=[N:20]5)[CH:12]=[CH:13]3)=[N:8]2)=[CH:4][CH:3]=1.ClC[C:36]([N:38]([CH3:40])[CH3:39])=[O:37]>>[NH2:25][C:23]1[C:24]2=[C:16]([C:11]3[CH:12]=[CH:13][C:14]4[C:9]([CH:10]=3)=[N:8][N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:33][CH:32]=3)[CH:15]=4)[CH:17]=[C:18]([CH:26]3[CH2:27][CH2:28][N:29]([C:36]([N:38]([CH3:40])[CH3:39])=[O:37])[CH2:30][CH2:31]3)[N:19]2[N:20]=[CH:21][N:22]=1
Reactant: CN(C)C(=O)CCl
Reactant: Nc1ncnn2c(C3CCNCC3)cc(-c3ccc4cn(Cc5ccc(F)cc5)nc4c3)c12
Product: CN(C)C(=O)N1CCC(c2cc(-c3ccc4cn(Cc5ccc(F)cc5)nc4c3)c3c(N)ncnn23)CC1
Yield: 49 %

Procedure:
In a manner similar to the procedure described for Example 369 and using 5-[2-(4-fluorobenzyl)-2H-indazol-6-yl]-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine and substituting dimethycarbamyl chloride for 2-chloro-N,N-dimethylacetamide as starting materials, 20 mg (49%) of the desired product was isolated. 1H NMR (400 MHz, CD2Cl2) δ 8.05 (s, 1 H) 7.89 (s, 1 H) 7.78 (d, 1 H) 7.74 (s, 1 H) 7.33-7.39 (m, 2 H) 7.24 (dd, 1 H) 7.10 (ddd, 2 H) 6.59 (s, 1 H) 5.61 (s, 2 H) 3.79 (d, 2 H) 3.38-3.47 (m, 1 H) 2.97 (td, 2 H) 2.84 (s, 6 H) 2.17 (d, 1 H) 2.14 (s, 1 H) 1.76-1.71 (m, 2 H). LC-MS [M+H]+=513.1, RT=2.57 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:17])[CH2:9][CH2:10][C:11]([CH3:16])([CH3:15])[C:12]([OH:14])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.[Br-:30].[NH2:31][CH2:32][CH2:33][CH2:34][CH2:35][P+:36]([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>CN(C)C=O.C(Cl)Cl>[Br-:30].[CH3:15][C:11]([CH3:16])([CH2:10][CH2:9][N:8]([CH3:17])[C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:12](=[O:14])[NH:31][CH2:32][CH2:33][CH2:34][CH2:35][P+:36]([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: NCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CN(CCC(C)(C)C(=O)O)C(=O)OC(C)(C)C
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Br-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN(CCC(C)(C)C(=O)NCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.2 %

Procedure:
4-[(tert-butoxycarbonyl)(methyl)amino]-2,2-dimethylbutanoic acid (Organic and Molecular Chemistry, 2011, 9, 1846-1854, 117 mg, 0.48 mmol) was dissolved in N,N-dimethylformamide (1.2 mL) and treated with N,N-carbonyldiimidazole (104 mg, 0.64 mmol). The mixture was stirred at room temperature for 30 minutes. (4-Aminobutyl)(triphenyl)phosphonium bromide (277 mg, 0.67 mmol) was added, and the reaction was stirred overnight at room temperature. The reaction mixture was then diluted with methylene chloride and washed with 5% aqueous lithium chloride (3 times), 1N aqueous hydrogen chloride, and saturated sodium bicarbonate. The organic solution was dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (210 mg, 69%) as a white foam. Sample was used crude in next step.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][Li])=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].OS([O-])(=O)=O.[K+]>C(OCC)(=O)C>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: [Li]OC(=O)CCCO[Si](C)(C)C(C)(C)C
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCCCC(=O)O
Yield: 94.9 %

Procedure:
To a solution of 4-[tert-butyl(dimethyl)silyl]oxybutanoyloxylithium (8.0 g, 35.71 mmol) in ethyl acetate (10 mL), was carefully added KHSO4 (5%) to adjust pH to about 1. It was then extracted with ethyl acetate three times and organic extracts washed with brine and dried with anhydrous NaSO4. The organic extracts were concentrated to give the title compound (7.4 g, 95%). [M+H] Calc'd for C10H22O3Si, 219; Found, 219.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[O:9][CH2:8][CH2:7][C:6]=2[CH:14]=1.Cl[C:16]1[N:21]=[C:20]([NH:22][C:23]2[CH:34]=[CH:33][CH:32]=[CH:31][C:24]=2[CH2:25][N:26]([CH3:30])[C:27](=[O:29])[CH3:28])[C:19]([Cl:35])=[CH:18][N:17]=1>>[Cl:35][C:19]1[C:20]([NH:22][C:23]2[CH:34]=[CH:33][CH:32]=[CH:31][C:24]=2[CH2:25][N:26]([CH3:30])[C:27](=[O:29])[CH3:28])=[N:21][C:16]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[N:11]([CH3:12])[C:10](=[O:13])[O:9][CH2:8][CH2:7][C:6]=3[CH:14]=2)=[N:17][CH:18]=1
Reactant: CC(=O)N(C)Cc1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CN1C(=O)OCCc2cc(N)ccc21
Product: CC(=O)N(C)Cc1ccccc1Nc1nc(Nc2ccc3c(c2)CCOC(=O)N3C)ncc1Cl

Procedure:
Following a procedure analogous to Example 1741e, 2-amino-5-methyl-8,9-dihydro-5H-7-oxa-5-aza-benzocyclohepten-6-one and N-[2-(2,5-dichloro-pyrimidin-4-ylamino)-benzyl]-N-methyl-acetamide was converted to N-{2-[5-chloro-2-(5-methyl-6-oxo-5,6,8,9-tetrahydro-7-oxa-5-aza-benzocyclohepten-2-ylamino)-pyrimidin-4-ylamino]-benzyl}-N-methyl-acetamide. TFA salt: 1H NMR (300 MHz, CD3OD) δ 8.10 (s, 1H), 7.5 (m, 4H), 7.28 (d, 1H), 7.1 (m, 2H), 4.56 (s, 2H), 4.34 (t, 2H), 3.3 (s, 3H), 2.89 (s, 3H), 2.71 (t, 2H), 2.05 (s, 3H); MS (m/e) 481 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([CH2:15][C:16]2[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=2[F:24])[C:19]#[N:20])[CH:12]=[CH:11][CH:10]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:35][Si:36]([CH3:45])([CH3:44])[C:37]#[C:38][C:39](OCC)=[O:40]>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([CH:15]([C:16]2[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=2[F:24])[C:19]#[N:20])[C:39](=[O:40])[C:38]#[C:37][Si:36]([CH3:45])([CH3:44])[CH3:35])[CH:12]=[CH:11][CH:10]=1
Reactant: N#Cc1ccc(F)c(Cc2cccc(-c3ccc(F)cc3F)n2)c1
Reactant: CCOC(=O)C#C[Si](C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C[Si](C)(C)C#CC(=O)C(c1cccc(-c2ccc(F)cc2F)n1)c1cc(C#N)ccc1F
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 417.3 %

Procedure:
To a solution of 3-{[6-(2,4-difluorophenyl)pyridin-2-yl]methyl}-4-fluorobenzonitrile (from Step C above, 30.0 g, 92.3 mmol) in THF (700 mL) was added LiHMDS (276 mL, 276 mmol, 1M solution in THF) via cannula at −78° C. After stirring for 1 hr and 15 min at −78° C., ethyl 3-(trimethylsilyl)prop-2-ynoate (4.01 mL, 21.37 mmol) was added. The reaction was allowed to stir at −78° C. for 1 hr and was allowed to warm to 0° C. over 3 hours. The reaction was quenched with aqueous NH4Cl, extracted with ethyl acetate (2×). The organic layers were combined, washed with 0.5 N HCl, water, brine (2×), dried over MgSO4, and condensed in vacuo to yield a black oil. The crude material was purified via silica gel chromatography (100% CH2Cl2) to give the title compound (40.0 g).
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][O:10][C@@H:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:8]2)=[CH:4][CH:3]=1.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[C:13]1([C@@H:9]2[O:10][CH2:11][CH2:12][N:7]([CH2:6][C:5]3[CH:19]=[CH:20][C:2]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[C:22]([F:33])([F:32])[F:21])=[CH:3][CH:4]=3)[CH2:8]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: Brc1ccc(CN2CCO[C@@H](c3ccccc3)C2)cc1
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: Cc1ccccc1
Product: FC(F)(F)c1ccccc1-c1ccc(CN2CCO[C@@H](c3ccccc3)C2)cc1
Temperature: 120 °C
Yield: 69.6 %

Procedure:
106 mg of (S)-4-(4-Bromo-benzyl)-2-phenyl-morpholine was combined with 91 mg of 2-(Trifluoromethyl)phenyl boronic acid, 18 mg of tetrakis(triphenylphosphine)palladium(0), 1.1 mL of 2M sodium carbonate solution, 2.9 mL toluene and 1.4 mL ethanol. The reaction mixture was heated in a sealed tube at 120° C. overnight in an oil bath. The reaction mixture was filtered through Celite and concentrated in vacuo. The residue was diluted with water and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by flash chromatography eluting in a 10 to 40% ethyl acetate/hexanes gradient. The product fractions were pooled and concentrated to afford 88.3 mg of product. ES MS (+) m/z 398.
Reaction SMILES: [C:1]1([C:11]2[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][N:12]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:19][Mg]Br>>[C:1]1([C:11]2[N:12]=[CH:13][C:14]([CH:15]([OH:16])[CH3:19])=[CH:17][CH:18]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccc(-c2cccc3ccccc23)nc1
Reactant: C[Mg]Br
Product: CC(O)c1ccc(-c2cccc3ccccc23)nc1

Procedure:
Synthesized using compound 54b (231 mg, 0.99 mmol) and methylmagnesium bromide (1.98 mL, 1.98 mmol, 1 M in THF) according to Method D. Crude product was purified by flash chromatography on silica-gel using a mixture of hexane/ethyl acetate (2:1) as eluent. White solid. Yield: 172 mg, 70%. 1H NMR (CDCl3, 500 MHz): δH (ppm)=1.59 (d, J=6.1 Hz, 3H), 5.00 (m, 1H), 7.44-7.62 (m, 5H), 7.80-7.86 (m, 1H), 7.90-7.96 (m, 2H), 8.07 (d, J=7.9 Hz, 1H), 8.74 (s, 1H); (ESI): m/z=250.29 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@H:10]2[O:17][CH2:16][C@H:15]3[C@@H:11]2[CH2:12][O:13][C@H:14]3[C:18]2[CH:19]=[CH:20][C:21]([OH:26])=[C:22]([O:24][CH3:25])[CH:23]=2)[CH:6]=[CH:7][C:8]=1[OH:9].Br[C:28]([C@@H:30]([C@H:32]([C@@H:34]([C@@H:36]([CH2:38][OH:39])[OH:37])[OH:35])[OH:33])[OH:31])=O>N1C2C(=CC=CC=2)C=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@H:10]2[O:17][CH2:16][C@H:15]3[C@@H:11]2[CH2:12][O:13][C@@H:14]3[C:18]2[CH:19]=[CH:20][C:21]([O:26][C@@H:28]3[O:37][C@H:36]([CH2:38][OH:39])[C@@H:34]([OH:35])[C@H:32]([OH:33])[C@H:30]3[OH:31])=[C:22]([O:24][CH3:25])[CH:23]=2)[CH:6]=[CH:7][C:8]=1[O:9][C@@H:28]1[O:37][C@H:36]([CH2:38][OH:39])[C@@H:34]([OH:35])[C@H:32]([OH:33])[C@H:30]1[OH:31]
Reactant: O=C(Br)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: COc1cc([C@H]2OC[C@H]3[C@@H]2CO[C@H]3c2ccc(O)c(OC)c2)ccc1O
Solvent: c1ccc2ncccc2c1
Product: COc1cc([C@H]2OC[C@H]3[C@@H]2CO[C@@H]3c2ccc(O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c(OC)c2)ccc1O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 33.7 %

Procedure:
Pinoresinol-diglucoside - Silver oxide (2.24 g, 9.65 mmol) was added to a stirred reaction mixture of pinoresinol (358 mg, 1 mmol) and aceto-α bromo glucose (2.24 g, 5.45 mmol) in 6 ml of dry quinoline over a period of 15 min. After stirring the reaction mixture for 16 hours at 25° C., the reaction mixture was extracted with 20 ml of ether. The organic ethereal layer was successively washed with water (2 × 10 ml), 1 N HCl (5 × 5 ml), dilute NaHCO3 (3 × 5 ml) and dried over Na2SO4. After evaporation of the organic solvent in vacuo, the residue was dissolved in 20 ml of methanol containing 1 ml of 5 N NaOH and the mixture was stirred for 2 hours at 0° C. After acidification to pH 4.5 with 2N HCl, this mixture was evaporated to dryness. The residue was dissolved in 5 ml of water and chromatographed over an Amberlite XAD-2 column (1.9 × 38 cm). The column was washed with 150 ml of water to remove salts. The diglucoside was then eluted off the column with 250 ml of 20% aqueous acetone. The combined acetone fractions were evaporated to dryness and the residue was chromatographed over a silica-gel column (3.5 × 44 cm). Elution of the column with solvent system, CHCl3 :CH3OH:H2O (65:30:10) gave 230 mg (34%) of pure pinoresinol diglucoside, m.p. 238-250°; uv (H2O) 276 nm (ε6,600) and 226 (ε21,900); [α]D25 -15.3° (c, 0.4, H2O); IR (KBr) 1600, 1515, 1414, 1275, 1260, 1230, 1080, 1050, 1030, 993 810 cm-1. Anal calcd for C32H42O16.4H2O: C, 50.92; H, 6.68. Found: C, 50.70; H, 6.70.
Reaction SMILES: [CH:1]1[C:14]2[CH:13]([C:15]([O:17][CH3:18])=[O:16])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[Li+].[CH3:20]C([N-]C(C)C)C.IC.[Cl-].[NH4+]>C1COCC1>[CH3:20][C:13]1([C:15]([O:17][CH3:18])=[O:16])[C:14]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[O:6][C:7]2[C:12]1=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: COC(=O)C1c2ccccc2Oc2ccccc21
Reactant: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)C1(C)c2ccccc2Oc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
3.25 g (13.53 mmol) of methyl 9H-xanthene-9-carboxylate are dissolved in 70 ml THF, the solution is cooled with an ice bath and 10.15 ml (20.29 mmol) of a 2M solution of LDA are added drop wise whilst keeping the temperature at 0° C. After stirring at room temperature for 1 hr, 1.68 ml (27.06 mmol) of iodomethane are added drop wise and the system is stirred at rt overnight. The solution is poured over excess of saturated solution of ammonium chloride and is extracted thrice with ethyl ether. After washing with brine, the solution is dried and concentrated to give a reddish residue which is purified by column chromatography (Cl3CH/hexane from 1:3 to 1:1) to give 2.6 g of the title compound (75% yield) as a white solid.
Reaction SMILES: [OH-:1].[K+].[CH2:3]1O[CH:4]1[CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[O:12][CH2:11]1>>[O:12]1[C:10]2([O:1][CH:11]12)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:4][CH3:3]
Reactant: C(CCC1CO1)CC1CO1
Reactant: [OH-]
Agent: [K+]
Product: CCCCCCC12OC1O2

Procedure:
A 1-liter resin flask was charged with 200 g of PEG-7500 and 0.3 g KOH and vacuum stripped at 100° C. for one-half hour. To this stirred solution under nitrogen were added 5.5 g of 1,2,7,8-diepoxyoctane at 100° C. over 15 minutes. The mixture was maintained at this temperature for an additional one and one-half hours followed by quenching with 250 g of water.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[S:12][C:13]([S:16]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)(=[O:18])=[O:17])=[CH:14][CH:15]=2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[NH2:25][CH2:26][CH2:27][N:28]1[CH2:32][CH2:31][NH:30][C:29]1=[O:33].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:22]1[CH2:23][CH2:24][N:19]([S:16]([C:13]2[S:12][C:11]([C:9]3[CH:8]=[CH:7][N:6]=[C:5]([NH:25][CH2:26][CH2:27][N:28]4[CH2:32][CH2:31][NH:30][C:29]4=[O:33])[N:10]=3)=[CH:15][CH:14]=2)(=[O:18])=[O:17])[CH2:20][CH2:21]1
Reactant: CS(=O)(=O)c1nccc(-c2ccc(S(=O)(=O)N3CCOCC3)s2)n1
Reactant: NCCN1CCNC1=O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C1NCCN1CCNc1nccc(-c2ccc(S(=O)(=O)N3CCOCC3)s2)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 2-(methylsulfonyl)-4-(5-(morpholinosulfonyl)thiophen-2-yl)pyrimidine (100 mg, 0.26 mmol), 1-(2-aminoethyl)imidazolidin-2-one (36 mg, 0.28 mmol) and triethylamine (56 mg, 0.52 mmol) in toluene (3 mL) was refluxed for 6 h. After cooling to rt, the solvent was evaporated in vacuo and then methanol (5 mL) was added. After stirring for 15 min the solid was filtered and dried to give the title compound with a light yellow color (81 mg, 72%). MS (M+H)+ 439.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[CH2:13](O)[CH2:14][OH:15].O>C1(C)C=CC=CC=1>[CH2:14]1[O:15][CH:6]([C:5]2[CH:8]=[CH:9][C:2]([OH:1])=[C:3]([N+:10]([O-:12])=[O:11])[CH:4]=2)[O:7][CH2:13]1
Reactant: OCCO
Reactant: O=Cc1ccc(O)c([N+](=O)[O-])c1
Solvent: Cc1ccccc1
Solvent: O
Product: O=[N+]([O-])c1cc(C2OCCO2)ccc1O

Procedure:
25 g of 4-hydroxy-3-nitrobenzaldehyde is mixed in toluene with 1.1 equivalents of ethylene glycol and 370 mg of paratoluenesulfonic acid. It is boiled for 4 hours in a water separator. The mixture is poured onto sodium bicarbonate solution, extracted with ethyl acetate, the organic phase is washed with brine, dried with magnesium sulfate and concentrated by evaporation. 23.6 g of crude product, which is suitable for further reactions, results.
Reaction SMILES: O.[ClH:2].Cl.C([N:11](CC1C=CC=CC=1)[CH2:12][CH2:13][CH:14]1[CH2:18][N:17]([CH2:19][CH3:20])[C:16](=[NH:21])[N:15]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[ClH:2].[ClH:2].[NH2:11][CH2:12][CH2:13][CH:14]1[CH2:18][N:17]([CH2:19][CH3:20])[C:16](=[NH:21])[N:15]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: [H][H]
Reactant: CCN1CC(CCN(Cc2ccccc2)Cc2ccccc2)N(c2ccccc2)C1=N
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCN1CC(CCN)N(c2ccccc2)C1=N
Yield: 70 %

Procedure:
A solution of 10.0 g (0.023 mole) of 4-(2-dibenzylaminoethyl)-1-ethyl-2-imino-3-phenylimidazolidine dihydrochloride hydrate in 175 ml of ethanol was shaken for 7 hours in a Parr apparatus at 70° C. with palladium catalyst at 45 p.s.i. hydrogen. After filtering and concentrating the filtrate in vacuo, the solid residue was recrystallized from a 80/20% mixture of isopropanol-ethanol. The salt weighed 4.55 g (70% yield); m.p. 223°-224° C.
Reaction SMILES: CC(C)([O-])C.[Na+].[CH:7]1([CH2:10][CH2:11][OH:12])[CH2:9][CH2:8]1.Cl[C:14]1[N:22]=[C:21]2[C:17]([N:18]=[CH:19][N:20]2[CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)=[C:16]([NH2:29])[N:15]=1.O>COCCOC>[CH:7]1([CH2:10][CH2:11][O:12][C:14]2[N:22]=[C:21]3[C:17]([N:18]=[CH:19][N:20]3[CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][O:24]3)=[C:16]([NH2:29])[N:15]=2)[CH2:9][CH2:8]1
Reactant: OCCC1CC1
Reactant: Nc1nc(Cl)nc2c1ncn2C1CCCCO1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Nc1nc(OCCC2CC2)nc2c1ncn2C1CCCCO1

Procedure:
To a stirring solution of sodium tert.-butoxide (13.45 g) in DME (80 ml) was added dropwise under nitrogen a solution of 2-cyclopropylethanol (12.1 g) in DME (40 ml) over 5 min. After 30 min 2-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (11.84 g) was added and the stirring mixture refluxed for 20 h. After cooling the mixture was treated with water and extracted twice with ethyl acetate. The combined extracts were washed with water then brine, dried by passing through a hydrophobic frit and evaporated to a brown oil. This was re-evaporated twice from toluene then purified on a silica column using an ISCO Companion, eluting with methanol:ethyl acetate (0-12%) to give the title compound. Yield 6.53 gm.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([S:18]([C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH:13]=[C:12]2[C@H:28]1[CH2:30][C@H:29]1C(=C)C(OC)=O)#[N:8].[O:37]1CCC[CH2:38]1>>[C:7]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([S:18]([C:21]1[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=1)(=[O:19])=[O:20])[CH:13]=[C:12]2[C@H:28]1[CH2:30][C@H:29]1[CH2:38][OH:37])#[N:8]
Reactant: C1CCOC1
Reactant: C=C(C(=O)OC)[C@@H]1C[C@@H]1c1cn(S(=O)(=O)c2ccc(C)cc2)c2ccc(C#N)cc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: Cc1ccc(S(=O)(=O)n2cc([C@H]3C[C@H]3CO)c3cc(C#N)ccc32)cc1
Temperature: -20 °C
Reaction time: 1.5 h
Yield: 76 %

Procedure:
Powdered lithium aluminum hydride (120 mg, 3.16 mmol) was carefully added to a stirred solution of methyl [cis-2-[5-Cyano-1-(p-toluenesulfonyl)indol-3-yl]cycloprop-1-yl]-acrylate (185 mg, 0.47 mmol) in anhydrous tetrahydrofuran (10 ml) at −30° C. The resulting mixture was stirred at −20° C. for 1.5 h. The reaction was quenched with ethyl acetate (5 ml) and allowed to warmed to room temperature. After 10 min, water (120 μL) was added and after 5 min followed by a solution of aqueous sodium hydroxide (1N, 360 μL). After a further 5 min water (120 ml) was added and the solution was stirred 20 min. The aluminum salts were removed by vacuum filtration. The salts were rinsed with ethyl acetate (100 ml) and the combined filtrates were concentrated in vacuo. The crude material was purified by silica gel column chromatography with 45% ethyl acetate in hexanes to afford 131 mg (76% yield) of cis-2-[5-Cyano-1-(p-toluenesulfonyl)indol-3-yl]cyclopropanemethanol as a white solid: 1H NMR (400 MHz, CDCl3): δ 8.04 (1H, d, J=8.6 Hz), 7.99 (1H, d, J=1.0 Hz), 7.74 (2H, d, J=6.8 Hz), 7.57 (1H, dd, J=8.6, 1.6 Hz), 7.44 (1H, d, J=1.3 Hz), 7.26 (2H, d, J=8.2 Hz), 3.50 (1H, m), 3.16 (1H, m), 2.36 (3H, s), 2.05 (1H, m), 1.60 (1H, m), 1.19 (1H, m), 0.99 (1H, t, J=5.5 Hz), 0.72 (1H, q, J=5.6 Hz); MS m/e 349 (M−OH)−.