Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:19]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]/[CH:29]=[CH:30]\[CH2:31]/[CH:32]=[CH:33]\[CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH2:39]([OH:45])[CH2:40][CH:41]([OH:44])[CH2:42]O.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:1]([C:19]1([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]/[CH:29]=[CH:30]\[CH2:31]/[CH:32]=[CH:33]\[CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[O:44][CH:41]([CH2:40][CH2:39][OH:45])[CH2:42][O:20]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCC(=O)CCCCCCCC/C=C\C/C=C\CCCCC
Reactant: OCCC(O)CO
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Product: CCCCC/C=C\C/C=C\CCCCCCCCC1(CCCCCCCC/C=C\C/C=C\CCCCC)OCC(CCO)O1
Temperature: 25 °C

Procedure:
A mixture of dilinoleyl ketone (I, previously prepared as described in Example 1, 527 mg, 1.0 mmol), 1,3,4-butanetriol (technical grade, ca. 90%, 236 mg, 2 mmol) and pyridinium p-toluenesulfonate (50 mg, 0.2 mmol) in 50 mL of toluene was refluxed under nitrogen overnight with a Dean-Stark tube to remove water. The resulting mixture was cooled to room temperature. The organic phase was washed with water (2×30 mL), brine (50 mL), and dried over anhydrous Na2SO4. Evaporation of the solvent resulted in a yellowish oily residual (0.6 g). The crude product was purified by column chromatography on silica gel (230-400 mesh, 100 mL) with dichloromethane as eluent. This afforded 0.5 g of pure II as colourless oil. 1H NMR (400 MHz, CDCl3) δ: 5.25-5.48 (8H, m, 4×CH═CH), 4.18-4.22 (1H, m, OCH), 4.08 (1H, dd, OCH), 3.82 (2H, t, OCH2), 3.53 (1H, t, OCH), 2.78 (4H, t, 2×C═C—CH2—C═C), 2.06 (8H, q, 4× allylic CH2), 1.77-1.93 (2H, m, CH2), 1.52-1.68 (4H, m, 2×CH2), 1.22-1.45 (32H, m), 0.86-0.94 (6H, t, 2×CH3) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([O:17][Si:18]([CH2:23][CH3:24])([CH2:21][CH3:22])[CH2:19][CH3:20])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[NH:25][C:26](=O)[CH3:27].B.C1COCC1>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([O:17][Si:18]([CH2:19][CH3:20])([CH2:21][CH3:22])[CH2:23][CH3:24])([C:13]([F:14])([F:15])[F:16])[C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[NH:25][CH2:26][CH3:27]
Reactant: CC[Si](CC)(CC)OC(c1ccc(NC(C)=O)c(Cl)c1)(C(F)(F)F)C(F)(F)F
Agent: B
Solvent: C1CCOC1
Product: CCNc1ccc(C(O[Si](CC)(CC)CC)(C(F)(F)F)C(F)(F)F)cc1Cl
Yield: 61.8 %

Procedure:
A solution of 1.54 g (3.42 mmol) of crude N-[2-chloro-4-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-phenyl]-acetamide in 20 mL of THF was treated with 6.85 mL of a 1M solution of BH3THF-complex in THF. The mixture was kept at reflux for 3 hours and the solvent evaporated. The residue was distributed between a saturated aqueous solution of NH4Cl and Et2O. The combined organic phases were dried over Na2SO4 and the solvent was evaporated. Column chromatography on silica gel with n-heptane/EtOAc 95:5 yielded 0.922 g (61%) of [2-chloro-4-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-phenyl]-N-ethyl-amine, colorless liquid, MS: 436 (MH+, 1Cl).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:10]3[CH:11]=[N:12][N:13](CC4C=CC(OC)=CC=4)[C:14]=3[CH:15]=[CH:16][CH:17]=2)[CH:5]=[CH:4][N:3]=1.[O:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:38]=[C:37]([NH2:39])[CH:36]=[C:35]([N:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)[N:34]=2)[CH2:29][CH2:28]1.C1(OC)C=CC=CC=1>>[O:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:38]=[C:37]([NH:39][C:2]3[N:7]=[C:6]([NH:8][C:9]4[CH:17]=[CH:16][CH:15]=[C:14]5[C:10]=4[CH:11]=[N:12][NH:13]5)[CH:5]=[CH:4][N:3]=3)[CH:36]=[C:35]([N:40]3[CH2:41][CH2:42][O:43][CH2:44][CH2:45]3)[N:34]=2)[CH2:29][CH2:28]1
Reactant: COc1ccc(Cn2ncc3c(Nc4ccnc(Cl)n4)cccc32)cc1
Reactant: Nc1cc(N2CCOCC2)nc(N2CCOCC2)c1
Solvent: COc1ccccc1
Product: c1cc(Nc2ccnc(Nc3cc(N4CCOCC4)nc(N4CCOCC4)c3)n2)c2cn[nH]c2c1
Temperature: 130 °C
Yield: 34.5 %

Procedure:
N-(2-chloropyrimidin-4-yl)-1-(4-methoxybenzyl)-1H-indazol-4-amine (400 mg, 1.09 mmol) and 2,6-dimorpholinopyridin-4-amine (289 mg, 1.09 mmol) were reacted according to procedure of Example 1. After filtration of the solids and evaporation of the solvents, the resulting gum was dissolved in TFA (8.2 mL) and anisole (0.594 mL, 5.47 mmol) and sealed into a microwave tube. The reaction was heated to 130° C. over a period of 30 minutes in a Personal Chemistry EMRYS™ Optimizer EXP microwave synthesisor. The reaction mixture was concentrated to dryness, diluted with dichloromethane (20 ml), washed with water (20 ml), brine (20 ml), dried over magnesium sulfate and concentrated. The crude product was purified by flash chromatography on silica gel eluting with 0 to 5% methanol in dichloromethane. The solvent was evaporated to dryness. The resulting solid was triturated with diethyl ether/petroleum ether (1/1), collected by filtration and dried under vacuum to give N2-(2,6-dimorpholinopyridin-4-yl)-N4-(1H-indazol-4-yl)pyrimidine-2,4-diamine (178 mg, 34.4%) as a pale beige solid. NMR Spectrum: (DMSOd6) 3.17 (bs, 8H), 3.61 (bs, 8H), 6.47 (s, 1H), 6.59 (s, 2H), 7.22 (s, 1H), 7.27 (s, 1H), 7.79 (s, 1H), 8.12 (s, 1H), 8.21 (s, 1H), 9.16 (s, 1H), 9.46 (s, 1H), 13.06 (s, 1H); Mass spectrum: MH+ 474.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[CH:11][C:12]3[O:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14][C:13]=3[CH:26]=2)[CH:5]=[N:6][C:7]=1[NH2:8].[CH2:27]([O:34][C:35]([NH:37][C:38](=NC(OCC1C=CC=CC=1)=O)SC)=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(O)(=O)C>[C:28]1([CH2:27][O:34][C:35]([NH:37][C:38]2[NH:1][C:2]3[C:7]([N:8]=2)=[N:6][CH:5]=[C:4]([C:9]2[CH:10]=[CH:11][C:12]4[O:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[CH2:14][C:13]=4[CH:26]=2)[CH:3]=3)=[O:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CSC(=NC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc(-c3cnc(N)c(N)c3)cc2C1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCOc2ccc(-c3cnc4nc(NC(=O)OCc5ccccc5)[nH]c4c3)cc2C1
Temperature: 50 °C
Yield: 89.5 %

Procedure:
To a solution of 1,1-dimethylethyl 7-(5,6-diaminopyridin-3-yl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (example 15, step 2) (0.23 g, 0.65 mmol) in acetic acid (10 mL) was added 1,3-bis(benzyloxycarbonyl)-2-methyl-2-thiopseudourea (0.27 g, 0.76 mmol) and the resulting mixture was heated at 50° C. After 4 h the reaction mixture was concentrated then suspended in ethyl acetate (10 mL). Filtration followed by washing the cake with ethyl acetate (2×10 mL) provided 1,1-dimethylethyl 7-[2-({[(phenylmethyl)oxy]carbonyl}amino)-1H-imidazo[4,5-b]pyridin-6-yl]-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (0.3 g, 91% yield) as a white solid. MS (EI) for C28H29N5O5: 516 (MH+).
Reaction SMILES: [Br-].[CH2:2]([O:4][C:5]([CH2:7][CH2:8][CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:6])[CH3:3].[F:29][C:30]1[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:31]=1[C@H:37]1[CH2:42][CH2:41][C@H:40]([CH:43]=O)[CH2:39][CH2:38]1.O1CCCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].O1CCCC1>CCOCC>[F:29][C:30]1[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:31]=1[C@H:37]1[CH2:38][CH2:39][C@H:40]([CH:43]=[CH:9][CH2:8][CH2:7][C:5]([O:4][CH2:2][CH3:3])=[O:6])[CH2:41][CH2:42]1
Reactant: O=C[C@H]1CC[C@H](c2cccc(F)c2F)CC1
Reactant: CCOC(=O)CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)CCC=C[C@H]1CC[C@H](c2cccc(F)c2F)CC1
Temperature: 25 °C

Procedure:
First, 25.7 g of 3-ethoxycarbonylpropyltriphenylphosphonium bromide, 10.1 g of trans-4-(2,3-difluorophenyl)cyclohexanecarbaldehyde, and 150 ml of dry tetrahydrofuran were placed in a 300 ml flask. Then, 56.3 ml of 1.0M sodium bis(trimethylsilyl)amide/tetrahydrofuran solution was added dropwise to the reaction mixture at -70° C. to -60° C. The reaction mixture was stirred while being allowed to warm to room temperature over 6 hours. Ether was added to the reaction mixture. The ether solution was washed with water and dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled away. The residue was purified by silica gel column chromatography (eluent: toluene/hexane=1/1) to obtain 9.0 g of 2,3-difluoro-1-[trans-4-(4-ethoxycarbonyl-1-butenyl)cyclohexyl]benzene (Y: 62%). The compound thus obtained had a purity of 89.2% (mixture of E and Z isomers) by GC.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH:12]2[CH2:16][S:15][C:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[N:13]2)(=O)=O)=CC=1.[SH:26][C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C>[N:30]1[CH:31]=[CH:32][C:27]([S:26][CH2:11][CH:12]2[CH2:16][S:15][C:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[N:13]2)=[CH:28][CH:29]=1
Reactant: Sc1ccncc1
Reactant: Cc1ccc(S(=O)(=O)OCC2CSC(NC(=O)OC(C)(C)C)=N2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1=NC(CSc2ccncc2)CS1
Yield: 28.2 %

Procedure:
a suspension of 1.5 g of tert-butyl N-[(4RS)-4-(p-toluenesulphonyl-oxymethyl)-4,5-dihydro-2-thiazolyl]carbamate in 50 cm3 of acetonitrile is heated until the reagent has dissolved and 0.604 g of 4-mercaptopyridine is then added with stirring. After cooling to a temperature in the region of 20° C., 1.07 g of potassium carbonate are added. After stirring for 48 hours at a temperature in the region of 20° C., the reaction mixture is filtered. The filtrate is concentrated under reduced pressure (1 kPa) at a temperature in the region of 50° C. The residue obtained is taken up in ethyl acetate and water and the phases are separated after settling has taken place. The organic phase is washed with sodium chloride solution, dried over magnesium sulphate and chromatographed on a column of alumina, eluting with successive mixtures of ethyl acetate/cyclohexane (50/50 by volume). The fractions containing the expected product are purified by chromatography on a column of silica gel, eluting with ethyl acetate. The fractions containing the expected product are combined and then concentrated under the above conditions. 0.356 g of tert-butyl N-[(4RS)-4-(4-pyridylsulphanylmethyl)-4,5-dihydro-2-thiazolyl]carbamate is obtained in the form of a yellow oil [1H NMR spectrum (300 MHz, (CD3)2SO-d6, δ in ppm): 1.42 (s: 9H); 3.09 (dd, J=11.5 and 6 Hz: 1H); 3.29 (mt: 2H); 3.40 (dd, J=11.5 and 8 Hz: 1H); 4.25 (mt: 1H); 7.35 (dd, J=5 and 1.5 Hz: 2H); 8.40 (dd, J=5 and 1.5 Hz: 2H); from 9.70 to 10.00 (broad unresolved complex: 1H)]
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([O:26][CH3:27])[CH:25]=1)[O:6][CH2:7][C@@H:8]1[C@:17]2([CH3:18])[C@H:12]([C:13]([CH3:20])([CH3:19])[CH2:14][CH2:15][CH2:16]2)[CH2:11][CH2:10][C@@:9]1([CH3:22])O.Cl[Sn](Cl)(Cl)Cl>C(Cl)Cl>[CH3:27][O:26][C:24]1[CH:25]=[C:3]([O:2][CH3:1])[CH:4]=[C:5]2[C:23]=1[C@@:9]1([CH3:22])[C@H:8]([CH2:7][O:6]2)[C@:17]2([CH3:18])[C@H:12]([C:13]([CH3:20])([CH3:19])[CH2:14][CH2:15][CH2:16]2)[CH2:11][CH2:10]1
Reactant: COc1cc(OC)cc(OC[C@@H]2[C@@]3(C)CCCC(C)(C)[C@@H]3CC[C@@]2(C)O)c1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1cc(OC)c2c(c1)OC[C@@H]1[C@@]3(C)CCCC(C)(C)[C@@H]3CC[C@@]21C
Temperature: -78 °C

Procedure:
To a solution of (1S,2R,4aS,8aS)-1-(3,5-dimethoxyphenoxymethyl)-2,5,5,8a-tetramethyl-decahydronaphthalen-2-ol (37) (0.68 g, 1.8 mmol) in CH2Cl2 (20 mL), cooled to −78° C., a solution of SnCl4 (1 mL, 8 mmol) in CH2Cl2 (10 mL) was added dropwise. The temperature was maintained at −78° C. for 4 h then the mixture was allowed to warm to room temperature overnight. The reaction was quenched with saturated aqueous sodium bicarbonate (50 mL). The organic layer was separated, dried (Na2SO4) and concentrated. Purification by column chromatography on silica gel (Hexanes/EtOAc, 6:1) gave (1R,10R,11S,16S)-3,5-dimethoxy-1,11,15,15-tetramethyl-8-oxatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-triene (Compound No. 38) (0.49 g, 76%) as a colourless oil. 1H NMR (CDCl3): δ 6.00 (d, 1H), 5.95 (d, 1H), 4.21 (m, 1H), 3.95 (t, 1H), 3.72 (d, 6H), 3.00 (m, 1H), 1.80-0.95 (m, 13H), 0.90 (s, 3H), 0.88 (m, 1H), 0.83 (s, 3H), 0.80 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][NH:14][C:15]1[C:16]([O:28][C:29]2[CH:34]=[CH:33][C:32]([NH:35]C(OCC3C=CC=CC=3)=O)=[CH:31][CH:30]=2)=[N:17][C:18]([C:21]2[CH:22]=[N:23][CH:24]=[C:25]([F:27])[CH:26]=2)=[N:19][CH:20]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd].CCO>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][NH:14][C:15]1[C:16]([O:28][C:29]2[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=2)=[N:17][C:18]([C:21]2[CH:22]=[N:23][CH:24]=[C:25]([F:27])[CH:26]=2)=[N:19][CH:20]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CNc1cnc(-c2cncc(F)c2)nc1Oc1ccc(NC(=O)OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC[C@H]1CNc1cnc(-c2cncc(F)c2)nc1Oc1ccc(N)cc1
Reaction time: 20 h

Procedure:
To a Parr bottle was placed 10% Pd/C (100 mg), Compound 12a (1.2 g; 1.9 mmol) and EtOH (35 mL). The reaction mixture was placed under a 50-psi H2 atmosphere and the reaction was shaken for 20 h. The catalyst was collected by vacuum filtration and the filtrate was evaporated in vacuo to afford Compound 12b. The compound was used in the next step without further purification. MS: m/z 481.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1(OC)[CH2:15][CH2:14][C:13]([O:21]C)([CH:16]([O:19][CH3:20])[O:17][CH3:18])[O:12]1.CC(C)=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11](=[O:12])[CH2:15][CH2:14][C:13](=[O:21])[CH:16]([O:19][CH3:20])[O:17][CH3:18]
Reactant: COC(=O)CCCCCCCC1(OC)CCC(OC)(C(OC)OC)O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)CCCCCCCC(=O)CCC(=O)C(OC)OC
Yield: 93.7 %

Procedure:
8-(2,5-Dimethoxy-5-dimethoxymethyl-tetrahydro-2-furyl)-octanoic acid methyl ester (1.00 g, 0.0028 mole), 20 ml of acetone and p-toluenesulfonic acid (0.002 g) were stirred for 2 hours at room temperature. The clear solution was poured into cold water (100 ml, 0° C) and extracted with two 50-ml portions of ether. The combined ethereal extracts were washed with 6% aqueous sodium hydrogen carbonate (30 ml) and then with two 50-ml portions of water, dried with magnesium sulfate, and evaporated to dryness from a water bath (60° C), at last under 15 mm Hg. The distillation of residual oil gave 0.83 g (95%) of the title compound, b0.1 154°-156° C, nD25 1.4531.
Reaction SMILES: O[CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:3]1.COCCN(S(F)(F)[F:35])CCOC.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>ClCCl>[F:35][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:3]1
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: COC(=O)c1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1ccc(C2CCN(C(=O)OC(C)(C)C)CC2F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
tert-Butyl 3-hydroxy-4-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylate described in Production Example 6-2 (518 mg, 1.54 mmol) was dissolved in dichloromethane (15 mL), [bis-(2-methoxyethyl)amino]sulfur trifluoride (0.313 mL, 1.70 mmol) was added at −78° C. over 3 minutes, and the mixture was stirred for 1 hour while warming to room temperature. A saturated aqueous sodium bicarbonate solution and ethyl acetate were serially added to the reaction mixture. The aqueous layer was extracted with ethyl acetate three times and then the organic layers were combined, dried over anhydrous sodium sulfate, and filtered. The solvent was evaporated and the resultant residue was purified with silica gel column chromatography (n-heptane:ethyl acetate=19:1-3:2) to obtain the title compound (402 mg, 77%).
Reaction SMILES: [OH:1][Si:2]1([CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C1(N=C=NC2CCCCC2)CCCCC1.[N+:30]([C:33]1[CH:38]=[CH:37][C:36](O)=[CH:35][CH:34]=1)([O-:32])=[O:31]>C(OCC)(=O)C>[OH:1][Si:2]1([CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][C:36]2[CH:37]=[CH:38][C:33]([N+:30]([O-:32])=[O:31])=[CH:34][CH:35]=2)=[O:13])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=C(O)CCCC[Si]1(O)CCCCC1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Product: O=C(CCCC[Si]1(O)CCCCC1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.3 %

Procedure:
To 5-(1-hydroxysilinan-1-yl)pentanoic acid (130 mg, 0.601 mmol) in ethyl acetate (5 mL), N,N′-dicyclohexylcarbodiimide (186 mg, 0.901 mmol) was added. The reaction was stirred under nitrogen at ambient temperature for 30 minutes. After this time, 4-nitrophenol (100 mg, 0.719 mmol) was added, and the reaction was stirred for 16 hours at ambient temperature. After this time, the reaction was filtered to remove any solids, the filter cake was washed with ethyl acetate, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography eluting with hexanes to 1:3 ethyl acetate/hexanes to afford 4-nitrophenyl 5-(1-hydroxysilinan-1-yl)pentanoate (106 mg, 52%) as a colorless oil. 1H NMR (500 MHz, CDCl3) δ 8.26 (dt, J=9.0, 2.5 Hz, 2H), 7.27 (dt, J=9.0, 2.5 Hz, 2H), 2.61 (t, J=7.5 Hz, 2H), 1.84-1.78 (m, 2H), 1.76-1.67 (m, 4H), 1.56-1.44 (m, 4H), 1.40-1.33 (m, 1H), 0.75-0.63 (m, 6H).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[O:8]([CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClCCCl>[CH:15]1([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:4]([CH2:3][CH2:2][C:1]([OH:6])=[O:7])=[O:5])=[CH:11][CH:10]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: c1ccc(OC2CCCCC2)cc1
Reactant: O=C1CCC(=O)O1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: O=C(O)CCC(=O)c1ccc(OC2CCCCC2)cc1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
A solution of succinic anhydride (20 g.) and phenoxycyclohexane (35.1 g.) in 1,2-dichloroethane (250 ml.) was stirred at 0° C and treated with powdered anhydrous aluminium chloride (58.2 g.) and stirring was continued for 5 hours at 0°-5° C. It was then poured carefully with stirring into ice-water (1 liter) containing concentrated hydrochloric acid (100 ml.). The organic layer was separated, washed with water and extracted with a solution of sodium hydroxide (8 g.) in water (250 ml.). The alkaline extract was adjusted to pH 4-6 by the addition of dilute hydrochloric acid to yield the product (6.8 g.), m.p. 190°-192° C after crystallisation from aqueous methanol.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21](I)[C:16]2=[CH:15][N:14]=1.[CH2:23]([N:25]1[CH2:34][CH2:33][C:32]2[C:27](=[CH:28][CH:29]=[C:30](B3OC(C)(C)C(C)(C)O3)[CH:31]=2)[C:26]1=[O:44])[CH3:24]>>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21]([C:30]3[CH:31]=[C:32]4[C:27](=[CH:28][CH:29]=3)[C:26](=[O:44])[N:25]([CH2:23][CH3:24])[CH2:34][CH2:33]4)[C:16]2=[CH:15][N:14]=1
Reactant: COc1cc(OC)c(Cl)c(-c2ncc3c(I)n[nH]c3n2)c1Cl
Reactant: CCN1CCc2cc(B3OC(C)(C)C(C)(C)O3)ccc2C1=O
Product: CCN1CCc2cc(-c3n[nH]c4nc(-c5c(Cl)c(OC)cc(OC)c5Cl)ncc34)ccc2C1=O

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 8, Step 2 starting from 6-(2,6-dichloro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidine and 2-ethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinolin-1(2H)-one. LCMS (M+H)+=498.1/500.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([S:12]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:7]=[C:6]2[C:22]1[C:23]2[CH:30]=[C:29]([C:31]3[C:39]4[C:34](=[CH:35][CH:36]=[C:37]([O:40][CH3:41])[CH:38]=4)[NH:33][CH:32]=3)[N:28]([S:42]([C:45]3[CH:50]=[CH:49][C:48]([CH3:51])=[CH:47][CH:46]=3)(=[O:44])=[O:43])[C:24]=2[N:25]=[CH:26][N:27]=1.[H-].[Na+].[CH3:54]I>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([S:12]([C:15]1[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=1)(=[O:13])=[O:14])[CH:7]=[C:6]2[C:22]1[C:23]2[CH:30]=[C:29]([C:31]3[C:39]4[C:34](=[CH:35][CH:36]=[C:37]([O:40][CH3:41])[CH:38]=4)[N:33]([CH3:54])[CH:32]=3)[N:28]([S:42]([C:45]3[CH:46]=[CH:47][C:48]([CH3:51])=[CH:49][CH:50]=3)(=[O:44])=[O:43])[C:24]=2[N:25]=[CH:26][N:27]=1
Reactant: CI
Reactant: COc1ccc2[nH]cc(-c3cc4c(-c5cn(S(=O)(=O)c6ccc(C)cc6)c6ccc(OC)cc56)ncnc4n3S(=O)(=O)c3ccc(C)cc3)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c(-c1cc3c(-c4cn(S(=O)(=O)c5ccc(C)cc5)c5ccc(OC)cc45)ncnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-(5-methoxy-1-[(4-methylphenyl)sulfonyl]-1H-indol-3-yl)-6-(5-methoxy-1H-indol-3-yl)-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine [270 mg, Reference Example 10] in dimethylformamide (10 mL) was added the sodium hydride (10 mg, 60% dispersion in oil) and methyl iodide (0.025 mL) under inert atmosphere. The solution was stirred for 16 hours at room temperature and the solvent was evaporated under reduced pressure. The residue was partitioned between water and ethyl acetate The organic phase was separated, then dried over magnesium sulfate and then evaporated under reduced pressure. The residue was subjected to flash column chromatography on silica eluting with a mixture of ethyl acetate and cyclohexane (50:50, v/v) to give the title compound (93 mg) as an amorphous solid. MS: 732 [MH]+. LCMS (Method B) RT=4.68 minutes.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][CH2:11][OH:12])=[N:2]1.C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][CH2:11][O:12][S:21]([CH3:20])(=[O:23])=[O:22])=[N:2]1
Reactant: CS(=O)(=O)Cl
Reactant: OCCc1noc2ccccc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCc1noc2ccccc12
Reaction time: 1 h
Yield: 103.1 %

Procedure:
To a solution of 2-benzo[d]isoxazol-3-yl-ethanol (0.537 g, 3.29 mmol, from step (i) above ) and triethylamine (0.55 mL, 3.95 mmol) in dichloromethane (20 mL) was added methanesulfonyl chloride (0.31 mL, 3.95 mmol) at 0° C. The reaction mixture was stirred for 1 hour and was then extracted with water (2×20 mL) and brine (20 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo, which afforded 818 mg (98%) of the title compound.