Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH:13]=O)[C@H:10]([CH2:15][N:16]([C:20](=[O:35])[C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH3:28])=[C:23]([O:29][CH2:30][CH2:31][CH2:32][O:33][CH3:34])[CH:22]=2)[CH:17]([CH3:19])[CH3:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:36][NH2:37].[BH4-].[Na+].C(Cl)Cl.CO.[NH4+].[OH-]>>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][NH:37][CH3:36])[C@H:10]([CH2:15][N:16]([C:20](=[O:35])[C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH3:28])=[C:23]([O:29][CH2:30][CH2:31][CH2:32][O:33][CH3:34])[CH:22]=2)[CH:17]([CH3:19])[CH3:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCc1ccc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2C=O)C(C)C)cc1OCCCOC
Reactant: CN
Agent: [BH4-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CCc1ccc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CNC)C(C)C)cc1OCCCOC

Procedure:
In a similar manner as described in Example 9 for the reaction step J, the following starting materials is prepared from (3R,4S)-3-({[4-ethyl-3-(3-methoxy-propoxy)-benzoyl]-isopropyl-amino}-methyl)-4-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester (3.5 g, 6 mmol), methyl amine (0.93 mL, 30 mmol) and NaBH4 (0.454 g, 12 mmol) and purification by flash chromatography on silica gel (CH2Cl2/MeOH 1:1) to (CH2Cl2/MeOH/NH4OH 89:10:1) to give the title compound as colorless oil. TLC, Rf (CH2Cl2/MeOH/NH4OH 89:10:1)=0.29. MS (LC-MS): 506.2 [M+H]+; tR (HPLC, Macherey-Nagel Nucleosil C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 mL/min): 5.38 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:15][CH2:16][CH:17]=[CH2:18])([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C1C=CC=CN=1)C.[C:28](OC(=O)C)(=[O:30])[CH3:29].C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([O:14][C:28](=[O:30])[CH3:29])([CH2:15][CH2:16][CH:17]=[CH2:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCCC1(O)CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCCC1(OC(C)=O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 20 °C
Reaction time: 8 h
Yield: 78.8 %

Procedure:
A solution of tert-butyl-4-(but-3-en-1-yl)-4-hydroxypiperidine-1-carboxylate (3.7 g, 14.51 mmol) in dichloromethane (20 mL) was treated with dimethylaminopyridine (1.8 g, 14.51 mmol), acetic anhydride (4.1 mL, 43.53 mmol) and triethylamine (6.1 mL, 43.53 mmol), stirred overnight at 20° C. The solvent was removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The aqueous layer was extracted twice with ethyl acetate. Combined organic extracts were washed with water, dried (Na2SO4) and filtered. The filtrate was concentrated under reduced pressure, purified by flash chromatography to provide the title compound 16C as colorless oil (3.4 g).
Reaction SMILES: C1(N[CH:8]=[N:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)C=CC=CC=1.NC1C=CC=CC=1.C(OCC)(OCC)[O:24][CH2:25][CH3:26]>>[C:10]1([N:9]=[CH:8][O:24][CH2:25][CH3:26])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CCOC(OCC)OCC
Reactant: C(=Nc1ccccc1)Nc1ccccc1
Solvent: Nc1ccccc1
Product: CCOC=Nc1ccccc1

Procedure:
The synthesis is achieved in three steps. The first step is the preparation of N,N′-diphenyl formamidine (by the reaction of aniline with triethyl orthoformate). This intermediate is then further reacted with triethyl orthoformate to produce ethyl N-phenylimidoformate. The final step is the reaction of ethyl phenylimidoformate with 4-aminostyrene to give the product.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:17]=1)[C:12](Cl)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:26][C:27]([F:36])([F:35])[C:28]1[CH:29]=[C:30]([CH:32]=[CH:33][CH:34]=1)[NH2:31]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:17]=1)[C:12]([NH:31][C:30]1[CH:32]=[CH:33][CH:34]=[C:28]([C:27]([F:26])([F:35])[F:36])[CH:29]=1)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: O=C(Cl)c1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Solvent: C1CCOC1
Product: O=C(Nc1cccc(C(F)(F)F)c1)c1cc(OCc2ccccc2)cc(OCc2ccccc2)c1

Procedure:
(Examplary Compound 8). The title compound was prepared according to the procedure of Scheme I-A, starting from 3,5-bis(benzyloxy)benzoic acid chloride and 3-(trifluoromethyl)aniline in THF solution. White solid, yield 0.250 g (69%). 1H NMR (DMSO-d6, 400 MHz), δ: 10.47 (s, 1H); 8.24 (s, 1H); 8.06 (d, J=8.3 Hz, 1H); 7.60 (t, J=8.0 Hz, 1H); 7.51-7.32 (m, 11H); 7.25 (s, 2H); 6.95 (s, 1H); 5.18 (s, 4H). Anal: Calcd. for C28H22F3NO3: 70.43; H, 4.64; N, 2.93. Found: C, 70.58; H, 4.67; N, 2.91.
Reaction SMILES: Cl[C:2]1([CH2:7][C:8]([Cl:11])(Cl)[Cl:9])[O:5][C:4](=O)[CH2:3]1.Cl.[NH2:13][C:14]([NH2:16])=[NH:15].Cl>>[NH2:16][C:14]1[N:15]=[C:2]([CH:7]=[C:8]([Cl:11])[Cl:9])[CH:3]=[C:4]([OH:5])[N:13]=1
Reactant: N=C(N)N
Reactant: O=C1CC(Cl)(CC(Cl)(Cl)Cl)O1
Agent: Cl
Product: Nc1nc(O)cc(C=C(Cl)Cl)n1
Temperature: 140 °C
Reaction time: 0.75 h

Procedure:
119 Parts of 4-chloro-4-(2,2,2-trichloroethyl)-oxetan-2-one and 95.5 parts of guanidine hydrochloride were charged to a reaction flask and heated in an oil bath at 140° C. for 15 minutes. The solid dissolved and HCl gas was evolved. The oil bath temperature was raised to 160° C. and heating was continued for a further 45 minutes. The heat was removed and the reaction mass was stirred until cool and solidified. The solid was stirred with 250 parts of ethyl acetate and filtered. The filtrate was discarded and the solid dissolved in 1000 parts of hot water, treated with charcoal and filtered. The aqueous solution was cooled and neutralised by the addition of saturated sodium acetate solution. The precipitated solid was filtered and washed with water. This crude product was then dissolved in 550 parts of concentrated hydrochloric acid, diluted with 800 parts of water and stirred with 5 parts of charcoal for 20 minutes. The solution was filtered and the product precipitated by the addition of saturated sodium acetate solution to pH 6. The solid was filtered, washed with water and dried in a vacuum oven at 110° C. to give 2-amino-4-(2,2-dichloro-vinyl)-6-hydroxypyrimidine m.p. 245°-248° C. (decomposition).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:5]=1[C:6]#[N:7])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[CH:20]=[CH2:21]>CC(C)=O>[CH2:21]([O:12][C:9]1[CH:10]=[CH:11][C:4]([O:3][CH2:1][CH3:2])=[C:5]([CH:8]=1)[C:6]#[N:7])[CH:20]=[CH2:19]
Reactant: CCOc1ccc(O)cc1C#N
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc(OCC)c(C#N)c1

Procedure:
25 g of 2-ethoxy-5-hydroxybenzonitrile (153.2 mmol) (example 36A) and potassium carbonate (63.52 g, 459.6 mmol) are initially charged in 750 ml of acetone, 19.9 ml of allyl bromide (229.8 mmol) are added, and the mixture is stirred under reflux overnight. The mixture is filtered off and concentrated giving a mobile orange oil.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[C:12]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][C:14]=2[CH3:22])=[C:11]([CH3:23])[O:10][N:9]=1.O[N:25]=[C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[O:34][C:35]([F:38])([F:37])[F:36])[NH2:27].CCN(C(C)C)C(C)C>>[CH3:7][C:8]1[C:12]([C:13]2[CH:21]=[CH:20][C:16]([C:17]3[O:19][N:27]=[C:26]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[O:34][C:35]([F:36])([F:37])[F:38])[N:25]=3)=[CH:15][C:14]=2[CH3:22])=[C:11]([CH3:23])[O:10][N:9]=1
Reactant: Cc1cc(C(=O)O)ccc1-c1c(C)noc1C
Reactant: NC(=NO)c1ccccc1OC(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(-c2nc(-c3ccccc3OC(F)(F)F)no2)ccc1-c1c(C)noc1C

Procedure:
Oxalyl chloride (132 μL; 1.56 mmol; 3 eq.), Intermediate 30 (120 mg; 0.52 mmol; 1 eq.), Intermediate 2 (114 mg; 0.52 mmol, 1 eq.) and DIEA (268 μL; 1.56 mmol; 3 eq.) were reacted according to general procedure 2. Purification by column chromatography c-hexane/ethyl acetate, 80/20) afforded the title compound as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([S:9][C:10]([F:13])([F:12])[F:11])[CH:3]=1.[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[S:9][C:10]([F:13])([F:11])[F:12])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ccc(Br)cc1SC(F)(F)F
Product: FC(F)(F)Sc1cc(Br)ccc1OCc1ccccc1
Reaction time: 1 h

Procedure:
1-Benzyloxy-4-bromo-2-trifluoromethylthiobenzene was prepared from 4-bromo-1-hydroxy-2-trifluoromethylthiobenzene following Method C. The reaction was conducted at 50° C. for 1 h using benzyl bromide as an alkylating agent and the resulting product was purified by column chromatography using hexanes as an eluent to afford 1-benzyloxy-4-bromo-2-trifluoromethylthiobenzene in 63% yield.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11](Cl)=[O:12])[C:6]=1[CH3:14])(=[O:3])[CH3:2].C([O-])([O-])=O.[Na+].[Na+].[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CC(C)=O>Cl[Pd]Cl.O>[C:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11](=[O:12])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:6]=1[CH3:14])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cccc(C(=O)Cl)c1C
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)Oc1cccc(C(=O)c2ccccc2)c1C
Yield: 64.3 %

Procedure:
A mixture of 3-(chlorocarbonyl)-2-methylphenyl acetate (10.0 g, 47.0 mmole), PdCl2 (83.4 mg, 0.470 mmole), Na2CO3 (8.13 g, 76.7 mmole) and phenyl boronic acid (6.02 g, 49.4 mmole) in a 3:1 acetone:H2O mixture (300 mL) was stirred at room temperature for 5 days. The acetone was removed in vacuo and the aqueous mixture was extracted with EtOAc (2×200 mL). The combined extracts were washed with brine (100 mL), dried over MgSO4, filtered and concentrated in vacuo to give 7.68 g (64% yield) of the product as a white crystalline solid: E1HRMS m/z 254.0939 (M+, C16H14O3, Calc'd 254.0943).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:21])[C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][C:13]=2[C:22]([O:24]C)=O.[NH3:26]>C1COCC1.[OH-].[NH4+]>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:21])[C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][C:13]=2[C:22](=[O:24])[NH2:26]
Reactant: N
Reactant: COC(=O)c1cccc2c1c1c(O)cccc1n2Cc1ccccn1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NC(=O)c1cccc2c1c1c(O)cccc1n2Cc1ccccn1
Temperature: 35 °C
Yield: 54 %

Procedure:
A solution of the 9-[(2-pyridyl)methyl]-4-hydroxy-5-carbomethoxy carbazole (480 mg, 1.43 mmol) in 10 mL THF and 40 mL concentrated aqueous ammonium hydroxide was treated with a stream of NH3 gas to ensure saturation. The reaction vessel was capped and the mixture heated to 35° C. with stirring until tlc indicated complete consumption of starting material (20 hours). The THF was evaporated and the aqueous layer saturated with solid sodium chloride. The mixture was extracted three times with THF. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The foam was taken up in hot ethyl acetate and passed over a shoroom temperaturecolumn of silica gel using ethyl acetate as the eluent to afford 247 mg (54%) of the 9-[(2-pyridyl)methyl]-4-hydroxy-5-carbamoyl carbazole as a white solid. 1H NMR (DMSO-d6) δ10.46 (s, 1H), 8.81 (br s, 1H), 8.46 (d, 1H, J=5.8 Hz), 8.36 (br s, 1H), 7.8 (dd, 1H, J=2.9 and 6.4 Hz), 7.67-7.59 (m, 1H), 7.47-7.41 (m, 2H), 7.30-7.20 (m, 2H), 7.05 (d, 1H, J=7.9 Hz), 6.87 (d, 1H, J=8.3 Hz), 6.57 (d, 1H, J=7.8 Hz), and 5.73 (s, 2H). IR (KBr, cm−1) 3404, 3051, 1652, 1618, 1595, 1582, 1567, 1559, 1450, 1436, 1334, 1266, 1226, 776, 763 and 647. MS (ES) m/e 318 (M+1).
Reaction SMILES: [CH2:1]([NH:4][CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3].C([BH3-])#N.[Na+].C(OC)(OC)OC.[Si:19]([O:26][CH2:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[CH:34]=[C:33]([CH2:38][CH2:39][CH:40]=O)[CH:32]=[CH:31]2)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>CO>[Si:19]([O:26][CH2:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[CH:34]=[C:33]([CH2:38][CH2:39][CH2:40][N:4]([CH2:5][CH2:6][CH3:7])[CH2:1][CH2:2][CH3:3])[CH:32]=[CH:31]2)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc2cc(CCC=O)ccc2c1
Reactant: CCCNCCC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: COC(OC)OC
Solvent: CO
Product: CCCN(CCC)CCCc1ccc2cc(CO[Si](C)(C)C(C)(C)C)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.6 %

Procedure:
Dipropylamine (363 mg) was dissolved in anhydrous methanol (20 ml) and then added with sodium cyanoborohydride (281 mg), trimethyl orthoformate (0.490 ml), and the compound (981 mg) obtained in Example 121-7, followed by stirring overnight at room temperature under a nitrogen atmosphere. After completion of the reaction, the solvent was distilled off. Then, the residue was dissolved in chloroform and added with a saturated aqueous sodium bicarbonate solution, followed by stirring. The solution was extracted with chloroform and the extract was then washed with a saturated aqueous sodium bicarbonate solution and saturated saline solution. After that, the organic layer was dried with anhydrous sodium sulfate. Subsequently, the solvent was distilled off and the residue was then purified through silica gel column chromatography (chloroform/ethyl acetate), thereby obtaining the subject compound (1.28 g) as a brown liquid.
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][C:5](=[O:10])[CH2:4][C:3]1([CH3:12])[CH3:11].[CH3:13]S(C)=O.OO>O>[CH3:13][O:1][N:2]1[C:7]([CH3:8])([CH3:9])[CH2:6][C:5](=[O:10])[CH2:4][C:3]1([CH3:12])[CH3:11]
Reactant: CS(C)=O
Reactant: CC1(C)CC(=O)CC(C)(C)N1O
Agent: OO
Solvent: O
Product: CON1C(C)(C)CC(=O)CC1(C)C
Temperature: 30.5 °C
Reaction time: 0.5 h
Yield: 77.9 %

Procedure:
A 5.0 L 4 neck mechanically stirred flask is charged with 1oxyl-2,2,6,6-tetramethyl-4-piperidone (300 g, 1.76 moles), ferrous sulfate heptahydrate (513.7 g, 1.85 moles) and dimethylsulfoxide (1450 g). Hydrogen peroxide, 30% (279.2 g, 2.46 moles), is added over a 1 hour 45 min span. The temperature is maintained at 29-32° C. The Content is stirred for an additional 30 min at 25-30° C. and then chilled below 10° C. Water (1250 ml) is added and the mixture is extracted with four 750 ml portions of ethyl acetate. The combined extracts are washed, 2×1.0 L of H2O, then 1×500 ml of saturated NaCl and then dried over anhydrous MgSO4. Ethyl acetate is evaporated and the product is distilled (82-84° C./0.33×10−2 bar), yielding 254 g of a pale yellow oil (yield: 78% of theory; IR-spectrum: Ketone carbonyl, 1710 cm−1).
Reaction SMILES: [ClH:1].Cl.[OH:3][NH:4][C:5]([NH:17][CH3:18])=[N:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[NH:15][CH:14]=[N:13][C:12]=1[CH3:16].Cl.[CH3:20]ON.C(=O)([O-])O.[K+].[Cl-].[Na+]>O>[ClH:1].[ClH:1].[CH3:20][O:3][NH:4][C:5]([NH:17][CH3:18])=[N:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[NH:15][CH:14]=[N:13][C:12]=1[CH3:16]
Reactant: CON
Reactant: CNC(=NCCSCc1[nH]cnc1C)NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: O
Product: CNC(=NCCSCc1[nH]cnc1C)NOC
Yield: 72.5 %

Procedure:
A mixture of the isothiourea dihydrochloride from Example I (i) (6.6 g), methoxyamine hydrochloride (5.0 g), potassium hydrogen carbonate (8.0 g) and water (60 ml) was refluxed for 24 hours. Following cooling, an excess of sodium chloride was added and the solution extracted with chloroform (5×100 ml). The chloroform extracts were concentrated to give the free base which was purified on a column of silica gel by elution with chloroform-methanolic ammonia. After treatment with an excess of ethanolic hydrogen chloride, the residue was triturated with acetonitrile to give the title compound (2.5 g), m.p. 182°-185°.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[C:9](Br)[N:8]([C@@H:25]3[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:37][C:38]1(C)[C:42](C)(C)OB(C(C)=C)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[C:9]([C:38]([CH3:42])=[CH2:37])[N:8]([C@@H:25]3[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](n2c(Br)c(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
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: C1COCCO1
Product: C=C(C)c1c(-c2ccc(Oc3ccccc3)cc2)c2c(N)ncnc2n1[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 80 °C
Yield: 85.4 %

Procedure:
A mixture of (R)-tert-butyl 3-(4-amino-6-bromo-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylate (9) (150 mg, 0.27 mmol), 4,4,5,5-tetra methyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (136 mg, 0.81 mmol), tetrakis (31 mg, 0.027 mmol) and Na2CO3 (0.40 mL, 2M solution in water) in dioxane (3.0 mL) was purged with N2 before heated at 80° C. overnight. After cooled down to r. t., the reaction mixture was concentrated under reduced pressure to give the crude product which was purified by column chromatographic (silica gel, 0 to 70% ethyl acetate in petroleum ether) to afford (R)-tert-butyl 3-(4-amino-5-(4-phenoxyphenyl)-6-(prop-1-en-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylate (116) (118 mg, 85% yield) as a brown solid. LC-MS (ESI): m/z (M+1) 512.1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12](Cl)=[CH:11][C:10]=1[Br:16])([CH3:4])([CH3:3])[CH3:2].BrC1C=CC([F:25])=CC=1O.BrCC(OC(C)(C)C)=O>>[C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[C:13]([F:25])[CH:12]=[CH:11][C:10]=1[Br:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)COc1ccc(Cl)cc1Br
Reactant: Oc1cc(F)ccc1Br
Agent: CC(C)(C)OC(=O)CBr
Product: CC(C)(C)OC(=O)COc1cc(F)ccc1Br
Yield: 95 %

Procedure:
Following the general method as outlined in Intermediate 1, starting from 2-bromo-5-fluorophenol and tert-butyl bromoacetate (Aldrich), the title compound was obtained as a white solid in 95% yield.
Reaction SMILES: [NH2:1][CH:2]([CH:20]([CH3:22])[CH3:21])[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]=1)=[O:4].[CH2:23](Br)[C:24]#[CH:25]>>[CH2:25]([NH:1][CH:2]([CH:20]([CH3:22])[CH3:21])[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]=1)=[O:4])[C:24]#[CH:23]
Reactant: C#CCBr
Reactant: CC(C)C(N)C(=O)OCc1cccc(Oc2ccccc2)n1
Product: C#CCNC(C(=O)OCc1cccc(Oc2ccccc2)n1)C(C)C

Procedure:
Following the procedure of Example 2, (6-phenoxy-2-pyridyl)methyl 2-amino-3-methylbutanoate and 2-propyn-1-yl bromide are reacted, resulting in a mixture of two end products, which are separated to give (6-phenoxy-2-pyridyl)methyl 2-[N-(2-propynyl)amino]-3-methylbutanoate and (6-phenoxy-2-pyridyl)methyl 2-[N,N-(di-2-propynyl)amino-3-methylbutanoate.
Reaction SMILES: [CH:1]1([N:4]([CH2:18][C:19]2[O:20][CH:21]=[C:22]([C:24]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[O:25])[N:23]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:3][CH2:2]1.[CH3:32][C:33]1[N:38]=[CH:37][CH:36]=[C:35]([CH:39]=O)[CH:34]=1.CC(O)=O>ClCCCl>[CH:1]1([N:4]([CH2:18][C:19]2[O:20][CH:21]=[C:22]([C:24]([N:26]3[CH2:31][CH2:30][N:29]([CH2:39][C:35]4[CH:36]=[CH:37][N:38]=[C:33]([CH3:32])[CH:34]=4)[CH2:28][CH2:27]3)=[O:25])[N:23]=2)[S:5]([C:8]2[C:9]([CH3:17])=[CH:10][C:11]([O:15][CH3:16])=[CH:12][C:13]=2[CH3:14])(=[O:6])=[O:7])[CH2:2][CH2:3]1
Reactant: Cc1cc(C=O)ccn1
Reactant: COc1cc(C)c(S(=O)(=O)N(Cc2nc(C(=O)N3CCNCC3)co2)C2CC2)c(C)c1
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COc1cc(C)c(S(=O)(=O)N(Cc2nc(C(=O)N3CCN(Cc4ccnc(C)c4)CC3)co2)C2CC2)c(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of N-cyclopropyl-4-methoxy-2,6-dimethyl-N-{[4-(piperazin-1-ylcarbonyl)-1,3-oxazol-2-yl]methyl}benzenesulfonamide (30 mg, 0.07 mmol) in DCE (2 mL) were added 6-methyl-4-pyridinecarboxaldehyde (10 mg, 0.08 mmol) and AcOH (3 μL, 0.07 mmol) and the reaction mixture was stirred for 1 h at ambient temperature. STAB (20 mg, 0.09 mmol) was added and the reaction was stirred for 16 h. The reaction mixture was quenched with H2O (2 mL) and extracted with DCM (3×2 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified using prep method D to afford the title compound.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:15][CH3:16])[C:4]1[C:9](Br)=[CH:8][C:7]([O:11][CH3:12])=[C:6]([O:13][CH3:14])[CH:5]=1.[CH:17](=[O:19])[CH3:18]>>[CH3:1][O:2][CH:3]([O:15][CH3:16])[C:4]1[C:9]([CH:17]([OH:19])[CH3:18])=[CH:8][C:7]([O:11][CH3:12])=[C:6]([O:13][CH3:14])[CH:5]=1
Reactant: COc1cc(Br)c(C(OC)OC)cc1OC
Reactant: CC=O
Product: COc1cc(C(C)O)c(C(OC)OC)cc1OC

Procedure:
6-Bromo-3,4-dimethoxybenzaldehyde dimethylacetal and acetaldehyde are treated in the same manner as in Reference Example 3 to give 3,4-dimethoxy-6-(1-hydroxyethyl)benzaldehyde dimethylacetal as oil.
Reaction SMILES: [C:1]([C:4]1[CH:16]=[CH:15][C:7]([CH:8]=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:5]=1)(O)=[O:2].S(Cl)([Cl:19])=O.C1(C)C=CC=CC=1>CN(C)C=O>[Cl:19][C:1]([C:4]1[CH:16]=[CH:15][C:7]([CH:8]=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:5]=1)=[O:2]
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)C=Cc1ccc(C(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)C=Cc1ccc(C(=O)Cl)cc1
Yield: 78.8 %

Procedure:
14.8 g (67 mmols) of ethyl 4-carboxycinnamate, 9.57 g (80 mmols) of thionyl chloride, 100 ml of toluene and 0.18 ml of N,N-dimethylformamide are boiled under reflux for 30 minutes. The reaction mixture is evaporated and the crude product is recrystallised from n-hexane. 12.6 g (79% of theory) of ethyl 4-chloroformylcinnamate are obtained in the form of white crystals; melting point 76.8° C.
Reaction SMILES: Br[C:2]12[CH2:11][CH:7]([CH2:8][CH2:9][CH2:10]1)[CH:6]1[CH2:12][CH:3]2[CH2:4][CH2:5]1.[CH2:13]([OH:15])[CH3:14]>[Ag]=O>[CH2:13]([O:15][C:2]12[CH2:11][CH:7]([CH2:8][CH2:9][CH2:10]1)[CH:6]1[CH2:12][CH:3]2[CH2:4][CH2:5]1)[CH3:14]
Reactant: CCO
Reactant: BrC12CCCC(C1)C1CCC2C1
Agent: O=[Ag]
Product: CCOC12CCCC(C1)C1CCC2C1
Yield: 82.6 %

Procedure:
A mixture of 5.0 g of 1-bromotricyclo[4.3.1.12,5 ]undecane, 3.0 g of silver oxide and 30 ml of anhydrous ethanol was refluxed for 2 hours. Thereafter, the mixture was treated in the same manner as described in Example 1 to obtain 3.5 g (yield, 82.6%) of 1-ethoxytricyclo[4.3.1.12,5 ]undecane having a boiling point of 97° to 98° C./4 mmHg.
Reaction SMILES: Br[CH2:2][C:3]1[N:8]([CH3:9])[C:7](=[O:10])[N:6]([CH3:11])[C:5](=[O:12])[C:4]=1[C:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=1.[NH2:22][CH2:23][C@@H:24]([OH:27])[CH2:25][OH:26].C(N(CC)CC)C>CCO>[Cl:20][C:16]1[CH:15]=[C:14]([C:13]2[N:22]([CH2:23][C@@H:24]([OH:27])[CH2:25][OH:26])[CH:2]=[C:3]3[C:4]=2[C:5](=[O:12])[N:6]([CH3:11])[C:7](=[O:10])[N:8]3[CH3:9])[CH:19]=[CH:18][CH:17]=1
Reactant: Cn1c(CBr)c(C(=O)c2cccc(Cl)c2)c(=O)n(C)c1=O
Reactant: NC[C@@H](O)CO
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cn1c(=O)c2c(-c3cccc(Cl)c3)n(C[C@@H](O)CO)cc2n(C)c1=O
Temperature: 100 °C

Procedure:
A mixture of 6-(bromomethyl)-5-(3-chlorobenzoyl)-1,3-dimethylpyrimidine-2,4(1H,3H)-dione (2 g, 5.38 mmol), (R)-3-aminopropane-1,2-diol (0.490 g, 5.38 mmol) and triethylamine (0.750 ml, 5.38 mmol) in EtOH (17.94 ml) was heated under microwave irradiation at 100° C. for 1 hour. The mixture was evaporated under vacuum and the residue partitioned between DCM (20 mL) and 1M HCl (20 mL). The phases were separated and the organic phase was washed with water (2×20 mL). The organic phase was passed through a hydrophobic frit and evaporate under vacuum to afford the title compound.