Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](OS(C)(=O)=O)[CH:8]=[CH2:9].[O:15]1[C:19]2[CH:20]=[CH:21][C:22]([CH:24]3[CH:30]([CH3:31])[C:29]45[CH2:38][CH:26]([O:27][C:28]4=[CH:35][C:34](=[O:36])[C:33]([OH:37])=[CH:32]5)[CH2:25]3)=[CH:23][C:18]=2[O:17][CH2:16]1>CN(C=O)C.C(Cl)Cl>[O:15]1[C:19]2[CH:20]=[CH:21][C:22]([CH:24]3[CH:30]([CH3:31])[C:29]45[CH2:38][CH:26]([O:27][C:28]4=[CH:35][C:34](=[O:36])[C:33]([OH:37])=[C:32]5[CH2:9][CH:8]=[CH2:7])[CH2:25]3)=[CH:23][C:18]=2[O:17][CH2:16]1
Reactant: CC1C(c2ccc3c(c2)OCO3)CC2CC13C=C(O)C(=O)C=C3O2
Reactant: C=CCOS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C=CCC1=C(O)C(=O)C=C2OC3CC(c4ccc5c(c4)OCO5)C(C)C21C3
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Potassium carbonate (172.7 mg, 1.25 mmol) and mesyl allyl ether (113 mg, 0.83 mmol) are added to a stirred solution of 4-(1,3-benzodioxol-5-yl)-2,3,4,5-tetrahydro-7-hydroxy-5-methyl-8H-2,5a-methano-1-benzoxepin-8-one (109, as prepared in Example 54) in DMF (4 ml). The reaction is stirred at room temperature overnight, after which time TLC still shows unreacted starting material present. An additional 50 μl mesyl allyl ether is then added to the reaction and the reaction is then starred for another 24 hours. The reaction is diluted with methylene chloride and washed with 10% HCl followed by water. The extract is dried over sodium sulfate and concentrated in vacuo. The reaction is best purified by medium pressure liquid chromatography (MPLC) (i.e., flash chromatography on silica gel (25 g, 1:1 hexane-ethyl acetate as eluant) produces a contaminated product as determined by 1H NMR and flash chromatography on silica gel (30 g silica, 1:1:1 hexane-ethyl ether-methylene chloride) also produces a contaminated product as determined by 1H NMR). M+(CI)=367. 1H NMR: 0.64 (3H, d), 1.67 (1H, dd), 1.89 (1H, d), 2.06 (1H, m), 2.26 (2H, m), 2.49 (3H, m), 2.72 (1H, dd), 3.05 (1H, t), 5.08 (3H, m), 5.92 (2H, s), 6.15 (1H, s), 6.65 (3H, m).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3I)[C@H:14]2[CH3:31])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:34][O:35][C:36]1[S:37][C:38]([CH3:44])=[CH:39][C:40]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>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>[F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[C:40]3[CH:39]=[C:38]([CH3:44])[S:37][C:36]=3[O:35][CH3:34])[C@H:14]2[CH3:31])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1I
Reactant: COc1sc(C)cc1B(O)O
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+]
Product: COc1sc(C)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C

Procedure:
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one (Intermediate 21, 13 mg; 0.0219 mmol) was treated with (2-methoxy-5-methyl-3-thienyl)boronic acid (Step C, 10.4 mg; 0.0657 mmol), tetrakis(triphenylphosphine)palladium (0) (3 mg; 0.0026 mmol), and sodium carbonate (20 mg) as described in Example 291 to afford (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(2-methoxy-5-methyl-3-thienyl)-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one as a yellow glass. LCMS=598.2 (M+1)+. 1H NMR (benzene-d6, 500 MHz): δ 7.75 (s, 1 H), 7.57 (s, 1 H), 7.31-29 (m, 1H), 7.24 (s, 2 H), 7.12-7.10 (m, 1 H), 6.14 (s, 1 H), 4.96 (d, J=16 Hz, 1 H), 4.57 (d, J=8 Hz, 1 H), 3.99 (d, J=15.8 Hz, 1 H), 3.30 (s, 3 H), 2.95-2.92 (m, 1 H), 2.05 (s, 3 H), −0.28 (d, J=6.7 Hz, 3 H).
Reaction SMILES: CS(OO[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])(=O)=O.[NH2:25][C:26]1[CH:36]=[CH:35][C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:28][CH:27]=1>CN(C)P(N(C)C)(N(C)C)=O>[CH3:22][Si:21]([CH3:24])([CH3:23])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][NH:25][C:26]1[CH:27]=[CH:28][C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:35][CH:36]=1
Reactant: C[Si](C)(C)CCCCCCCCCCCCCCOOS(C)(=O)=O
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)c1ccc(NCCCCCCCCCCCCCC[Si](C)(C)C)cc1

Procedure:
A solution of 20.8 g. 14-(trimethylsilyl)tetradecyloxy methanesulfonate and 20 g. ethyl 4-aminobenzoate in 50 ml. hexamethylphosphoramide was stirred at 110° for 18 hr. The reaction was diluted with 100 ml. water and extracted three times with 150 ml. portions of methylene chloride. The combined organic layers were washed with brine, dried with anhydrous magnesium sulfate, passed through a pad of hydrous magnesium silicate, and evaporated. The residue was crystallized from 250 ml. ethanol to yield the title compound as a crystalline solid, m.p. 91°-92° C.
Reaction SMILES: [C:1]([N:3]1[CH2:6][CH:5]([C:7]2[O:11][N:10]=[C:9]([C:12]3[CH:13]=[CH:14][C:15]([CH3:30])=[C:16]([NH:18][C:19]([C:21]4[N:25]5[CH:26]=[CH:27][CH:28]=[CH:29][C:24]5=[N:23][CH:22]=4)=[O:20])[CH:17]=3)[N:8]=2)[CH2:4]1)#[N:2].Cl.[NH2:32][OH:33].CCN(C(C)C)C(C)C>C(O)C>[OH:33][N:32]=[C:1]([N:3]1[CH2:4][CH:5]([C:7]2[O:11][N:10]=[C:9]([C:12]3[CH:13]=[CH:14][C:15]([CH3:30])=[C:16]([NH:18][C:19]([C:21]4[N:25]5[CH:26]=[CH:27][CH:28]=[CH:29][C:24]5=[N:23][CH:22]=4)=[O:20])[CH:17]=3)[N:8]=2)[CH2:6]1)[NH2:2]
Reactant: NO
Reactant: Cc1ccc(-c2noc(C3CN(C#N)C3)n2)cc1NC(=O)c1cnc2ccccn12
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2noc(C3CN(C(N)=NO)C3)n2)cc1NC(=O)c1cnc2ccccn12
Temperature: 78 °C

Procedure:
A stirring mixture of N-(5-(5-(1-cyanoazetidin-3-yl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (82) (50 mg, 0.125 mmol), hydroxylamine HCl (13 mg, 0.188 mmol) and DIEA (44 uL, 0.250 mmol) in ethanol was heated at 78° C. for 2 hours. The solvent was concentrated and dried under high vacuum. Crude N-(5-(5-(1-(N′-hydroxycarbamimidoyl)azetidin-3-yl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (83) was used in the next step without further purification. MS m/z 433.17 (M+1)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][OH:9])[CH2:4][CH2:3]1.[N+:10]([C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20](=O)[O:21]C2C=CC([N+]([O-])=O)=CC=2)=[CH:15][CH:14]=1)([O-:12])=[O:11].CN1CCOCC1>C(Cl)Cl>[C:20](=[O:21])([O:19][C:16]1[CH:15]=[CH:14][C:13]([N+:10]([O-:12])=[O:11])=[CH:18][CH:17]=1)[O:9][CH2:8][CH:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)Oc1ccc([N+](=O)[O-])cc1
Reactant: CN1CCC(CO)CC1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CN1CCC(COC(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Reaction time: 90 h
Yield: 73.6 %

Procedure:
(1-Methylpiperidin-4-yl)methanol (2.50 g, 19.3 mmol) in DCM (50 mL) was added to a solution of bis-(4-nitrophenyl)carbonate (7.06 g, 23.2 mmol) in DCM (100 mL), followed by NMM (1.70 mL, 15.5 mmol). The reaction mixture was stirred for 90 hours and then washed sequentially with aliquots of 1 M aq Na2CO3 solution until the aqueous layer was colourless. The organic layer was dried (MgSO4) and concentrated in vacuo to give (1-methylpiperidin-4-yl)methyl 4-nitrophenyl carbonate (4.18 g, 73%) as a yellow solid.
Reaction SMILES: [NH:1]([CH3:13])[C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(O)CCC.[OH-].[Na+].C(O[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])(C)(C)C>O>[CH3:31][C:28]([O:27][C:26]([N:1]([C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH3:13])=[O:32])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: CN[C@@H](Cc1ccccc1)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCCCO
Product: CN(C(=O)OC(C)(C)C)[C@@H](Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
3.6 g of H-MePhe-OH are dissolved in a mixture of ter.-butanol, 25 ml of 10% aqueous KHCO3 solution and 5 ml of 4 N sodium hydroxide. 8 ml of di-tert.-butylcarbonate are added and the mixture stirred for 2 days at room temperature. The reaction mixture is diluted with ca. 100 ml of water and extracted with ether. The aqueous phase is acidified, with stirring to pH 2. The precipitated product is extracted with acetic acid, the extract washed with water and dried over Na2SO4. The liquid is evaporated and the product crystallised from ether/petroleum ether to yield Boc-MePHe-OH. M.P. 87°.
Reaction SMILES: [N+:1]([C:4]1[CH:51]=[CH:50][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][Si:13]([CH3:49])([CH3:48])[O:14][Si:15]([CH3:47])([CH3:46])[O:16][Si:17]([CH3:45])([CH3:44])[O:18][Si:19]([CH3:43])([CH3:42])[O:20][Si:21]([CH3:41])([CH3:40])[O:22][Si:23]([CH2:26][CH2:27][CH2:28][CH2:29][O:30][C:31]2[CH:36]=[CH:35][C:34]([N+:37]([O-])=O)=[CH:33][CH:32]=2)([CH3:25])[CH3:24])=[CH:6][CH:5]=1)([O-])=O.[H][H]>[Pd]>[NH2:1][C:4]1[CH:51]=[CH:50][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][Si:13]([CH3:48])([CH3:49])[O:14][Si:15]([CH3:47])([CH3:46])[O:16][Si:17]([CH3:45])([CH3:44])[O:18][Si:19]([CH3:43])([CH3:42])[O:20][Si:21]([CH3:41])([CH3:40])[O:22][Si:23]([CH2:26][CH2:27][CH2:28][CH2:29][O:30][C:31]2[CH:32]=[CH:33][C:34]([NH2:37])=[CH:35][CH:36]=2)([CH3:24])[CH3:25])=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: C[Si](C)(CCCCOc1ccc([N+](=O)[O-])cc1)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)CCCCOc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Product: C[Si](C)(CCCCOc1ccc(N)cc1)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)CCCCOc1ccc(N)cc1
Yield: 99.6 %

Procedure:
1.02 g of the above (2A) (1.25 mmol) and 10 mL of a 10 wt % Pd/C (0.0203 g) ethyl acetate solution were mixed, and stirred for 2 days in a hydrogen atmosphere at room temperature. The solution was filtrated by Celite and then concentrated to obtain a colorless oily material of 1,11-bis[4-(4-aminophenoxy)butyl]-1,1,3,3,5,5,7,7,9,9,11,11-dodecamethylhexasiloxane (3A) (0.943 g, 99% of yield) represented by the following formula. Various measurements were carried out with regard to the obtained (3A), and results are shown below.
Reaction SMILES: C(Cl)Cl.[O:4]=[CH:5][C@@H:6]([C@H:8]([C@@H:10]([C@@H:12]([CH2:14][OH:15])[OH:13])[OH:11])[OH:9])[OH:7].O=[CH:17][C@@H:18]([C@H:20]([C@@H:22]([C@@H:24]([CH2:26]O)O)O)O)[OH:19].C(O[BH:33][O:34][CH2:35][CH2:36][CH2:37][CH3:38])CCC>O>[O:4]=[CH:5][C@@H:6]([C@H:8]([C@@H:10]([C@@H:12]([CH2:14][OH:15])[OH:13])[OH:11])[OH:9])[OH:7].[C:35]1([O:34][BH:33][O:19][C:18]2[CH:17]=[CH:26][CH:24]=[CH:22][CH:20]=2)[CH:36]=[CH:37][CH:38]=[CH:6][CH:5]=1
Reactant: CCCCOBOCCCC
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: O
Solvent: ClCCl
Product: B(Oc1ccccc1)Oc1ccccc1
Reaction time: 0 h

Procedure:
A solution of 100 mg/dL of glucose bis phenylboronate and dry methylene chloride was prepared and applied to CLINISTIX® glucose test strip pad. No color development was observed. The pads were then wetted with water and in 2 or 3 minutes color development was observed. Glucose bis butylboronate was similarly applied to CLINISTIX® strips. Again no color was observed upon application. After wetting with water strong color development was observed in 10 to 15 seconds.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:19])[C:7](I)=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:9]2)=[CH:4][CH:3]=1.[C:20]([O:24][C:25](=[O:46])[NH:26][C:27]1([C:31]2[CH:36]=[CH:35][C:34](B3OC(C)(C)C(C)(C)O3)=[CH:33][CH:32]=2)[CH2:30][CH2:29][CH2:28]1)([CH3:23])([CH3:22])[CH3:21].C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC>[C:20]([O:24][C:25](=[O:46])[NH:26][C:27]1([C:31]2[CH:32]=[CH:33][C:34]([C:7]3[C:6](=[O:19])[C:5]4[C:10](=[CH:11][C:2]([Br:1])=[CH:3][CH:4]=4)[O:9][C:8]=3[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:35][CH:36]=2)[CH2:28][CH2:29][CH2:30]1)([CH3:23])([CH3:21])[CH3:22]
Reactant: O=c1c(I)c(-c2ccccc2)oc2cc(Br)ccc12
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4cc(Br)ccc4c3=O)cc2)CCC1
Temperature: 125 °C
Yield: 48.8 %

Procedure:
7-Bromo-3-iodo-2-phenyl-chromen-4-one (320 mg, 0.75 mmol), {1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (295 mg, 0.8 mmol), tetrakis(triphenyphosphine)palladium (0) (87 mg, 0.075 mmol) and sodium carbonate (159 mg, 1.5 mmol) were suspended in DME (10 mL) and water (5 mL) in a microwave vial. The vial was sealed, evacuated and flushed twice with nitrogen. The reaction mixture was heated in a microwave at 125° C. for 15 min. The resulting mixture was partitioned between ethyl acetate (40 mL) and water (20 mL) and the phases separated. The organic layer was washed with brine (20 mL), dried (Na2SO4), filtered and concentrated in vacuo. The resulting residue was subjected to flash chromatography (SiO2, 20% ethyl acetate in cyclohexane) to give the title compound as a pale yellow foam (200 mg, 49%). LCMS (Method A): RT=5.45 min, [M+H]+=546/548.
Reaction SMILES: [C:1]1([C:7]2[CH:22]=[CH:21][C:10]3[N:11]=[C:12]([CH2:14][C:15]4[O:19][C:18]([OH:20])=[N:17][N:16]=4)[S:13][C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.BrC1C=CC2N=C(CC3[O:36]C(O)=NN=3)SC=2C=1.OO>C(O)(=O)C.O>[OH:20][C:18]1[O:19][C:15]([C:14]([C:12]2[S:13][C:9]3[CH:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:22]=[CH:21][C:10]=3[N:11]=2)=[O:36])=[N:16][N:17]=1
Reactant: Oc1nnc(Cc2nc3ccc(-c4ccccc4)cc3s2)o1
Reactant: Oc1nnc(Cc2nc3ccc(Br)cc3s2)o1
Agent: OO
Solvent: O
Solvent: CC(=O)O
Product: O=C(c1nnc(O)o1)c1nc2ccc(-c3ccccc3)cc2s1
Temperature: 50 °C
Yield: 80 %

Procedure:
To a suspension of 5-((6-phenylbenzo[d]thiazol-2-yl)methyl)-1,3,4-oxadiazol-2-ol (25 mg, 0.081 mmol) in acetic acid (1 mL) (prepared according to a similar procedure described for Compound 51a) was added 30% hydrogen peroxide in water (0.17 mL, 1.6 mmol) and the reaction mixture heated at 50° C. for 16 h. The reaction mixture was allowed to cool to rt then diluted with water and filtered. The solid was washed with water and rinsed with ether, then dried under vacuum to afford Compound 88a (21 mg, 80% yield) as a yellow solid. LCMS=0.96 min using analytical method (M), 324.1 (M+H). 1H NMR (400 MHz, DMSO-d6) δ 8.64 (d, J=1.5 Hz, 1H), 8.40 (d, J=8.5 Hz, 1H), 8.02 (dd, J=8.5, 1.8 Hz, 1H), 7.89-7.79 (m, 2H), 7.63-7.50 (m, 2H), 7.50-7.41 (m, 1H), 5.76 (s, 1H).
Reaction SMILES: [CH:1]1([C:4]([OH:6])=O)[CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[CH2:16]1[C:22]2[CH:23]=[CH:24][C:25]([O:27][CH:28]3[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]3)=[CH:26][C:21]=2[CH2:20][CH2:19][NH:18][CH2:17]1>CN(C)C=O>[CH:1]1([C:4]([N:18]2[CH2:19][CH2:20][C:21]3[CH:26]=[C:25]([O:27][CH:28]4[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]4)[CH:24]=[CH:23][C:22]=3[CH2:16][CH2:17]2)=[O:6])[CH2:3][CH2:2]1
Reactant: O=C(O)C1CC1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc3c(c2)CCNCC3)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc3c(c2)CCN(C(=O)C2CC2)CC3)CC1
Temperature: 25 °C

Procedure:
16 l cyclopropylcarboxylic acid are placed in 3 ml dimethylformamide, then 174 l diisopropylethylamine and 93.1 mg O-(7-azabenzotriazol-1-yl-)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) are added. After 15 min 77.5 mg tert-butyl 4-(2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-piperidine-1-carboxylate are added. The reaction mixture is stirred at ambient temperature until there is no further reaction and the product is purified directly by preparative HPLC (method B). 70 mg of the product are obtained as a solid. Analytical HPLC-MS (method D): RT=1.37 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([NH:17][C@H:18]([C:20]4[N:25]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[C:24](=[O:32])[C:23]5=[C:33]([CH3:36])[CH:34]=[CH:35][N:22]5[N:21]=4)[CH3:19])=[N:14][CH:13]=[N:12][C:11]=3[N:10]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[CH:9]=2)=[C:4]([O:45][CH3:46])[CH:3]=1.N1C=CC=CC=1.[O:53]1[CH2:58][CH2:57][CH:56]([CH2:59][S:60](Cl)(=[O:62])=[O:61])[CH2:55][CH2:54]1>O1CCCC1>[CH3:46][O:45][C:4]1[CH:3]=[C:2]([NH:1][S:60]([CH2:59][CH:56]2[CH2:57][CH2:58][O:53][CH2:54][CH2:55]2)(=[O:62])=[O:61])[CH:7]=[CH:6][C:5]=1[C:8]1[C:16]2[C:15]([NH:17][C@H:18]([C:20]3[N:25]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:24](=[O:32])[C:23]4=[C:33]([CH3:36])[CH:34]=[CH:35][N:22]4[N:21]=3)[CH3:19])=[N:14][CH:13]=[N:12][C:11]=2[N:10]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:43])([CH3:42])[CH3:44])[CH:9]=1
Reactant: O=S(=O)(Cl)CC1CCOCC1
Reactant: COc1cc(N)ccc1-c1cn(COCC[Si](C)(C)C)c2ncnc(N[C@@H](C)c3nn4ccc(C)c4c(=O)n3-c3ccccc3)c12
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COc1cc(NS(=O)(=O)CC2CCOCC2)ccc1-c1cn(COCC[Si](C)(C)C)c2ncnc(N[C@@H](C)c3nn4ccc(C)c4c(=O)n3-c3ccccc3)c12
Temperature: 50 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
(S)-2-(1-((5-(4-Amino-2-methoxyphenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (50 mg, 0.08 mmol) was treated with pyridine (19 μL, 0.23 mmol) and (tetrahydro-2H-pyran-4-yl)methanesulfonyl chloride (31 mg, 0.16 mmol) in tetrahydrofuran (0.5 ml) according to the method described in Preparation 175 but stirring at 50° C. overnight. The title compound was obtained (54 mg, 68% yield, 80% purity) without further purification.
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].C[Si](C)(C)N[Si](C)(C)C.[Cl:18][C:19]1[CH:20]=[C:21]([CH:40]=[CH:41][C:42]=1[Cl:43])[C:22]([NH:24][C:25]1[CH:26]=[N:27][C:28]([O:31][C:32]2[CH:37]=[CH:36][C:35]([CH2:38]Cl)=[CH:34][CH:33]=2)=[CH:29][CH:30]=1)=[O:23]>[Sn](Cl)(Cl)(Cl)Cl.CO>[Cl:18][C:19]1[CH:20]=[C:21]([CH:40]=[CH:41][C:42]=1[Cl:43])[C:22]([NH:24][C:25]1[CH:26]=[N:27][C:28]([O:31][C:32]2[CH:37]=[CH:36][C:35]([CH2:38][N:1]3[CH:8]=[CH:7][C:5](=[O:6])[NH:4][C:2]3=[O:3])=[CH:34][CH:33]=2)=[CH:29][CH:30]=1)=[O:23]
Reactant: O=C(Nc1ccc(Oc2ccc(CCl)cc2)nc1)c1ccc(Cl)c(Cl)c1
Reactant: O=c1cc[nH]c(=O)[nH]1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CO
Product: O=C(Nc1ccc(Oc2ccc(Cn3ccc(=O)[nH]c3=O)cc2)nc1)c1ccc(Cl)c(Cl)c1
Temperature: 150 °C
Reaction time: 5.5 h

Procedure:
To uracil (200 mg, 1.8 mmol) was added hexamethyldisilazane (5 mL), and the resulting solution was stirred for 5.5 hours at 150° C. Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was dissolved in a solution of acetonitrile (10 mL)-THF (5 mL), and to this solution were added 3,4-dichloro-N-[6-(4-chloromethylphenoxy)pyridin-3-yl]benzamide (500 mg, 1.2 mmol) and tin tetrachloride (3 drops). The resulting solution was refluxed for 2.5 hours. To this reaction solution was added methanol (1 mL), and the resulting solution was stirred for 30 minutes at room temperature. The resulting reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol:chloroform=1:99→3:97), to thereby yield 20 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8]C)=O.[H-].[Na+].[C:21]1(C)[CH:26]=CC=C[CH:22]=1>>[CH3:1][O:2][C:3]1[C:4]2[O:13][C:14]([CH2:26][CH:21]=[CH2:22])([C:15]([O:17][CH3:18])=[O:16])[C:6](=[O:8])[C:5]=2[CH:10]=[CH:11][CH:12]=1
Reactant: COC(=O)COc1c(OC)cccc1C(=O)OC
Reactant: Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Product: C=CCC1(C(=O)OC)Oc2c(OC)cccc2C1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 92 %

Procedure:
Methyl 3-methoxy-2-(methoxycarbonylmethoxy)benzoate (19.39 g) was dissolved in toluene (200 ml). To this solution, sodium hydride (3.36 g) was added and the resultant was stirred at room temperature for 20 minutes, followed by refluxing the mixture for 2 hours. Toluene was evaporated off under reduced pressure and the residue was dissolved in DMF (150 ml). To this solution, acetic acid (2 ml) was added and the solvent was evaporated off under reduced pressure. The residue was dissolved in toluene (200 ml) and the solution was refluxed for 1 hour. The reaction solution was cooled to room temperature and poured into water (150 ml), followed by separating the organic layer. The aqueous layer was extracted with ethyl acetate (100 ml) and the organic layers were combined. The resultant was washed with saturated aqueous sodium hydrogen carbonate solution and with saturated brine, followed by drying the resultant over sodium sulfate. After removing sodium sulfate by filtration, the solvent was evaporated off, and the residue was purified by column chromatography (solvent: hexane/ethyl acetate=3/1) using silica gel to obtain the desire compound (18.42 g, yield: 92%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][CH:10]2[C:13]([OH:15])=O)=[CH:5][CH:4]=1.[CH:16]([C:19]1[CH:24]=[CH:23][C:22]([NH:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]([F:38])([F:37])[F:36])=[CH:29][CH:28]=2)=[CH:21][CH:20]=1)([CH3:18])[CH3:17]>>[CH:16]([C:19]1[CH:24]=[CH:23][C:22]([N:25]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]([F:36])([F:37])[F:38])=[CH:29][CH:28]=2)[C:13]([CH:10]2[C:11]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)[CH2:7][CH2:8][CH2:9]2)=[O:15])=[CH:21][CH:20]=1)([CH3:18])[CH3:17]
Reactant: COc1ccc2c(c1)C(C(=O)O)CCC2
Reactant: CC(C)c1ccc(NCc2ccc(OCC(F)(F)F)cc2)cc1
Product: COc1ccc2c(c1)C(C(=O)N(Cc1ccc(OCC(F)(F)F)cc1)c1ccc(C(C)C)cc1)CCC2
Yield: 36.7 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.64 g) and (4-isopropylphenyl){[4-(2,2,2-trifluoroethoxy)phenyl]methyl}amine (1.0 g) as starting materials, N-(4-isopropylphenyl)-7-methoxy-N-{[4-(2,2,2-trifluoroethoxy)phenyl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.58 g) was obtained. melting point: 125-127° C.