Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[C:10]([CH2:12][OH:13])[CH:9]=[C:8]([CH2:14][OH:15])[CH:7]=1.[CH3:16][C:17]([S:24][S:25][CH3:26])([CH3:23])[CH2:18][CH2:19][C:20](O)=[O:21].C(N=C=NC(C)C)(C)C.O.ON1C2C=CC=CC=2N=N1>CN(C)C=O.O>[CH3:16][C:17]([S:24][S:25][CH3:26])([CH3:23])[CH2:18][CH2:19][C:20]([NH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[C:10]([CH2:12][OH:13])[CH:9]=[C:8]([CH2:14][OH:15])[CH:7]=1)=[O:21]
Reactant: NCCCOc1cc(CO)cc(CO)c1
Reactant: CSSC(C)(C)CCC(=O)O
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CSSC(C)(C)CCC(=O)NCCCOc1cc(CO)cc(CO)c1
Reaction time: 15 h
Yield: 54.7 %

Procedure:
To a solution of 1-(3-amino-propyloxy)-3,5-bis-(hydroxymethyl)-benzene (50 mg) in dimethylformamide (1 mL) was added 4-methyl-4-methyldisulfanyl-pentanoic acid (44 mg), N,N′-diisopropylcarbodiimide (35 mL) and 1-hydroxybenzotriazole hydrate (5.8 mg). After 15 h at room temperature, water was added to the reaction mixture and the aqueous solution was extracted twice with ethyl acetate. The combined organic solutions were washed with a saturated sodium chloride aqueous solution, dried over magnesium sulfate and concentrated in vacuo to a residue. The residue was purified by silica gel chromatography (Interchrom Puriflash 5 g column, SiOH 15-35 μm), eluted with methanol/dichloromethane, 5:95 to give 1-[3-(4-methyl-4-methyldisulfanyl-pentanoylamino)-propyloxy]-3,5-bis-(hydroxymethyl)-benzene (48 mg):
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[N:3]=1.[OH-].[K+].[Cl-].[Na+].S(=O)(=O)(O)[OH:17]>[Cr].[Co]>[OH:17][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[N:3]=1
Reactant: FC(F)(F)c1cccc(Cl)n1
Reactant: O=S(=O)(O)O
Agent: [Co]
Agent: [Cr]
Agent: [Cl-]
Product: Oc1cccc(C(F)(F)F)n1
Temperature: 150 °C
Reaction time: 5 h

Procedure:
2-Chloro-6-trifluoromethylpyridine (10.0 g; 55.1 mmol; 1 equiv) was charged to a 100 ml Hastelloy C Parr reactor, the reactor sealed and pressure tested with nitrogen. When a sealed system had been achieved, the pressure was released, the reactor resealed, and heated to 150° C. Potassium hydroxide solution (10% strength; 68.0 g; 121.1 mmol; 2.2 equiv) was added via an HPLC pump over 1 hour, while the mixture was maintained at 150° C. Addition of base caused the pressure to rise to 5 bar. The reaction mixture was held at this temperature and pressure for a further 5 hours. Following this period the reactor was cooled, dismantled and sodium chloride (5 g) added. The solution was cooled to 5° C., acidified to pH 5-6 by the addition of concentrated sulphuric acid, filtered and pulled dry. The filter cake was washed with water (10 g), pulled dry, discharged and allowed to dry overnight to afford 2-hydroxy-6-trifluoromethylpyridine as a colourless powder (9.5 g; 95% strength; 92% isolated yield).
Reaction SMILES: Br[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Br:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]#[CH:25])=[CH:20][CH:19]=1>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[Br:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]#[C:25][C:2]2[C:7]([C:8]#[N:9])=[CH:6][N:5]=[CH:4][CH:3]=2)=[CH:20][CH:19]=1
Reactant: N#Cc1cnccc1Br
Reactant: C#Cc1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#Cc1cnccc1C#Cc1ccc(Br)cc1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a solution of 4-bromo-nicotinonitrile (1.10 g, 6.00 mmol) in DMF (20 ml) are added bis(triphenylphosphine)-palladium(II)-chloride (211 mg, 0.30 mmol), copper(I) iodide (34 mg, 0.18 mmol), triethylamine (1.66 ml, 12.0 mmol) and 1-bromo-4-ethynyl-benzene (1.19 g, 6.6 mmol). The mixture is flushed with nitrogen, heated to 80° C. and stirred in a closed reaction vial at this temperature for 4 hours. The reaction mixture is allowed to cool to room temperature and partitioned between water and dichloromethane. The organic phase is washed with 1 N HCl, dried over sodium sulfate and evaporated under vacuum. The residue is chromatographed on a silica gel column with cyclohexane/ethyl acetate as eluent to give 4-(4-bromo-phenylethynyl)-nicotinonitrile as light yellow powder; HPLC/MS 2.09 min (B), [M+H] 283/285.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:23]([F:26])([F:25])[F:24])[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-])=O)[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Sn](Cl)Cl.Cl>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:23]([F:25])([F:24])[F:26])[O:13][N:12]=[C:11]([C:14]3[CH:15]=[C:16]([NH2:20])[CH:17]=[CH:18][CH:19]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=[N+]([O-])c1cccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CC(C)O
Product: Nc1cccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c1
Temperature: 0 °C
Yield: 58.4 %

Procedure:
To a solution of 5-(3,5-dichloro-phenyl)-3-(3-nitro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazole (15.0 g, 37 mmol) (Example I2) in isopropanol (120 ml) was added tin(II) chloride (25 g, 133 mmol). The mixture was cooled to 0° C. and aqueous hydrochloric acid (concentrated) (23 ml) was added slowly at 0° C. The reaction mixture was heated to 80° C. for 2 hours. Then ⅓ of the total volume of isopropanol was evaporated. Water (100 ml) was added to the mixture and aqueous sodium hydroxide (4N) was added to adjust the pH to 8-9. The aqueous phase was extracted three times with ethyl acetate (200 ml). The combined organic extracts were dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: cyclohexane/ethyl acetate 1:1) to give 3-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-phenylamine (8.1 g, 58% yield). 1H-NMR (CDCl3, 400 MHz): 7.56 (m, 2H), 7.43 (m, 1H), 7.20 (t, 1H), 7.05 (m, 1H), 6.97 (m, 1H), 6.78 (m, 1H), 4.08 (d, 1H), 3.8 (s, 1H), 3.68 (d, 1H).
Reaction SMILES: Cl.Cl.[O:3]([CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[O:15][C:14]([C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][N:20]=3)=[O:17])=[C:13]([NH:26][C:27]([C@H:29]3[CH2:34][CH2:33][C@H:32]([N:35]4[CH2:39][CH2:38][CH2:37][C:36]4=[O:40])[CH2:31][CH2:30]3)=[O:28])[C:12]=2[CH:41]=1)N.C(N(CC)C(C)C)(C)C.[C:51]([O:55][C:56]([NH:58][C:59]([N:68]1C=CC=N1)=[N:60][C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])=[O:57])([CH3:54])([CH3:53])[CH3:52]>CN(C)C=O>[C:64]([O:63][C:61]([N:60]([O:3][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[O:15][C:14]([C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][N:20]=3)=[O:17])=[C:13]([NH:26][C:27]([C@H:29]3[CH2:30][CH2:31][C@H:32]([N:35]4[CH2:39][CH2:38][CH2:37][C:36]4=[O:40])[CH2:33][CH2:34]3)=[O:28])[C:12]=2[CH:41]=1)[C:59]([NH:58][C:56]([O:55][C:51]([CH3:52])([CH3:53])[CH3:54])=[O:57])=[NH:68])=[O:62])([CH3:65])([CH3:66])[CH3:67]
Reactant: NOCCOc1ccc2oc(C(=O)Nc3ccc(Cl)cn3)c(NC(=O)[C@H]3CC[C@H](N4CCCC4=O)CC3)c2c1
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)n1cccn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC(=N)N(OCCOc1ccc2oc(C(=O)Nc3ccc(Cl)cn3)c(NC(=O)[C@H]3CC[C@H](N4CCCC4=O)CC3)c2c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Trans-5-(2-aminoxyethoxy)-3-[4-(2-oxopyrrolidin-1-yl)cyclohexylcarbonylamino]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide dihydrochloride (90 mg) obtained in Example 183 is dissolved in N,N-dimethyl formamide (3 ml), and thereto are added N,N-diisopropylethylamine (38 μl) and N,N′-bis(t-butoxycarbonyl)-1H-pyrazole-1-carboxamidine (57 mg), and the mixture is stirred at room temperature for one day. The reaction solution is concentrated under reduced pressure, and the residue is poured into water, and extracted with chloroform. The organic layer is dried over sodium sulfate, and the solvent is evaporated under reduced pressure. The resulting residue is purified by NH-silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/1, then ethyl acetate) to give trans-5-{2-[N,N′-bis(t-butoxycarbonyl)-guanidinoxy]ethoxy}-3-[4-(2-oxopyrrolidin-1-yl)cyclohexylcarbonylamino]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (82 mg).
Reaction SMILES: [N:1]1[C:6]2[S:7][C:8]3[CH2:13][NH:12][CH2:11][CH2:10][C:9]=3[C:5]=2[C:4]([NH:14][C:15]2[CH:16]=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=2)=[N:3][CH:2]=1.Cl.[CH3:23][N:24]([CH:31]([CH3:33])[CH3:32])[CH2:25]/[CH:26]=[CH:27]/[C:28](O)=[O:29]>>[CH3:23][N:24]([CH:31]([CH3:33])[CH3:32])[CH2:25]/[CH:26]=[CH:27]/[C:28]([N:12]1[CH2:11][CH2:10][C:9]2[C:5]3[C:4]([NH:14][C:15]4[CH:16]=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=4)=[N:3][CH:2]=[N:1][C:6]=3[S:7][C:8]=2[CH2:13]1)=[O:29]
Reactant: Oc1cccc(Nc2ncnc3sc4c(c23)CCNC4)c1
Reactant: CC(C)N(C)C/C=C/C(=O)O
Agent: Cl
Product: CC(C)N(C)C/C=C/C(=O)N1CCc2c(sc3ncnc(Nc4cccc(O)c4)c23)C1

Procedure:
In analogy to Example 89, the title compound was prepared from 3-(5,6,7,8-tetrahydropyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-ylamino)phenol from Example 16A (100 mg, 0.25 mmol) and (2E)-4-[methyl(1-methylethyl)amino]but-2-enoic acid hydrochloride from Example 2A (68 mg, 0.35 mmol) to yield 35 mg (31%).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([CH:7]1[CH2:11][CH:10](O)[CH2:9][CH:8]1[C:13]([O:15]C)=[O:14])=[O:6].Cl>CO>[O:14]=[C:13]1[CH:8]2[CH2:9][CH:10]([CH2:11][CH:7]2[C:5]([OH:4])=[O:6])[O:15]1
Reactant: COC(=O)C1CC(O)CC1C(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C1CC2CC1C(=O)O2
Reaction time: 4 h
Yield: 89.3 %

Procedure:
Sodium hydroxide (1M, 74 mL, 0.074 mol) was added to a stirred solution of compound 3a (3.73 g, 0.018 mol) in methanol (105 mL) at room temperature. After 4 h, the reaction mixture was neutralized with 3M HCl, evaporated and co-evaporated with toluene several times. Pyridine (75 mL) and Ac2O (53 mL) were added and the reaction mixture was allowed to shake overnight at room temperature. The mixture was then co-evaporated with toluene and purified by flash column chromatography (ethyl acetate+1% acetic acid) which gave the title compound (2.51 g, 88%) as a yellow oil.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:25][CH3:26])[C:4]1[C:13]([CH2:14][NH:15][CH2:16][CH2:17][S:18][CH2:19][C:20](OCC)=[O:21])=[CH:12][C:11]2[CH2:10][CH2:9][CH2:8][NH:7][C:6]=2[N:5]=1>C1(C)C=CC=CC=1>[CH3:1][O:2][CH:3]([O:25][CH3:26])[C:4]1[C:13]([CH2:14][N:15]2[CH2:16][CH2:17][S:18][CH2:19][C:20]2=[O:21])=[CH:12][C:11]2[CH2:10][CH2:9][CH2:8][NH:7][C:6]=2[N:5]=1
Reactant: CCOC(=O)CSCCNCc1cc2c(nc1C(OC)OC)NCCC2
Solvent: Cc1ccccc1
Product: COC(OC)c1nc2c(cc1CN1CCSCC1=O)CCCN2

Procedure:
A solution of ethyl 2-((2-(((2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methyl)amino)ethyl)thio)acetate (intermediate 209, 929 mg, 1.696 mmol) in toluene (5 ml) was stirred at reflux for 20 h. The reaction mixture was concentrated and the crude product was purified using silica gel column chromatography eluting with a gradient of MeOH (0-5%) in DCM. Fractions containing the product were combined and evaporated to yield the title compound as a brown solid. (UPLC-MS 3) tR 0.51 min, ESI-MS 338.3 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.15 (s, 1H), 5.16 (s, 1H), 4.74 (s, 2H), 3.57-3.50 (m, 2H), 3.45-3.38 (m, 8H), 3.37 (s, 2H), 2.75 (t, 2H), 2.70 (t, 2H), 1.93-1.84 (m, 2H).
Reaction SMILES: [O:1]=[C:2]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH3:25][S:26][CH2:27]Cl>CC(C)=O.C(OCC)C.C(OCC)(=O)C.O>[CH3:25][S:26][CH2:27][N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:10]=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:2]1=[O:1]
Reactant: CSCCl
Reactant: CCOC(=O)c1nc2ccccc2[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CCOC(=O)c1nc2ccccc2n(CSC)c1=O
Yield: 54.9 %

Procedure:
5.0 g (22.9 mmol) of ethyl 2-oxo-1,2-dihydroquinoxaline-3-carboxylate, 3.8 g (27.5 mmol) of potassium carbonate, 4.56 g (27.5 mmol) of potassium iodide and 2.43 g (25.2 mmol) of chloromethyl methyl sulfide were dissolved in acetone (100 mL), and the solution was refluxed for 5 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and to the residue thus obtained, a mixture of water and ethyl acetate was added. The resulting mixture was separated. The organic layer was dried over anhydrous magnesium sulfate, and the inorganic matter was separated by filtration. The solvent was distilled off under reduced pressure, and the residue thus obtained was solidified using diethyl ether, to obtain 3.5 g (yield: 55%) of ethyl 1-(methylthiomethyl)-2-oxo-1,2-dihydroquinoxaline-3-carboxy late as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]2[CH:17]=[CH:16][C:15]([NH:18]C(=O)C)=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[OH-].[Na+]>CCO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)(=[O:10])=[O:11])=[CH:7][CH:8]=1
Reactant: COc1ccc(S(=O)(=O)c2ccc(NC(C)=O)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(S(=O)(=O)c2ccc(N)cc2)cc1
Temperature: 80 °C

Procedure:
To a solution of N-(4-((4-methoxyphenyl)sulfonyl)phenyl)acetamide (111 mg, 0.36 mmol) in EtOH (8 mL) is added NaOH (10 M in water, 0.6 mL, 6 mmol). The mixture is heated at 80° C. for 4 h and the solvent is evaporated. The residue is partitioned between EtOAc (15 mL) and brine (10 mL) and the layers are separated. The aqueous layer is extracted with EtOAc (10 mL) and the combined extracts are dried (Na2SO4) and evaporated. The white solid obtained (76 mg, 80%) is used to the next step without further purification.
Reaction SMILES: N1C=CC=CC=1.[Cl:7][C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:15][C:16](Cl)=[O:17].[CH3:19][C:20]1(C)[O:27]C(=O)C[C:22](=O)[O:21]1.Cl>ClCCl>[Cl:7][C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:15][C:16](=[O:17])[CH2:19][C:20]([O:21][CH3:22])=[O:27]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=C(Cl)Cc1cccc(Cl)c1Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)CC(=O)Cc1cccc(Cl)c1Cl
Temperature: 20 °C
Reaction time: 12 h

Procedure:
At 0° C., 36.3 g (0.46 mol) of pyridine and then within 2 hours a solution of 42.5 g (0.19 mol) of 2,3-dichlorophenylacetyl chloride in 100 ml of dichloromethane were added dropwise to a solution of 28.8 g (0.20 mol) of Meldrum's acid in 200 ml of dichloromethane. The mixture was then stirred for 12 hours at about 20° C. and subsequently stirred into 100 ml of 10% strength hydrochloric acid. The organic phase was then separated off and the aqueous phase was extracted two more times with dichloromethane. Finally, the combined extracts were dried over magnesium sulfate and concentrated. The residue was dissolved in 300 ml of methanol and heated under reflux until the formation of gas had ceased. The mixture was then concentrated. Yield: quantitative.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[N:8][C:9]([NH2:10])=[C:4]2[CH:3]=[N:2]1.[I:11]N1C(=O)CCC1=O>CN(C)C=O.O>[I:11][C:3]1[C:4]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:10])[NH:1][N:2]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Nc1ncnc2[nH]ncc12
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ncnc2[nH]nc(I)c12
Temperature: 80 °C
Reaction time: 5 h
Yield: 51.8 %

Procedure:
A mixture of 1H-pyrazolo[3,4-d]pyrimidin-4-amine (150 g, 1.11 mol, 1.00 equiv) and N-iodo-succinimide (375 g, 1.67 mol, 1.58 equiv) in N,N-dimethylformamide (2.5 L) was stirred at 80° C. for 5 h. The reaction mixture was cooled to room temperature and then diluted with 10 L of water. The solid was collected by filtration, washed with 2×1 L of saturated aqueous sodium sulfite, and dried under vacuum to give 150 g of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][OH:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>ClCCl.CN(C)C1C=CN=CC=1>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][O:9][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCOc1ccc(Br)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCOc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.4 %

Procedure:
2-(4-Bromo-phenoxy)-ethanol (5 g, 23 mmol) is dissolved in dichloromethane (40 mL). Triethylamine (2.8 g, 28 mmol) and 4-dimethylaminopyridine (140 mg, 1.15 mmol) were then added followed by tert-butyldimethylsilyl chloride (3.65 g, 24.3 mmol) as a solution in dichloromethane (10 mL). The reaction is allowed to stir at ambient temperature for 18 hours. The reaction mixture is washed with 10% aqueous citric acid, the organic layer is separated and concentrated in vacuo to afford 7.5 g (98% yield) of the title compound. 1H NMR (CDCl3) δ 0.05 (s, 6H), 0.85 (s, 9H), 3.85-3.94 (m, 4H), 6.72 (d, 2H, J=6.90 Hz), 7.28 (d, 2H, J=6.90 Hz).
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH2:5][O:6][CH2:7][CH3:8])[CH2:3][OH:4].[Si:10](Cl)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]>>[CH3:1][C:2]([CH3:9])([CH2:3][O:4][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])[CH2:5][O:6][CH2:7][CH3:8]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCOCC(C)(C)CO
Product: CCOCC(C)(C)CO[Si](C)(C)C(C)(C)C

Procedure:
According to the procedure as described in Example 3,2,2-dimethyl-1-ethoxy-3-[(tert-butyldimethylsilyl)oxy]propane was prepared from intermediate 2,2-dimethyl-3-ethoxy-1-propanol and reagent tert-butyidimethylsilyl chloride.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1B(O)O.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Cl[C:47]1[CH:48]=[C:49]([CH:51]=[CH:52][C:53]=1[F:54])[NH2:50]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.O.C1(C)C=CC=CC=1>[F:54][C:53]1[CH:52]=[CH:51][C:49]([NH2:50])=[CH:48][C:47]=1[C:2]1[S:1][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: OB(O)c1cccs1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Nc1ccc(F)c(-c2cccs2)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
768 mg of thiophene-2-boronic acid, 90 mg of palladium(II) acetate, 328 mg of 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl, 1.7 g of potassium phosphate and 562 mg of 3-chloro-4-fluoroaniline were added to 8 ml of dry toluene. The mixture was stirred at 80° C. overnight under an argon atmosphere. The cooled reaction mixture was admixed with water and ethyl acetate, and filtered, and the filtrate was extracted by shaking three times with a mixture of ethyl acetate and toluene. The combined organic phases were dried over magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The chromatographic purification of the residue was effected by method [RP1]. 4-Fluoro-3-thiophen-2-yl-phenylamine (267.4) was obtained. Molecular weight 193.03 (C10H8FNS); retention time Rt=1.18 min. [B]; MS (ESI): 235.08 (MH++CH3CN).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:10]([OH:12])=[O:11])[CH:7]([CH3:9])[CH3:8])=[O:4].C1C([C@H](N)C(O)=O)C1>>[CH:7]1([C@H:6]([NH:5][C:3]([O:2][CH3:1])=[O:4])[C:10]([OH:12])=[O:11])[CH2:9][CH2:8]1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Agent: N[C@H](C(=O)O)C1CC1
Product: COC(=O)N[C@H](C(=O)O)C1CC1

Procedure:
(S)-2-cyclopropyl-2-(methoxycarbonylamino)acetic acid was synthesized similar to N-methoxycarbonyl-L-Valine, using L-cyclopropylglycine instead of L-Valine.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[N:41]([CH3:45])[CH:42]=[N:43][CH:44]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:46]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:55])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[N:41]([CH3:45])[CH:42]=[N:43][CH:44]=5)=[O:55])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:46]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4cncn4C)cc2)CCN3CC(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4cncn4C)cc2)CCN3CC(C)C)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 66.3 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(3-methylimidazol-4-yl)methylthio]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.53 g) was dissolved in dichloromethane (5 ml), and the mixture was cooled to −78° C. 3-chloroperbenzoic acid (0.31 g) in dichloromethane solution (5 ml) was added dropwise to the solution. The mixture was stirred for 1 hour at −78° C., and then, sodium thiosulfate solution was added to the mixture. The mixture was concentrated, and extracted with ethyl acetate. The organic layer was washed with aqueous sodium bicarbonate solution, water and saturated brine, and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off. The residue was purified by silica gel column chromatography (elution solvent: triethylamine/methanol/ethyl acetate), to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(3-methylimidazol-4-yl)methylsulfinyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 72) (0.36 g) as yellow amorphous.
Reaction SMILES: Br.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.C([N:21]1[CH2:30][CH2:29][C:28]2[C:23](=[CH:24][N:25]=[C:26](OC)[CH:27]=2)[CH2:22]1)(C)(C)C>>[CH2:24]1[C:23]2[C:28](=[CH:29][CH:30]=[N:21][CH:22]=2)[CH2:27][CH2:26][NH:25]1
Reactant: COc1cc2c(cn1)CN(C(C)(C)C)CC2
Agent: Br
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Product: c1cc2c(cn1)CNCC2

Procedure:
In Route C, commercially available 5-bromo-2-methoxy-4-methylpyridine in anhydrous tetrahydrofuran is metallated with n-BuLi and then treated with N,N-dimethylformamide to afford 6-methoxy-4-methylnicotinaldehyde. This was converted to the tert-butylimine with tert-butylamine in dichloromethane. Metallation with lithium 2,2,6,6-tetramethylpiperidide (Li-TMP) (cf. J. Org. Chem. 1993, 58, 2463-2467) and addition of N,N-dimethylformamide affords the iminoacetaldehyde which is reduced with sodium cyanoborohydride in methanol to give 2-tert-butyl-6-methoxy-1,2,3,4-tetrahydro-2,7-naphthyridine. Cleavage of the methyl group with refluxing 48% hydrobromic acid and treatment with triflic anhydride in the presence of base gives (VIIb) protected as the tert-butylamine.