Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:13]1[CH:19]=[CH:18][C:16]([OH:17])=[CH:15][C:14]=1[OH:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[N:21]([C:23]1[CH:29]=[CH:28][C:26]([OH:27])=[CH:25][C:24]=1O)=O>S(=O)(=O)(O)O>[CH2:1]([C:13]1[C:14](=[O:20])[CH:15]=[C:16]2[C:18](=[N:21][C:23]3[C:29]([O:17]2)=[CH:28][C:26]([OH:27])=[CH:25][CH:24]=3)[CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: O=Nc1ccc(O)cc1O
Reactant: CCCCCCCCCCCCc1ccc(O)cc1O
Agent: O=S(=O)(O)O
Product: CCCCCCCCCCCCc1cc2nc3ccc(O)cc3oc-2cc1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 47.9 %

Procedure:
A solution of 4-dodecylresorcinol (8.5 g, 30.53 mmole) (Aldrich Chemical Company) and 4-nitrosoresorcinol (5.0 g, 35.9 mmole) (Aldrich) in concentrated sulfuric acid (100 mL) is heated to 67° C. with stirring for 5 hours. The reaction mixture is allowed to cool to room temperature, poured into ice-water (1800 mL) and filtered. The resulting precipitate is washed with water until the filtrate is neutral to pH paper. This precipitate is dissolved in chloroform and the combined aqueous filtrates are back-extracted with chloroform (6×250 mL) to recover additional product. The combined chloroform layers are dried over anhydrous sodium sulfate and evaporated to a dark purple solid (2.55 g), homogenous by SiO2 -t.l.c. (45:5:1 chloroform:methanol:triethylamine) Rf =0.69. An additional 5.58 g of product is obtained by neutralization of the aqueous filtrates above with 8M KOH and extraction with chloroform (total yield=8.13 g, 68%). 1H NMR (d6 -DMSO) δ:7.57(d,1H); 7.27(s,1H); 6.79(D,1H); 6.66(s,1H); 6.23(s,1H); 4.14(c,1H); 2.46(t,2H); 1.52(c,2H); 1.23(c,18H); 0.85(c,3H).
Reaction SMILES: [Cl:1][C:2]1[N:6]([C@@H:7]2[O:19][C@H:18]([CH2:20][O:21]C(=O)C)[C@@H:13]([O:14]C(=O)C)[C@H:8]2[O:9]C(=O)C)[C:5]2[CH:25]=[C:26]([Cl:29])[CH:27]=[CH:28][C:4]=2[N:3]=1>N>[Cl:1][C:2]1[N:6]([C@@H:7]2[O:19][C@H:18]([CH2:20][OH:21])[C@@H:13]([OH:14])[C@H:8]2[OH:9])[C:5]2[CH:25]=[C:26]([Cl:29])[CH:27]=[CH:28][C:4]=2[N:3]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2c(Cl)nc3ccc(Cl)cc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: N
Product: OC[C@H]1O[C@@H](n2c(Cl)nc3ccc(Cl)cc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
2,6-Dichloro-1-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)benzimidazole (66) (1.8 grams) was dissolved in methanolic ammonia (35 ml). The reaction material was stirred in a pressure bottle for 5 hours at room temperature. Volatile materials were evaporated in vacuo to provide a white powdery precipitate. This residue was recrystallized from MeOH to yield 561 mg (2 crops, 85%) of 67 as colorless needles. MP 162-163° C. 1H NMR (DMSO-d6): d 8.30 (d, 1, 7-H, J7-5 =2.0 Hz), 7.64 (d, 1, 4-H, J4-5 =8.5 Hz), 7.31 (dd, 1, 5-H), 5.89 (d, 1, 1'-H, J1'2' =8.0 Hz), 5.49 (d, 1, 2'-OH, J2'-2' =6 5 Hz), 5.35 (t, 1, 5'-OH, J5'-5'OH =5.0 Hz), 5.28 (d, 1, 3'-OH, J3'-3'OH =4.5 Hz), 4.46 (m, 1, 2'-H, J2'-3' =5.-5 Hz), 4.14 (m, 1, 3'-H, J3'-4' =2.0 Hz), 4.00 (m, 1, 4'-H, J4'5' =J4'-5" =3.0 Hz), 3.70 (m, 2, 5'-H and 5"-H, J5'-5' =12.0 Hz). 13C NMR (DMSO-d6) d 140.72 (C2), 140.17 (C3a), 133.56 (C7a), 127.86 (C6), 123.23 (C5), 128.34 (C6), 120.03 (C4), 113.15 (C7), 89.00 (C1'), 86.26 (C4'), 71.37 (C2'), 69.72 (C3'), 61.12 (C5').
Reaction SMILES: [C:1]([C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8](=[O:30])[C:9]4[CH:21]=[CH:20][C:19](OS(C(F)(F)F)(=O)=O)=[CH:18][C:10]=4[C:11]([CH3:17])([CH3:16])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1)#[N:2].[CH3:31][S:32]([CH:35]1[CH2:39][CH2:38][NH:37][CH2:36]1)(=[O:34])=[O:33]>>[CH3:31][S:32]([CH:35]1[CH2:39][CH2:38][N:37]([C:19]2[CH:20]=[CH:21][C:9]3[C:8](=[O:30])[C:7]4[C:6]5[C:14](=[CH:15][C:3]([C:1]#[N:2])=[CH:4][CH:5]=5)[NH:13][C:12]=4[C:11]([CH3:17])([CH3:16])[C:10]=3[CH:18]=2)[CH2:36]1)(=[O:34])=[O:33]
Reactant: CS(=O)(=O)C1CCNC1
Reactant: CC1(C)c2cc(OS(=O)(=O)C(F)(F)F)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Product: CC1(C)c2cc(N3CCC(S(C)(=O)=O)C3)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21

Procedure:
Under the same conditions as the method for synthesizing Compound B2-1, the title compound was prepared from Compound B1 and 3-methanesulfonylpyrrolidine.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:21]([C:28]1[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[CH:30][CH:29]=1)[CH2:22][C:23]1[CH:24]=[N:25][NH:26][CH:27]=1)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:38][CH2:39][CH3:40]>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:21]([C:28]1[CH:29]=[CH:30][C:31]([CH:34]([CH3:36])[CH3:35])=[CH:32][CH:33]=1)[CH2:22][C:23]1[CH:27]=[N:26][N:25]([CH2:38][CH2:39][CH3:40])[CH:24]=1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cc1
Reactant: CCCBr
Product: CCCn1cc(CN(C(=O)C2CCCc3c(OCc4ccccc4)cccc32)c2ccc(C(C)C)cc2)cn1

Procedure:
By the reaction and treatment in the same manner as in Example 83 using 5-benzyloxy-N-(4-isopropylphenyl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.50 g) and 1-bromopropane (0.1 mL) as starting materials, 5-benzyloxy-N-(4-isopropylphenyl)-N-[(1-propylpyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.52 g) was obtained. By the reaction and treatment of this compound in the same manner as in Example 17, 5-hydroxy-N-(4-isopropylphenyl)-N-[(1-propylpyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.31 g) was obtained. melting point: 161° C.
Reaction SMILES: [O:1]=[S:2]1(=[O:18])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13]CC)=O)=[CH:9][N:8]=1.[CH:19]1([C:22]2[CH:27]=[C:26]([CH:28]3[CH2:30][CH2:29]3)[CH:25]=[CH:24][C:23]=2[N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH2:21][CH2:20]1>>[CH:19]1([C:22]2[CH:27]=[C:26]([CH:28]3[CH2:30][CH2:29]3)[CH:25]=[CH:24][C:23]=2[N:31]2[CH2:32][CH2:33][N:34]([C:11]([C:10]3[CH:9]=[N:8][C:7]([N:3]4[CH2:4][CH2:5][CH2:6][S:2]4(=[O:1])=[O:18])=[CH:17][CH:16]=3)=[O:13])[CH2:35][CH2:36]2)[CH2:20][CH2:21]1
Reactant: c1cc(N2CCNCC2)c(C2CC2)cc1C1CC1
Reactant: CCOC(=O)c1ccc(N2CCCS2(=O)=O)nc1
Product: O=C(c1ccc(N2CCCS2(=O)=O)nc1)N1CCN(c2ccc(C3CC3)cc2C2CC2)CC1
Yield: 72.4 %

Procedure:
Using ethyl 6-(1,1-dioxo-1λ6-isothiazolidin-2-yl)nicotinate (300 mg) described in Preparation Example 25 and 1-(2,4-dicyclopropylphenyl)piperazine (296 mg) described in Preparation Example 101 and by the reaction and treatment in the same manner as in Example 109, the title compound (375 mg) was obtained.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]2[N:9]=[C:10]([C:12]3[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=3[O:20][CH2:21][O:22][CH3:23])[O:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.[NH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1.C([O-])([O-])=O.[Na+].[Na+]>CC#N>[CH3:19][O:18][C:16]1[CH:15]=[CH:14][C:13]([O:20][CH2:21][O:22][CH3:23])=[C:12]([C:10]2[O:11][C:7]3[CH:6]=[CH:5][CH:4]=[C:3]([CH2:2][NH:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=4)[C:8]=3[N:9]=2)[CH:17]=1
Reactant: COCOc1ccc(OC)cc1-c1nc2c(CBr)cccc2o1
Reactant: NCc1ccccn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: COCOc1ccc(OC)cc1-c1nc2c(CNCc3ccccn3)cccc2o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.5 %

Procedure:
A mixture of 4-bromomethyl-2-(5-methoxy-2-methoxymethoxyphenyl)benzoxazole (F12) (567 mg, 1.5 mmol), 2-(aminomethyl)pyridine (1.08 g, 10 mmol), and Na2CO3 (excess) in CH3CN (30 mL) was stirred overnight at room temperature. After filtration of the reaction mixture, the filtrate was concentrated in vacuo. Water (20 mL) was added to the residue, which was extracted with CHCl3 (20 mL) three times. The combined organic layer was washed with brine and water, dried over MgSO4, and evaporated. The resulting oily material was purified by silica gel column chromatography (CHCl3-ethyl acetate) to afford the objective compound as a pale yellow oil (386 mg, 63%). 1H-NMR (400 MHz, CDCl3) δ3.52 (s, 3H), 3.87 (s, 3H), 4.01 (s, 2H), 4.30 (s, 2H), 5.23 (s, 2H), 7.02 (dd, 1H, J=9.2, 1.2 Hz), 7.15 (dd, 1H, J=7.6, 4.4 Hz), 7.21 (d, 1H, J=9.2 Hz), 7.29–7.36 (m, 2H), 7.41 (d, 1H, J=7.6 Hz), 7.49 (d, 1H, J=7.6 Hz), 7.62–7.65 (m, 2H), 8.55 (d, 1H, J=4.4 Hz).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][N:6](CC2C=CC=CC=2)[CH2:5][CH2:4][N:3]1[C:15]([O:17][CH2:18][CH3:19])=[O:16].[H][H]>[Pd].CO>[CH3:1][CH:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: [H][H]
Reactant: CCOC(=O)N1CCN(Cc2ccccc2)CC1C
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)N1CCNCC1C
Yield: 100 %

Procedure:
A mixture of 21 parts of ethyl 2-methyl-4-(phenylmethyl)-1-piperazinecarboxylate and 200 parts of methanol was hydrogenated at normal pressure and at room temperature with 3 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was distilled twice, yielding 23 parts (100%) of ethyl 2-methyl-1-piperazinecarboxylate; bp. 95°-98° C. at 66.5 Pa (int. 37).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:7]=[CH:8][CH:9]=1.Cl[C:16]1[C:25]2[C:20](=[CH:21][C:22]([O:28][CH3:29])=[C:23]([O:26][CH3:27])[CH:24]=2)[N:19]=[CH:18][N:17]=1>N1C=CC=CC=1.CN(C)C=O>[CH3:27][O:26][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][C:22]=1[O:28][CH3:29])[N:19]=[CH:18][N:17]=[C:16]2[CH:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([Br:3])[CH:5]=1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: COC(=O)Cc1cccc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: COC(=O)C(c1cccc(Br)c1)c1ncnc2cc(OC)c(OC)cc12
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 17.9 %

Procedure:
To a solvent mixture of pyridine (75 ml) and dimethylformamide (3 ml) at 0(C was added with 11.5 grams of sodium hydride (50% oil suspension). The mixture was stirred for another 20 minutes, added with 25 grams of methyl 3-bromophenylacetate, stirred for another 30 minutes and added with 21 grams of 4-chloro-6,7-dimethoxyquinazoline. The mixture was added with another 50 ml of pyridine and 50 ml of tetrahyudrofuran and stirred at room temperature for 2 hours. The mixture was then poured into 1200 ml of ice water mixture and extracted with ethyl acetate. The ethyl acetate layer was then washed with water, brine, dried over sodium sulfate, filtered and concentrated. The crude was then purified on a silica gel column with dichloromethane and methanol as the solvent to provide 7 grams of 6,7-dimethoxy-4-[1-(3-bromophenyl)-1-methoxycarbonylmeth yl] quinazoline as a white solid. M. P. 167-168° C. Alternatively, the reaction can be carried with bases such as sodium amide, lithium diisopropylamide or potassium bis(trimethylsilyl)amide in solvents such as tetrahydrofuran or dimethylforamide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:18])[CH2:9][O:10][CH2:11][CH2:12][O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[C:25](OC(=O)C)(=[O:27])[CH3:26].Cl>C(Cl)Cl>[C:25]([O:18][CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[CH2:9][O:10][CH2:11][CH2:12][O:13][C:14]([CH3:15])([CH3:17])[CH3:16])(=[O:27])[CH3:26]
Reactant: CC(C)(C)OCCOCC(O)c1cccc(Cl)c1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OC(COCCOC(C)(C)C)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 93.7 %

Procedure:
37.0 g of 1-(3-chlorophenyl)-2-(2-tert-butoxyethoxy)ethanol was dissolved in 70 ml of methylene chloride. To the solution were added 12.9 g of pyridine and 16.6 g of acetic anhydride. The resulting mixture was stirred for 24 hours at room temperature. The reaction mixture was added to a mixture of 150 ml of ice water and 100 ml of methylene chloride. The resulting mixture was adjusted to pH 2 with 6N hydrochloric acid. The organic layer was separated, washed with a saturatred aqueous sodium hydrogencarbonate solution and water in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to obtain 40.0 g of oily 1-acetoxy-1-(3-chlorophenyl)-2-(2-tert-butoxyethoxy)ethane.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[CH:9][C:10]=1[NH2:11])=[O:5])[CH3:2].[Si:12]([O:19][CH:20]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)[CH:21]=O)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]>>[CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[CH:9][C:10]=1[NH:11][CH2:21][CH:20]([O:19][Si:12]([C:15]([CH3:16])([CH3:18])[CH3:17])([CH3:13])[CH3:14])[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]ccc1N
Reactant: COc1ccc(C(C=O)O[Si](C)(C)C(C)(C)C)cc1
Product: CCOC(=O)c1[nH]ccc1NCC(O[Si](C)(C)C(C)(C)C)c1ccc(OC)cc1
Yield: 29 %

Procedure:
The title compound (0.13 g, 19%) was prepared in accordance with general method A using 3-amino-1H-pyrrole-2-carboxylic acid ethyl ester (0.16 g, 1.07 mmol) and {[tert-butyl(dimethyl)silyl]oxy}(4-methoxyphenyl)acetaldehyde (0.3 g, 1.07 mmol).
Reaction SMILES: [CH:1]1([C:4]([NH:6][NH:7][C:8](=O)[CH2:9][NH:10][C:11](=[O:34])[C:12]2[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[CH:20]([C:25]3[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([Cl:32])[CH:26]=3)[C:21]([F:24])([F:23])[F:22])=[CH:14][C:13]=2[CH3:33])=[O:5])[CH2:3][CH2:2]1>P(Cl)(Cl)(Cl)=O>[CH:1]1([C:4]2[O:5][C:8]([CH2:9][NH:10][C:11](=[O:34])[C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[CH:20]([C:25]4[CH:26]=[C:27]([Cl:32])[CH:28]=[C:29]([Cl:31])[CH:30]=4)[C:21]([F:22])([F:24])[F:23])=[CH:14][C:13]=3[CH3:33])=[N:7][N:6]=2)[CH2:2][CH2:3]1
Reactant: Cc1cc(/C=C/C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(=O)NCC(=O)NNC(=O)C1CC1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cc(/C=C/C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(=O)NCc1nnc(C2CC2)o1
Temperature: 50 °C

Procedure:
A solution of (E)-N-(2-(2-(cyclopropanecarbonyl)hydrazinyl)-2-oxoethyl)-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-enyl)-2-methylbenzamide (200 mg, 0.379 mmol) in phosphoryl chloride (POCl3, 2.0 mL) was stirred at ambient temperature for 10 min, then the resultant reaction mixture was heated to 50° C. for 1 h. The reaction mixture was quenched with ice water at 0° C. and extracted with EtOAc. The combined EtOAc layer was washed with saturated sodium bicarbonate (NaHCO3) solution and brine solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, 100-200 mesh; eluting with 50% EtOAc/pet ether) afforded the title compound as a light brown gummy material (70.0 mg, 36%): 1H NMR (400 MHz, CDCl3) δ 7.43 (m, 2H), 7.27 (m, 2H), 7.23 (m, 2H), 6.58 (d, J=16.0 Hz, 1H), 6.41 (dd, J=16.0, 7.6 Hz, 1H), 4.79 (d, J=5.6 Hz, 2H), 4.14 (m, 1H), 2.48 (s, 3H), 2.18 (m, 1H), 1.16 (m, 4H); ESIMS m/z 509.89 ([M+H]+); IR (thin film) 1666, 1166, 1112, 800 cm−1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH2:12]([N:14]([CH2:34][CH3:35])[CH2:15][CH2:16][CH2:17][NH:18][C:19]([C:21]1[C:25]([CH:26]([CH3:28])[CH3:27])=[C:24]([CH:29]=O)[NH:23][C:22]=1[CH:31]([CH3:33])[CH3:32])=[O:20])[CH3:13]>>[CH2:34]([N:14]([CH2:12][CH3:13])[CH2:15][CH2:16][CH2:17][NH:18][C:19]([C:21]1[C:25]([CH:26]([CH3:28])[CH3:27])=[C:24]([CH:29]=[C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=3)[NH:7][C:6]2=[O:11])[NH:23][C:22]=1[CH:31]([CH3:33])[CH3:32])=[O:20])[CH3:35]
Reactant: O=C1Cc2cc(Br)ccc2N1
Reactant: CCN(CC)CCCNC(=O)c1c(C(C)C)[nH]c(C=O)c1C(C)C
Product: CCN(CC)CCCNC(=O)c1c(C(C)C)[nH]c(C=C2C(=O)Nc3ccc(Br)cc32)c1C(C)C
Yield: 24.4 %

Procedure:
5-Bromo-1,3-dihydroindol-2-one (90 mg, 0.42 mmol) was condensed with 5-formyl-2,4-diisopropyl-1H-pyrrole-3-carboxylic acid (3-diethylaminopropyl)amide (140 mg) to give 54 mg (25%) of the title compound as red-brown solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([OH:11])=[CH:5][C:4]=1[N:12]=[CH:13][N:14]([CH3:16])[CH3:15])#[N:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:24][CH2:25][CH2:26][Cl:27]>C(#N)C>[Cl:27][CH2:26][CH2:25][CH2:24][O:11][C:6]1[C:7]([O:9][CH3:10])=[CH:8][C:3]([C:1]#[N:2])=[C:4]([N:12]=[CH:13][N:14]([CH3:15])[CH3:16])[CH:5]=1
Reactant: ClCCCBr
Reactant: COc1cc(C#N)c(N=CN(C)C)cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COc1cc(C#N)c(N=CN(C)C)cc1OCCCCl
Yield: 90.7 %

Procedure:
A mixture of N′-(2-cyano-5-hydroxy-4-methoxyphenyl)-N,N-dimethylimidoformamide (21.9 g, 66 mmol), caesium carbonate (998 g, 300 mmol) and 1-bromo-3-chloropropane (11 ml, 110 mmol) in acetonitrile (300 ml) was heated at reflux for 1 hour. The reaction mixture was cooled and the solvent evaporated in vacuo. Water (200 ml) was added and this was extracted with dichloromethane (2×150 ml). The organic solution was washed with brine (50 ml) and dried over magnesium sulphate. The solvent was evaporated in vacuo and the residue triturated with diethyl ether. The solid was collected by suction filtration and dried in vacuo to yield N′-(5-(3-chloropropoxy)-2-cyano-4-methoxyphenyl)-N,N-dimethylimidoformamide (17.7 g, 91% yield) as a white solid:
Reaction SMILES: [C:1]1(C)[CH:6]=CC(S(O)(=O)=O)=C[CH:2]=1.[OH:12][C@:13]([CH3:21])([CH2:19][OH:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15]>>[CH3:2][C:1]1([CH3:6])[O:12][C@@:13]([CH3:21])([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:19][O:20]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCOC(=O)[C@](C)(O)CO
Product: CCOC(=O)[C@@]1(C)COC(C)(C)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 2049.4 %

Procedure:
500 mg of p-toluenesulfonic acid were added to 10.7 g of ethyl (R)-2,3-dihydroxy-2-methylpropionate, dissolved in 35 ml of dry, freshly distilled 2,2-dimethoxypropane, and the mixture was stirred at room temperature overnight. The excess dimethoxypropane was removed at 45°/12 mmHg and the residue was vigorously stirred for 30 minutes with 5 ml of 1-N sodium bicarbonate. Then, 150 ml of ether were added thereto and the aqueous phase was separated. The ether solution was washed with saturated brine and then dried over sodium sulfate. After evaporation of the solvent, the product was distilled and there were obtained 11.2 g of ethyl (R)-2,2,4-trimethyl-1,3-dioxolan-4-carboxylate in the form of a colorless liquid; boiling point 81°/15 mmHg.
Reaction SMILES: Cl.C[O:3][C:4](=[O:29])[C@H:5]([CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)[NH:6][C:7](=[O:18])[C@@H:8]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH:9][CH3:10].[C:30](O)(=[O:32])[CH3:31]>>[C:30]([N:9]([CH3:10])[C@@H:8]([C:7]([NH:6][C@H:5]([C:4]([OH:3])=[O:29])[CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)=[O:18])[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)(=[O:32])[CH3:31]
Reactant: CN[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OC
Reactant: CC(=O)O
Agent: Cl
Product: CC(=O)N(C)[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O

Procedure:
Coupling of N-methyl-(D)-phenylalanyl-(L)-tryptophan methyl ester hydrochloride (see example 1) with acetic acid according to example 12 followed by hydrolysis of the methyl ester moiety according to example 1 gives N-acetyl-N-methyl-(D)-phenylalanyl-(L)-tryptophan; FAB-MS m/e 408 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]2[C:8](=[O:22])[N:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=3[O:20][CH3:21])[CH2:10][C:6]=2[C:5]([F:23])=[C:4]([NH:24][C@@H:25]2[CH2:30][CH2:29][CH2:28][CH2:27][C@@H:26]2[NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[N:3]=1.CC1(C)C(C)(C)OB([C:47]2[CH:48]=[N:49][N:50]3[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=23)O1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[CH3:21][O:20][C:13]1[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:12]=1[CH2:11][N:9]1[CH2:10][C:6]2[C:5]([F:23])=[C:4]([NH:24][C@@H:25]3[CH2:30][CH2:29][CH2:28][CH2:27][C@@H:26]3[NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[N:3]=[C:2]([C:47]3[CH:48]=[N:49][N:50]4[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=34)[C:7]=2[C:8]1=[O:22]
Reactant: CC1(C)OB(c2cnn3ccccc23)OC1(C)C
Reactant: COc1ccc(CN2Cc3c(F)c(N[C@@H]4CCCC[C@@H]4NC(=O)OC(C)(C)C)nc(Cl)c3C2=O)c(OC)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: COCCOC
Solvent: O
Product: COc1ccc(CN2Cc3c(F)c(N[C@@H]4CCCC[C@@H]4NC(=O)OC(C)(C)C)nc(-c4cnn5ccccc45)c3C2=O)c(OC)c1
Temperature: 85 °C
Reaction time: 3 h
Yield: 46.2 %

Procedure:
A mixture of tert-butyl (1S,2R)-2-(4-chloro-2-(2,4-dimethoxybenzyl)-7-fluoro-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)cyclohexylcarbamate (100 mg, 0.182 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine (53.4 mg, 0.219 mmol), sodium carbonate (48.3 mg, 0.455 mmol) and tetrakis(triphenylphosphine)palladium (21.05 mg, 0.018 mmol) in DME (1 mL) and H2O (0.333 mL) was stirred at 85° C. for 3 h. Following reaction, the mixture was filtered and the filtrate was diluted with EtOAc and H2O. The aqueous phase was extracted with EtOAc. The organic phases were combined, washed with brine, dried over MgSO4, and evaporated. The residue was purified by chromatography on SiO2 to give the title compound (53 mg, 46.1%). 1H NMR (500 MHz, CDCl3) δ ppm 1.17-2.03 (m, 17 H), 3.74-3.81 (m, 3 H), 3.84-3.89 (m, 3 H), 4.04 (br s, 1 H), 4.26 (br s, 2 H), 4.46 (br s, 1 H), 4.71 (br s, 2 H), 6.36-6.55 (m, 2 H), 6.83 (d, J=5.86 Hz, 1 H), 7.18-7.31 (m, 2 H), 8.42 (br s, 1 H), 8.47-8.57 (m, 1 H), 9.42 (br s, 1 H).
Reaction SMILES: [ClH:1].[CH3:2][N:3]1[C:7]([S:8][CH2:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([OH:21])=[C:17]([OH:20])[CH:18]=3)[CH2:13][CH2:12][N:11]=2)=[N:6][N:5]=[N:4]1.[BH4-].[Na+].Cl>CO>[ClH:1].[CH3:2][N:3]1[C:7]([S:8][CH2:9][CH:10]2[C:19]3[C:14](=[CH:15][C:16]([OH:21])=[C:17]([OH:20])[CH:18]=3)[CH2:13][CH2:12][NH:11]2)=[N:6][N:5]=[N:4]1
Reactant: Cn1nnnc1SCC1=NCCc2cc(O)c(O)cc21
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cn1nnnc1SCC1NCCc2cc(O)c(O)cc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 79.5 %

Procedure:
1-(1-methyl-1H-tetrazol-5-yl)thiomethyl-6,7-dihydroxy-3,4-dihydroisoquinoline hydrochloride (0.2 g) was dissolved in methanol (5 ml) under warming. To the solution was added sodium borohydride (50 mg) and the mixture was stirred for 1.5 hours at room temperature. 10% Hydrochloric acid was added to the reaction mixture and the solution was concentrated. Dried methanol was added to the residue and the insoluble material was filtered off, after which the filtrate was evaporated. The residue was crystallized by treating with acetone to give 1-(1-methyl-1H-tetrazol-5-yl)thiomethyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (0.16 g), mp 215° to 216°C (dec.).
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[OH:26])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[CH2:30][C:31]([CH2:33]Cl)=[CH2:32]>CN(C=O)C.CCOC(C)=O>[CH:1]1([C:7]2[C:15]3[CH:14]=[CH:13][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:11][C:10]=3[N:9]3[C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[O:26][CH2:33][C:31](=[CH2:30])[CH2:32]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3O)[nH]c2c1
Reactant: C=C(CCl)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=C1COc2ccccc2-c2c(C3CCCCC3)c3ccc(C(=O)OC)cc3n2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
To a solution of methyl 3-cyclohexyl-2-(2-hydroxyphenyl)-1H-indole-6-carboxylate (prepared as described in example 9, step 1) in dry DMF (0.06 M) was added NaH (2.5 eq., 60% suspension in mineral oil). After 30 min, 3-chloro-2-(chloromethyl)prop-1-ene (1.2 eq.) was added dropwise via syringe and the solution stirred at RT for 60 min. The reaction mixture was diluted with EtOAc and washed with 1N aqueous HCl and with brine, dried (Na2SO4) and evaporated. The crude residue was purified by flash chromatography (10:1 PE/EtOAc), affording the pure methyl 14-cyclohexyl-7-methylene-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate (70%) as light yellow foam; MS (ES+) m/z 402 (M+H)+.