Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]([OH:12])=O)[CH:6]=[CH:7][CH:8]=1.[Cl:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16][NH2:17].C(N(CC)CC)C.B(F)(F)F.CCOCC>C1(C)C=CC=CC=1>[Cl:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16][NH:17][C:10](=[O:12])[CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1cccc(CC(=O)O)c1
Reactant: NCc1ccccc1Cl
Agent: FB(F)F
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: COc1cccc(CC(=O)NCc2ccccc2Cl)c1

Procedure:
A mixture of 12.5 g of 3-methoxyphenylacetic acid, 21.2 g of 2-chlorobenzylamine, 15.1 g of triethylamine, 19.3 ml of borontrifluoride etherate, and 500 ml of toluene was stirred under reflux for 18 hours using a Dean-Stark moisture trap and allowed to cool. The mixture was extracted with aqueous sodium hydroxide, dilute hydrochloric acid, and water. The remaining organic solution was then evaporated and the residue crystallized from hexane to yield N-(2-chlorobenzyl)-3-methoxyphenylacetamide as a yellow solid, m.p. 89°-91° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH2:9])[C:3]=1I.[C:11]([C:13]1[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=1)#[CH:12].C(N(CC)CC)C>CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:8][C:6]1[N:5]=[C:4]([NH2:9])[C:3]([C:12]#[C:11][C:13]2[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=2)=[C:2]([Cl:1])[N:7]=1
Reactant: C#Cc1cccc(O)c1
Reactant: Nc1nc(N)c(I)c(Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1nc(N)c(C#Cc2cccc(O)c2)c(Cl)n1

Procedure:
The title compound is synthesized according to general procedure GP2 starting from 500 mg (1.8 mmol) 6-chloro-5-iodo-pyrimidine-2,4-diamine, 827 mg (7.0 mmol) 3-ethynyl-phenol, 35 mg (0.19 mmol) CuI, 129 mg (0.19 mmol) PdCl2(PPh3)2 and 4.1 mL triethylamine in 4 mL dry DMF. Yield after purification by RP-HPLC: 511 mg (100%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[CH:10]([CH2:16][NH2:17])[O:9][CH2:8][CH2:7]2.[CH2:18]=O.Cl>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[CH:10]([CH2:16][NH:17][CH3:18])[O:9][CH2:8][CH2:7]2
Reactant: C=O
Reactant: COc1cc2c(cc1OC)C(CN)OCC2
Agent: Cl
Product: CNCC1OCCc2cc(OC)c(OC)cc21
Reaction time: 0.33 h

Procedure:
A mixture of 6,7-dimethoxy-1-isochromanmethylamine hydrochloride (6.0 g), described in Example 1, and 37% formaldehyde solution (12 ml) is heated on the steam bath under a reflux condenser for 20 min. A further 6 ml formaldehyde solution is added and heating is continued for 20 min. The solution is evaporated to dryness and the residue is crystallized from isopropanol to give the hydrochloric acid addition salt of the title compound, m.p. 254°-256° C. (dec.).
Reaction SMILES: [NH2:1][C@H:2]([C:4]([C@@H:6]1[C@@H:11]([OH:12])[C@H:10]([OH:13])[C@@H:9]([CH2:14][OH:15])[O:8][C@@:7]1([NH2:54])[N:16]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[C:17](=[O:35])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]/[CH:25]=[CH:26]\[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:5])[CH3:3].[C:55]([O:59][C:60]([NH:62][C@H:63]([C:65]([NH:67][C@H:68]([C:70](O)=[O:71])[CH3:69])=[O:66])[CH3:64])=[O:61])([CH3:58])([CH3:57])[CH3:56]>ClCCl>[C:55]([O:59][C:60]([NH:62][C@H:63]([C:65]([NH:67][C@H:68]([C:70]([NH:1][C@H:2]([C:4]([C@@H:6]1[C@@H:11]([OH:12])[C@H:10]([OH:13])[C@@H:9]([CH2:14][OH:15])[O:8][C@@:7]1([NH2:54])[N:16]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[C:17](=[O:35])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]/[CH:25]=[CH:26]\[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:5])[CH3:3])=[O:71])[CH3:69])=[O:66])[CH3:64])=[O:61])([CH3:58])([CH3:57])[CH3:56]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)N(CCCCCCCCCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)[C@H](C)N
Reactant: C[C@H](NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(=O)O
Solvent: ClCCl
Product: CCCCCCCC/C=C\CCCCCCCC(=O)N(CCCCCCCCCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)OC(C)(C)C
Yield: 75 %

Procedure:
from N-(2-L-alanyl-amino-2-deoxy-β-D-glucopyranosyl)-N-octadecyl-oleamide and N-tert-butyloxycarbonyl-L-alanyl-L-alanine. Yield 75%. [α]D =+17.9° (c=0.96, dichloromethane).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH2:26][CH3:27])([C:13]2[CH:18]=[CH:17][C:16]([C:19]#[C:20][Si](C)(C)C)=[C:15]([CH3:25])[CH:14]=2)[CH2:11][CH3:12])=[CH:6][C:5]=1[CH3:28].[F-].[Cs+]>C(#N)C.O>[CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH2:11][CH3:12])([C:13]2[CH:18]=[CH:17][C:16]([C:19]#[CH:20])=[C:15]([CH3:25])[CH:14]=2)[CH2:26][CH3:27])=[CH:6][C:5]=1[CH3:28]
Reactant: CCC(CC)(c1ccc(C#C[Si](C)(C)C)c(C)c1)c1ccc(C(=O)OC)c(C)c1
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: CC#N
Product: C#Cc1ccc(C(CC)(CC)c2ccc(C(=O)OC)c(C)c2)cc1C
Yield: 98.7 %

Procedure:
To an ambient temperature suspension of 4-[1-Ethyl-1-(3-methyl-4-trimethylsilanylethynyl-phenyl)-propyl]-2-methyl-benzoic acid methyl ester (6.8 g, 16.72 mmol) in acetonitrile/water (180/30 ml) is added cesium fluoride (25.4 g, 167.2 mmol) and stirred for 3d. The reaction mixture is concentrated and partitioned between EtOAc (500 ml) and 1N HCl (200 ml). The aqueous phase is extracted with a second portion of EtOAc (200 ml) and the combined organic phases are washed with brine (200 ml), dried (MgSO4), concentrated and chromatographed (330 g SiO2, 1% EtOAc/Hexanes) to yield the title compound (5.52 g, 99%).
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([CH2:10][C:11](=[O:13])[CH3:12])[N:7]=[C:6]([NH:14][C@H:15]([CH2:17][CH3:18])[CH3:16])[CH:5]=1.[OH-].[Li+].Cl>C1COCC1>[C@@H:15]([NH:14][C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([CH2:10][C:11](=[O:13])[CH3:12])[N:7]=1)[C:3]([OH:19])=[O:2])([CH2:17][CH3:18])[CH3:16]
Reactant: CC[C@H](C)Nc1cc(C(=O)OC)cc(CC(C)=O)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC[C@H](C)Nc1cc(C(=O)O)cc(CC(C)=O)n1

Procedure:
Dissolve (S)-2-sec-butylamino-6-(2-oxopropyl)-isonicotinic acid methyl ester (50 mg, 0.19 mmol) in THF (2 mL). Slowly add 1 N lithium hydroxide (0.28 mL) and stir overnight at room temperature. Acidify the mixture to about pH=6 by 5 N HCl and concentrate to near dryness. Dilute with ethyl acetate (10 mL) and wash the organic layer with saturated aqueous sodium chloride. Dry (magnesium sulfate) and concentrate to give the title compound as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([CH:10]=[CH:11][C:12]([CH3:22])=[CH:13][CH:14]=[CH:15][C:16]([CH3:21])=[CH:17][C:18](Cl)=[O:19])=[C:5]([CH3:23])[C:4]=1[CH3:24].[CH2:25]([NH-:31])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>>[CH2:25]([NH:31][C:18](=[O:19])[CH:17]=[C:16]([CH3:21])[CH:15]=[CH:14][CH:13]=[C:12]([CH3:22])[CH:11]=[CH:10][C:6]1[C:7]([CH3:9])=[CH:8][C:3]([O:2][CH3:1])=[C:4]([CH3:24])[C:5]=1[CH3:23])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCC[NH-]
Reactant: COc1cc(C)c(C=CC(C)=CC=CC(C)=CC(=O)Cl)c(C)c1C
Product: CCCCCCNC(=O)C=C(C)C=CC=C(C)C=Cc1c(C)cc(OC)c(C)c1C

Procedure:
9-(4-methoxy-2,3,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oic acid chloride is reacted with hexylamide to produce 9-(4-methoxy-2,3,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oic acid hexylamide, m.p. 157°-158° C.
Reaction SMILES: OS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[Br:20][C:21]1[CH:22]=[C:23]([C:29]2([C:35]([CH:37]([C:43](OCC)=[O:44])[C:38]([O:40][CH2:41][CH3:42])=[O:39])=[O:36])[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]>CCOC(C)=O>[Br:20][C:21]1[CH:22]=[C:23]2[C:24]([C:43]([OH:44])=[C:37]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[C:35](=[O:36])[C:29]32[CH2:30][CH2:31][O:32][CH2:33][CH2:34]3)=[CH:25][C:26]=1[O:27][CH3:28]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)C1(c2ccc(OC)c(Br)c2)CCOCC1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=C(O)c2cc(OC)c(Br)cc2C2(CCOCC2)C1=O
Reaction time: 0.17 h
Yield: 25.2 %

Procedure:
In a 100 mL round bottom flask, 5 mL concentrated H2SO4 stirred at 0° C. was carefully treated with 2.5 g P2O5. The resulting mixture was stirred for 10 minutes. A mixture of diethyl 2-(4-(3-bromo-4-methoxyphenyl)-tetrahydro-2H-pyran-4-carbonyl)malonate (1.25 g, 2.7 mmol) in 2 mL EtOAc was added to the above H2SO4 mixture, and the mixture was stirred at room temperature for 2 hours, M+1=411/413. The reaction mixture was then poured into 200 g crushed ice. The mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, concentrated in vacuo, and purified by column chromatography eluting with 10-50% EtOAc/hexane to give 0.28 g of the product as a pale yellow solid. MS m/e=411/413 (M+H)+.
Reaction SMILES: C1(C2C=CC=CC=2)C=CC(S(N[C:11]([NH:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[C:26]4=[N:27][C:28]([CH3:32])=[CH:29][C:30]([CH3:31])=[C:25]4[N:24]=[C:23]3[CH2:33][CH3:34])=[CH:18][CH:17]=2)=[O:12])(=O)=O)=CC=1.[Cl:41][C:42]1[S:46][C:45]([S:47]([NH2:50])(=[O:49])=[O:48])=[CH:44][CH:43]=1>>[Cl:41][C:42]1[S:46][C:45]([S:47]([NH:50][C:11]([NH:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[C:26]4=[N:27][C:28]([CH3:32])=[CH:29][C:30]([CH3:31])=[C:25]4[N:24]=[C:23]3[CH2:33][CH3:34])=[CH:18][CH:17]=2)=[O:12])(=[O:49])=[O:48])=[CH:44][CH:43]=1
Reactant: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(-c3ccccc3)cc2)cc1
Reactant: NS(=O)(=O)c1ccc(Cl)s1
Product: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(Cl)s2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 18 from phenyl 2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylcarbamate (step 1 of Example 18) and 5-chloro-2-thiophenesulfonamide.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:25])[C@H:5]([CH:22]([CH3:24])[CH3:23])[NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]#[N:21])=[CH:10][CH:9]=1.C(=O)(O)[O-].[Na+].[C:31](Cl)(=[O:36])[CH2:32][CH2:33][CH2:34][CH3:35]>O.C1(C)C=CC=CC=1>[CH3:2][O:3][C:4](=[O:25])[C@H:5]([CH:22]([CH3:23])[CH3:24])[N:6]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]#[N:21])=[CH:10][CH:9]=1)[C:31](=[O:36])[CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: COC(=O)[C@@H](NCc1ccc(-c2ccccc2C#N)cc1)C(C)C
Reactant: CCCCC(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCC(=O)N(Cc1ccc(-c2ccccc2C#N)cc1)[C@H](C(=O)OC)C(C)C
Temperature: 28 °C
Reaction time: 0.42 h
Yield: 107.7 %

Procedure:
150 g N-[(2′-cyanobiphenyl-4-yl)methyl]-(L)-valine methyl ester hydrochloride was charged into a round bottomed flask containing a mixture of sodium bicarbonate (158.1 g), water (450 ml) and toluene (900 ml). The contents were stirred at 28° C. for 25 minutes and then cooled to 0° C. 110.9 g of valeryl chloride was added slowly to the reaction mass at 0-20° C. over about 55 minutes. The reaction mass was stirred at about 2-4° C. for about 2 hours. Reaction completion was confirmed by thin layer chromatography and the reaction mixture was allowed to attain 28° C. 450 ml of water was added to the reaction mass and stirred for about 20 minutes. The organic layer was separated, washed with a solution of sodium bicarbonate (30 g) in water (450 ml) twice, followed by washing with water (450 ml). The organic layer was concentrated under reduced pressure at 60-68° C. to obtain 183 g of the title compound.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:11]2[S:10](=[O:13])(=[O:12])[N:9]=[C:8]([C:14]3[C:15](=[O:30])[N:16]([NH:25][CH2:26][CH:27]4[CH2:29][CH2:28]4)[C:17]4[C:22]([C:23]=3[OH:24])=[CH:21][CH:20]=[CH:19][CH:18]=4)[NH:7][C:6]=2[S:5][CH:4]=1.C(N(CC)CC)C.[C:38]1([CH2:44][S:45](Cl)(=[O:47])=[O:46])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>CN(C)C=O>[CH:27]1([CH2:26][NH:25][N:16]2[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:23]([OH:24])=[C:14]([C:8]3[NH:7][C:6]4[S:5][CH:4]=[C:3]([CH2:2][NH:1][S:45]([CH2:44][C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)(=[O:47])=[O:46])[C:11]=4[S:10](=[O:12])(=[O:13])[N:9]=3)[C:15]2=[O:30])[CH2:28][CH2:29]1
Reactant: NCc1csc2c1S(=O)(=O)N=C(c1c(O)c3ccccc3n(NCC3CC3)c1=O)N2
Reactant: O=S(=O)(Cl)Cc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=c1c(C2=NS(=O)(=O)c3c(CNS(=O)(=O)Cc4ccccc4)csc3N2)c(O)c2ccccc2n1NCC1CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 35 %

Procedure:
To a solution of the product of Example 353E (16.5 mg, 0.037 mmol) in N,N-dimethylformamide (0.4 mL) was added triethylamine (0.011 mL, 0.079 mmol). The mixture was cooled to 0° C. and α-toluene sulfonyl chloride was added (0.008 g, 0.041 mmol). The reaction mixture was warmed to 23° C. and stirred for 0.5 hours. The reaction mixture was then heated to 50° C. and stirred for 1.75 hours. Additional triethylamine (0.010 mL, 0.074 mmol) and α-toluene sulfonyl chloride (0.007 g, 0.037 mmol) were added and the reaction mixture was stirred at 23° C. for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was purified by reverse phase chromatography, eluting with a gradient of 10% acetonitrile/0.1% trifluoroacetic acid in water to 95% acetonitrile/0.1% trifluoracetic acid in water to give the title compound (7.7 mg, 35%). 1H NMR (300 MHz, DMSO-d6) δ 0.15 (d, J=4.04 Hz, 2 H) 0.42 (d, J=7.72 Hz, 2 H) 1.00 (m, 1 H) 2.84 (d, J=7.35 Hz, 2 H) 4.23 (d, J=5.52 Hz, 2 H) 4.44 (s, 2 H) 6.37 (bs, 1 H) 7.32 (s, 1 H) 7.42 (m, 6 H) 7.86 (m, 2 H) 8.07 (d, J=8.46 Hz, 1 H) 8.16 (dd, 1 H) 14.50 (bs, 1 H).
Reaction SMILES: [N:1]1([CH:5]2[CH2:10][CH2:9][CH:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.N1CCC[CH2:20]1>>[N:1]1([CH:5]2[CH2:10][CH2:9][CH:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:7][CH2:6]2)[CH2:20][CH2:2][CH2:3][CH2:4]1
Reactant: C1CCNC1
Reactant: CC(C)(C)OC(=O)NC1CCC(N2CCC2)CC1
Product: CC(C)(C)OC(=O)NC1CCC(N2CCCC2)CC1

Procedure:
The title compound was prepared by an analogous method to the preparation of Intermediate 227, on a 2.34 mmol scale utilising pyrrolidine (Aldrich; 250 μL, 3.04 mmol), as a white solid (175 mg, 44%).
Reaction SMILES: [C:1]([C:3]1[C:4]([F:16])=[C:5]([CH:11]=[C:12]([F:15])[C:13]=1[F:14])[C:6]([O:8]CC)=[O:7])#[N:2].Cl.O>C(O)(=O)C>[C:1]([C:3]1[C:4]([F:16])=[C:5]([CH:11]=[C:12]([F:15])[C:13]=1[F:14])[C:6]([OH:8])=[O:7])#[N:2]
Reactant: CCOC(=O)c1cc(F)c(F)c(C#N)c1F
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: N#Cc1c(F)c(F)cc(C(=O)O)c1F
Temperature: 100 °C
Reaction time: 4 h
Yield: 97.4 %

Procedure:
Ethyl 3-cyano-2,4,5-trifluorobenzoate (3.35 g, 14.6 mmol) was suspended in glacial acetic acid (5 mL). Concentrated hydrochloric acid (10 mL) was added thereto, and the mixture was stirred at 100° C. for 4 hours. While cooling with ice, water (100 mL) was added to the reaction mixture. Subsequently, the resultant mixture was extracted with chloroform (100 mL×4), followed by drying with sodium sulfate anhydrate. After filtration, the filtrate was concentrated under reduced pressure. The residue was recrystallized from chloroform/n-hexane, to thereby yield the title compound as a white solid (2.86 g, 97%).
Reaction SMILES: [N:1]1C=[CH:5][C:4]([CH2:7][C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)=[CH:12][CH:11]=2)=[O:9])=[CH:3][CH:2]=1.[N:28]1C=CC(C)=CC=1>>[N:1]1[CH:2]=[CH:3][C:4]([CH2:7][C:8]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)=[CH:14][CH:15]=2)=[O:9])=[CH:5][N:28]=1
Reactant: O=C(Cc1ccncc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Reactant: Cc1ccncc1
Product: O=C(Cc1ccnnc1)c1ccc(OCc2ccc3ccccc3n2)cc1

Procedure:
Following the procedure for the preparation of 2-pyridin-4-yl-1-[4-(quinolin-2-ylmethoxy)-phenyl]-ethanone but substituting 4-methylpyridazine for 4-picoline provided the title compound. 1H NMR (400 MHz, CDCl3) δ 9.12 (d, J=5.4 Hz, 1H), 9.08 (d, J=8.7 Hz, 2.1H), 8.20 (d, J=8.3 Hz, 1H), 8.07 (d, J=8.3 Hz, 1H), 7.96 (m, 2H), 7.83 (d, J=7.9 Hz, 1H), 7.76 (m, 1H), 7.62 (d, J=8.3 Hz, 1H), 7.55 (m, 1H) 7.38 (dd, J=5.4, 2.5 Hz, 1H), 7.09 (m, 2H), 5.44 (s, 2H) 4.23 (s, 2H); MS: (M+H m/z=356.2).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][N:9]=2)[CH:4]=[C:3]1[CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]1[C:21]([CH3:22])=[CH:20][C:19]([C:23]2[N:24]=[N:25][N:26]([CH3:28])[N:27]=2)=[CH:18][C:17]=1[CH3:29].[BH4-].[Na+].O.[OH-].[Na+]>FC(F)(F)C(O)=O>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][N:9]=2)[CH2:4][CH:3]1[CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]1[C:17]([CH3:29])=[CH:18][C:19]([C:23]2[N:24]=[N:25][N:26]([CH3:28])[N:27]=2)=[CH:20][C:21]=1[CH3:22]
Reactant: Cc1cc(-c2nnn(C)n2)cc(C)c1OCCCCc1cc2cccnc2n1C
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2nnn(C)n2)cc(C)c1OCCCCC1Cc2cccnc2N1C
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 33 %

Procedure:
A solution of 1-methyl-2-[4-[4-(2-methyl-tetrazol-5-yl)-2,6-dimethylphenoxy]-butyl]-7-azaindole (580 mg, 1.49 mmol) in 16.5 ml of trifluoroacetic acid was added in portions at 0° C. 1.88 g (29.7 mmol) of sodium borohydride. The mixture was stirred at 20° C. for 30 min and then heated at 55°-60° C. for 72 h. To the above mixture was added water, 2N NaOH solution (to pH=8), and the resulting mixture was extracted with methylene chloride. The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica column chromatography (10 cm column, methylene chloride/acetone, 30/1-6/1) to yield 193 mg (33%) of 1-methyl-2-[4-[4-(2-methyl-tetrazol-5-yl)-2,6-dimethylphenoxy]-butyl]-2,3-dihydro-7-azaindole, as a solid, m.p. 54°-57° C.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][C:3]=1[CH3:18].I[C:20]1[CH:25]=[N:24][CH:23]=[CH:22][N:21]=1>>[Br:1][C:2]1[C:3]([CH3:18])=[CH:4][C:5]([C:20]2[CH:25]=[N:24][CH:23]=[CH:22][N:21]=2)=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C)c1Br
Reactant: Ic1cnccn1
Product: Cc1cc(-c2cnccn2)cc(C)c1Br

Procedure:
The title compound is prepared from 2-bromo-1,3-dimethyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzene and 2-iodo-pyrazine following a procedure analogous to that described in Step 1 of Intermediate 56. LC (method 9): tR=1.12 min; Mass spectrum (ESI+): m/z=263/265 (Br) [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[OH:9].[CH2:10](Cl)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].Cl>C1(=O)CCCCC1>[CH2:10]([O:9][C:3]1[CH:4]=[CH:5][C:6]([Br:8])=[CH:7][C:2]=1[F:1])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Oc1ccc(Br)cc1F
Reactant: ClCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C1CCCCC1
Product: Fc1cc(Br)ccc1OCc1ccccc1
Reaction time: 7 h
Yield: 97.7 %

Procedure:
A reaction vessel was charged with 19.4 g of 2-fluoro-4-bromophenol, 12.9 g of benzyl chloride, 23.3 g of potassium carbonate and 510 ml of cyclohexanone and the reaction was carried out with stirring at 120°-140° C. for 7 hours. The reaction liquid was poured into dilute hydrochloric acid and then extracted with benzene. The benzene layer was washed with water and dried over Glauber's salt. The benzene was distilled off and the residue was purified by way of column chromatography on silica gel (eluent: hexane/benzene=4/1) to obtain 27.9 g (yield 97.3%) of 2-fluoro-4-bromophenyl benzyl ether.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][C:12]1[CH2:13][C:14]([O:28][CH3:29])([C:21]([CH3:27])=[C:22]([CH3:26])[C:23]=1[O:24][CH3:25])[CH2:15][CH:16]([CH3:20])[CH2:17][CH2:18][OH:19].C(N(CC)CC)C>O.ClCCl>[CH3:11][C:12]1[CH2:13][C:14]([O:28][CH3:29])([C:21]([CH3:27])=[C:22]([CH3:26])[C:23]=1[O:24][CH3:25])[CH2:15][CH:16]([CH3:20])[CH2:17][CH:18]=[O:19]
Reactant: COC1=C(C)CC(CC(C)CCO)(OC)C(C)=C1C
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: COC1=C(C)CC(CC(C)CC=O)(OC)C(C)=C1C
Temperature: -60 °C
Reaction time: 0.25 h
Yield: 92.1 %

Procedure:
A dichloromethane solution (25 ml) of oxalyl chloride (1 ml, 11 mmole) was cooled to -70° C. under an atmosphere of argon, and a solvent mixture of DMSO (1.7 ml, 22 mmole) and dichloromethane (5 ml) was added dropwise to the solution, while maintaining its temperature at not higher than -60° C. Subsequently, a dichloromethane solution (10 ml) of 3-(3,5,6-trimethyl-1,4-dimethoxybenzyl)-butan-1-ol (3 g, 11 mmole) was added dropwise to the mixed solution, followed by stirring at -70° C. for 15 minutes, and triethylamine (7 ml, 50 mmole) was added dropwise. Then, stirring was continued until the temperature of the reaction solution reached the room temperature, and water (50 ml) was added to the reaction solution, followed by concentration under reduced pressure. The residue was extracted with IPE, and the organic layer was washed with IPE, dried and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give 3-(3,5,6-trimethyl-1,4-dimethoxybenzyl)butanal (2.7 g, 90%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][C:9](=[N:11][OH:12])[C:8]2[N:13]([CH3:16])[CH:14]=[CH:15][C:7]=2[S:6]1(=[O:18])=[O:17].[F:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.C(=O)([O-])O.[Na+].[I-].[Na+]>C(#N)C>[F:19][C:20]1[CH:21]=[CH:22][C:23]([N:26]2[CH2:31][CH2:30][N:29]([CH2:2][CH2:3][CH2:4][N:5]3[CH2:10][C:9](=[N:11][OH:12])[C:8]4[N:13]([CH3:16])[CH:14]=[CH:15][C:7]=4[S:6]3(=[O:18])=[O:17])[CH2:28][CH2:27]2)=[CH:24][CH:25]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: Cn1ccc2c1C(=NO)CN(CCCCl)S2(=O)=O
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: Cn1ccc2c1C(=NO)CN(CCCN1CCN(c3ccc(F)cc3)CC1)S2(=O)=O
Yield: 87.3 %

Procedure:
A suspension of 116 mg (0.4 mmol) of Compound 19, 108 mg (0.6 mmol) of 1-(4-fluorophenyl)piperazine, 134 mg (1.6 mmol) of sodium hydrogencarbonate and 120 mg (0.8 mmol) of sodium iodide in 8 ml of acetonitrile was refluxed for 23 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column (eluent: methanol/methylene chloride=1/20), whereby 152 mg of the title compound were obtained (yield: 87%).
Reaction SMILES: [CH2:1]([C:4]1([C:20]2[CH:29]=[CH:28][C:27]3[C:26]([CH3:31])([CH3:30])[CH2:25][CH2:24][C:23]([CH3:33])([CH3:32])[C:22]=3[CH:21]=2)[C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][C:15]([O:17]CC)=[O:16])[CH:11]=[CH:12][C:7]=2[O:6][CH2:5]1)[CH:2]=[CH2:3].[OH-].[Na+].O.Cl>C1COCC1.C(OCC)(=O)C>[CH2:1]([C:4]1([C:20]2[CH:29]=[CH:28][C:27]3[C:26]([CH3:31])([CH3:30])[CH2:25][CH2:24][C:23]([CH3:33])([CH3:32])[C:22]=3[CH:21]=2)[C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][C:15]([OH:17])=[O:16])[CH:11]=[CH:12][C:7]=2[O:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCC1(c2ccc3c(c2)C(C)(C)CCC3(C)C)COc2ccc(C=CC(=O)OCC)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CCC1(c2ccc3c(c2)C(C)(C)CCC3(C)C)COc2ccc(C=CC(=O)O)cc21

Procedure:
A solution of ethyl 3-[3-allyl-3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-2,3-dihydrobenzofuran-5-yl]acrylate (790 mg, 1.78 mmol) and sodium hydroxide (720 mg, 17.8 mmol) in THF (20 ml) is heated to reflux for 24 h. The mixture is treated with water and ethyl acetate, and acidified to pH 1 with a concentrated hydrochloric acid solution. After separation, the organic phase is washed twice with water, dried over magnesium sulphate, and concentrated in vacuo at 40° C. in a rotary evaporator. The solid obtained is washed with heptane.