Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[CH:3]=1.Br[C:10]1[CH:11]=[C:12]([CH:16]2[O:20][CH2:19][CH2:18][O:17]2)[CH:13]=[CH:14][CH:15]=1.CC(C)([O-])C.[Na+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:17]1[CH2:18][CH2:19][O:20][CH:16]1[C:12]1[CH:11]=[C:10]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[CH:3]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: Cc1cccc(N)c1
Reactant: Brc1cccc(C2OCCO2)c1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: Cc1cccc(Nc2cccc(C3OCCO3)c2)c1
Temperature: 25 °C

Procedure:
To a clean and dry 500 ml round bottom flask equipped with a reflux condenser and magnetic stir bar nitrogen was purged and anhydrous toluene (250.0 ml) was added by cannula. m-toluidine (5.1 ml, 0.0467 mol) was added to the reaction flask by syringe. Next, 2-(3-bromophenyl)-1,3-dioxolane (7.8 ml, 0.0513 mol) was added by syringe. The reaction solution was purged with a strong nitrogen flow for 30 minutes. Sodium tert-butoxide (6.73 g, 0.0701 mol) and Pd2dba3 (0.85 g, 0.0009 mol) were then added manually, followed by the addition of tri-tert-butylphosphine (0.57 g, 0.0028 mol) in toluene (˜8 ml) via syringe. The vessel was heated to reflux for approximately 4 hours. The reaction was then cooled to room temperature and filtered through a Celite and silica gel pad. Solvent was removed by rotary evaporation. The crude material was partially dissolved in a 10% ethyl acetate/hexane solution (20.0 ml) and purified by flash column chromatography providing near pure product. Further purification was carried out using an automatic column chromatography system using 5% ethyl acetate/hexane as an eluent. This provided pure product confirmed by NMR.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C@H:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][C@H:8]2[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:3][CH:2]=1.[O-]CC.[Na+]>C(O)C>[N:1]1[CH:6]=[CH:5][C:4]([C@@H:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:9][C@H:8]2[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:3][CH:2]=1
Reactant: CCOC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1c1ccncc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1c1ccncc1
Temperature: 60 °C

Procedure:
To an ethanol solution (0.4 M) of cis-1-(1,1-dimethylethyl) 3-ethyl 4-(4-pyridinyl)-1,3-piperidinedicarboxylate (1 eq.) from the previous step was added freshly prepared sodium ethoxide (1.1 eq.). The resulting yellow-orange solution was heated at 60° C. for 12 h. The volatiles were then removed in vacuo and the residue was partitioned between EtOAc and sat. aq. NH4Cl. The aqueous layer was separated and back-extracted with EtOAc. The combined organic extracts were washed further with water and brine, dried over Na2SO4, treated with activated charcoal, filtered and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of column chromatography (SiO2, 80:20 (v/v) Hex:EtOAc→EtOAc) afforded the title compound as a pale yellow oil.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:6]([O:10][C:11]([C:13]1[C:14](OS(C(F)(F)F)(=O)=O)=[N:15][C:16]2[C:21]([C:22]=1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]([CH3:31])[CH3:30])[CH:24]=1)=[CH:20][C:19]([Cl:32])=[CH:18][CH:17]=2)=[O:12])([CH3:9])([CH3:8])[CH3:7].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[C:6]([O:10][C:11]([C:13]1[C:14]([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[N:15][C:16]2[C:21]([C:22]=1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]([CH3:30])[CH3:31])[CH:24]=1)=[CH:20][C:19]([Cl:32])=[CH:18][CH:17]=2)=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)c1cccc(-c2c(C(=O)OC(C)(C)C)c(OS(=O)(=O)C(F)(F)F)nc3ccc(Cl)cc23)c1
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)c1cccc(-c2c(C(=O)OC(C)(C)C)c(N3CCCC3)nc3ccc(Cl)cc23)c1
Temperature: 90 °C
Reaction time: 3 h
Yield: 72.9 %

Procedure:
To a solution of pyrrolidine (0.093 ml, 1.13 mmol) in DMSO (7 ml) was added 6-chloro-4-(3-isopropyl-phenyl)-2-trifluoromethanesulfonyloxy-quinoline-3-carboxylic acid tert-butyl ester (prepared as described in example 78 step C, 400 mg, 0.76 mmol) and potassium carbonate (313 mg, 2.026 mmol) at 25° C. The resulting reaction mixture was stirred at 90° C. for 3 h. The reaction mixture was diluted with water (15 ml), and extracted with EtOAc (2×30 ml). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give a crude residue which was purified by flash column chromatography (5-10% EtOAc in hexane) to afford 6-chloro-4-(3-isopropyl-phenyl)-2-pyrrolidin-1-yl-quinoline-3-carboxylic acid tert-butyl ester (250 mg, 73%) as pale yellow solid. LC-MS (ESI): LC-MS (ESI): 451 (M+H)+.
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([OH:15])=[O:14])=[O:8])(=[O:3])[CH3:2].[I-].[K+].C(N(CC)CC)C.Cl[CH2:36][C:37]([N:39]([CH2:42][CH3:43])[CH2:40][CH3:41])=[O:38]>CN(C=O)C.O>[C:1]([S:4][CH2:5][CH:6]([CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([O:15][CH2:36][C:37]([N:39]([CH2:42][CH3:43])[CH2:40][CH3:41])=[O:38])=[O:14])=[O:8])(=[O:3])[CH3:2]
Reactant: CCN(CC)C(=O)CCl
Reactant: CC(=O)SCC(Cc1ccccc1)C(=O)Nc1cccc(C(=O)O)c1
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCN(CC)C(=O)COC(=O)c1cccc(NC(=O)C(CSC(C)=O)Cc2ccccc2)c1
Temperature: 25 °C
Yield: 74.9 %

Procedure:
3-[(2-Acetylthiomethyl-3-phenylpropionyl)amino]-benzoic acid (compound of Example 68-(b)-[1]) (0.72 g) and potassium iodide (0.37 g) are dissolved in DMF, and thereto are added triethylamine (0.2 g) and 2-chloro-N,N-diethylacetamide (0.33 g) with stirring at room temperature, and the mixture is reacted three nights. The reaction mixture is mixed with water and extracted with ethyl acetate. The extract is washed with water, dried over anhydrous magnesium sulfate, and ethyl acetate is distilled off under reduced pressure. The residue is purified by a medium pressure column chromatography using silica gel (eluant, chloroform). The fractions containing the desired compound are collected, and chloroform is distilled off under reduced pressure to give the title compound (0.71 g).
Reaction SMILES: [CH3:1][N:2]([CH2:20][CH2:21][OH:22])[C:3](=[O:19])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH3:1][N:2]([CH2:20][CH2:21][O:22][C:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:3](=[O:19])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCCCCCCCCCCCCCCC(=O)N(C)CCO
Product: CCCCCCCCCCCCCCCC(=O)N(C)CCOC(=O)c1ccccc1

Procedure:
N-methyl-N-(2-benzoyloxyethyl)palmitamide was prepared by the procedure of example 1 from 31 gms. (0.1 mole) of N-methyl-N-(2-hydroxyethyl)palmitamide and 14 gms. (0.1 mole) of benzoyl chloride. The structure of the final product was characterized on the basis of IR and NMR spectral analyses as described in example 1.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1.[C:12]1([OH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C[O-].[Na+]>C(#N)C>[N+:9]([C:5]1[C:6]([NH2:8])=[N:7][C:2]([O:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:3][CH:4]=1)([O-:11])=[O:10]
Reactant: Oc1ccccc1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Agent: C[O-]
Agent: [Na+]
Solvent: CC#N
Product: Nc1nc(Oc2ccccc2)ccc1[N+](=O)[O-]
Yield: 68.8 %

Procedure:
6-Chloro-3-nitro-2-pyridine amine (1.2 g), phenol (3.1 g) and sodium methoxide (0.4 g) were dissolved in acetonitrile (20 ml), and the solution was heated for 12 hours under reflux. After the completion of the reaction, the solvent was distilled off under reduced pressure. The residue was distributed into ethyl acetate and a saturated aqueous solution of sodium bicarbonate. The organic layer was washed with water and dried over MgSO4. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography. The fraction eluted with ethyl acetate-hexane (1:10, v/v) was concentrated under reduced pressure. The resulting crystals were collected by filtration to obtain 3-nitro-6-phenoxy-2-pyridine amine (1.1 g, 66%).
Reaction SMILES: [NH2:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:9]=2)=[O:7])=[CH:4][C:3]=1[OH:27].CO.[CH2:30]([C:32]1[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][CH:33]=1)[CH3:31].C([BH3-])#N.[Na+]>O.C(O)(=O)C>[CH2:30]([C:32]1[CH:39]=[CH:38][C:35]([CH2:36][NH:1][C:2]2[CH:26]=[CH:25][C:5]([C:6]([C:8]3[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]([CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:9]=3)=[O:7])=[CH:4][C:3]=2[OH:27])=[CH:34][CH:33]=1)[CH3:31]
Reactant: CCOC(=O)CCCn1cc(C(=O)c2ccc(N)c(O)c2)c2ccccc21
Reactant: CCc1ccc(C=O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: CCOC(=O)CCCn1cc(C(=O)c2ccc(NCc3ccc(CC)cc3)c(O)c2)c2ccccc21
Yield: 81.5 %

Procedure:
Ethyl 4-[3-(4-amino-3-hydroxybenzoyl)indol-1-yl]butanoate (5.0 g) was suspended in a mixed solvent containing methanol (50 ml) and water (5 ml), and 4-ethylbenzaldehyde (3.66 g) and sodium cyanoborohydride (1.80 g) were added to the suspension. Acetic acid (2.5 ml) was further added dropwise to the mixture over five minutes, and the resultant mixture was stirred at room temperature for one hour. Water (50 ml) was added to the reaction mixture, and crystals so precipitated were collected by filtration. The produced crystals were recrystallized from ethanol, to thereby obtain 5.39 g of ethyl 4-{3-[4-(4-ethylphenyl)methylamino-3-hydroxybenzoyl)indol-1-yl}butanoate as yellow crystals.
Reaction SMILES: Cl[C:2]1[CH:8]=[C:7]([S:9]([CH3:12])(=[O:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[Cu][C:14]#[N:15].N.O>CN1CCCC1>[NH2:4][C:3]1[CH:5]=[CH:6][C:7]([S:9]([CH3:12])(=[O:11])=[O:10])=[CH:8][C:2]=1[C:14]#[N:15]
Reactant: N#C[Cu]
Reactant: CS(=O)(=O)c1ccc(N)c(Cl)c1
Agent: CN1CCCC1
Agent: N
Solvent: O
Product: CS(=O)(=O)c1ccc(N)c(C#N)c1
Temperature: 180 °C
Reaction time: 72 h

Procedure:
To a solution of 2-chloro-4-methylsulfonyl aniline (1.0 g, 4.9 mmol) in N-methylpyrrolidine (10 mL) was added copper (I) cyanide (4.35 g, 48.6 mmol) under nitrogen. The reaction mixture was stirred at 180° C. for 72 hours, cooled to room temperature, poured to a 1:1 mixture of ammonia and water (200 mL), stirred for 1 hour, and then filtered off. The residue was washed with CH2Cl2 (50 mL) and filtrate was extracted with CH2Cl2 (3×20 mL). The combined organic layers were backwashed with water (50 mL), dried over sodium sulfate, and concentrated to provide crude material, which was purified by flash column chromatography (silica gel; 230-400 mesh; ethyl acetate/hexanes=1:5) to obtain 2-amino-5-methanesulfonyl-benzonitrile as a white solid. Yield: 0.1 g (13%). A suspension of potassium hydroxide (2.05 g, 36.7 mmol) in ethylene glycol (9 mL) was heated to 80° C. KOH was dissolved completely at this stage. 2-Amino-5-methanesulfonyl-benzonitrile (0.900 g, 4.59 mmol) was added to the reaction mixture and the bath temperature was increased to 185° C. and stirred for 16 hours. The resultant reaction mixture was cooled to room temperature, diluted with water (20 mL), and extracted with CH2Cl2 (3×30 mL). The aqueous layer was acidified with 2 N HCl to pH 4-5, extracted with EtOAc (3×30 mL), and the combined organic layers were backwashed with water (30 mL), then brine (30 mL), dried over sodium sulfate, and evaporated, to obtain 2-amino-5-methanesulfonyl-benzoic acid. Yield: 0.750 g (75%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[CH:17]=[C:16]([OH:19])[CH:15]=[CH:14]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:20]([Si:23](Cl)([CH:27]([CH3:29])[CH3:28])[CH:24]([CH3:26])[CH3:25])([CH3:22])[CH3:21].N1C=CN=C1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][Si:23]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:20]([CH3:22])[CH3:21])[CH:17]=2)[CH:12]=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cccc2ccc(O)cc12
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)[Si](Oc1ccc2cccc(NC(=O)OC(C)(C)C)c2c1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 8-(tert-butoxycarbonylamino)-2-naphthol, as described in Example 9, Step A, (8.00 g, 30.9 mmol), triisopropylsilyl chloride (7.92 mL, 37.0 mmol), and imidazole (4.20 g, 61.7 mmol) in DMF (75 mL) was stirred at ambient temperature for 18 hours, then poured into 10% aqueous citric acid (100 mL) and extracted with EtOAc (2×100 mL). The combined organic extracts were washed with H2O, then brine, then dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica, eluting with CH2Cl2—50% hexane to yield the desired product.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[S:10](=[O:13])(=[O:12])[NH2:11].[CH3:14][N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.CN(C)C=O>O>[CH3:14][N:15]1[CH2:20][CH2:19][N:18]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[S:10](=[O:13])(=[O:12])[NH2:11])[CH2:17][CH2:16]1
Reactant: N#Cc1ccc(Cl)c(S(N)(=O)=O)c1
Reactant: CN1CCNCC1
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCN(c2ccc(C#N)cc2S(N)(=O)=O)CC1

Procedure:
43.5 Grams of 4-Chloro-3-sulfamoylbenzonitrile (0.2 mole) were stirred with 45 g of N-methylpiperazine and 50 ml of dimethylformamide for 1 hour at a temperature of from 115° to 120° C., and the reaction solution was subsequently introduced into 0.5 l of water. The crystalline precipitate was suction-filtered, and the moist crude product which had been washed with water, was recrystallized from ethanol.
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]1([C:14]2[N:19]3[N:20]=[C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:22]=[C:18]3[N:17]=[C:16]([NH:29][NH2:30])[CH:15]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[Cl:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH:35]=O>C(O)C>[Cl:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH:35]=[N:30][NH:29][C:16]1[CH:15]=[C:14]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:19]2[N:20]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:22]=[C:18]2[N:17]=1
Reactant: NNc1cc(N2CCOCC2)n2nc(-c3ccccc3)cc2n1
Reactant: O=Cc1cccc(Cl)c1
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: Clc1cccc(C=NNc2cc(N3CCOCC3)n3nc(-c4ccccc4)cc3n2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 34 %

Procedure:
There was dissolved, in ethanol (2 mL), trifluoroacetic acid salt of (7-morpholin-4-yl-2-phenyl-pyrazolo[1,5-a]pyrimidin-5-yl)-hydrazine (30.8 mg, 0.0572 mM), then 3-chloro-benzaldehyde (6.5 μL, 0.057 mM) was added to the solution and the mixture was stirred at room temperature for one hour. This reaction liquid was filtered and the resulting solid was purified by the NH-silica gel column chromatography (methylene chloride) to thus give the title compound (9.6 mg, yield: 34%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)=[CH:4][CH:3]=1.Cl[CH2:18][C:19]1[N:20]=[C:21]([C:24]2[S:25][C:26]([CH3:29])=[CH:27][CH:28]=2)[S:22][CH:23]=1>>[N:12]1([CH2:11][CH2:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:18][C:19]3[N:20]=[C:21]([C:24]4[S:25][C:26]([CH3:29])=[CH:27][CH:28]=4)[S:22][CH:23]=3)=[CH:3][CH:4]=2)[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: Oc1ccc(CCCCn2ccnc2)cc1
Reactant: Cc1ccc(-c2nc(CCl)cs2)s1
Product: Cc1ccc(-c2nc(COc3ccc(CCCCn4ccnc4)cc3)cs2)s1
Yield: 74 %

Procedure:
In substantially the same manner as in Working Example 72, 1-[4-(4-hydroxyphenyl)butyl]imidazole was reacted with 4-chloromethyl-2-(5-methyl-2-thienyl)thiazole to obtain 4-[4-[4-(1-imidazolyl)butyl]phenoxymethyl]-2-(5-methyl-2-thienyl)thiazole. The yield was 74%. Recrystallization from ethyl acetate-hexane gave pale yellow needles, mp 81-82° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].F[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1.CCCC(C)C>CN(C=O)C.CCOC(C)=O.O>[N+:22]([C:19]1[CH:20]=[CH:21][C:16]([O:1][CH:2]2[CH2:3][CH2:4][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:7]2)=[CH:17][CH:18]=1)([O-:24])=[O:23]
Reactant: CCOC(=O)C1CCC(O)CC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)C1CCC(Oc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of ethyl 4-hydroxycyclohexanecarboxylate (2.0 g, 11.6 mmol) in DMF (3 ml) was added in one portion to a stirred suspension of sodium hydride (60% dispersion in mineral oil, 490 mg, 12.2 mmol) in DMF (15 mL) at 0° C. under an argon atmosphere. The mixture was stirred at 0° C. for 10 minutes and then warmed to room temperature and stirred for 20 minutes and then a solution of 1-fluoro-4-nitrobenzene (1.24 mL, 11.6 mmol) in DMF (2 mL) was added in one portion. The reaction mixture was stirred at room temperature for 2 h and then heated at 110° C. for 24 h. The solution was concentrated in vacuo to leave a residue that was taken up in EtOAc (250 mL) and water (150 mL) was added. The layers were separated and the organic layer was washed with H2O (2×100 mL) and brine (50 mL) and then dried (MgSO4) and concentrated in vacuo to leave an oil. The oil was taken up in a mixture of hot EtOAc and isohexane (1:1) and left for 20 h. Filtration, followed by concentration in vacuo of the filtrate left an oil, which was purified by column chromatography, using 10-40% EtOAc in isohexane as eluent, to give crude ethyl 4-(4-nitrophenoxy)cyclohexanecarboxylate as an off white solid that was used without further purification.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:7]=[N:8][C:9]([O:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[O:19][CH:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:17][CH2:16]3)=[CH:10][CH:11]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[NH:35]([CH2:39][CH2:40][OH:41])[CH2:36][CH2:37][OH:38].O>C(#N)C>[OH:38][CH2:37][CH2:36][N:35]([CH2:39][CH2:40][OH:41])[CH2:2][C:3]([NH:5][C:6]1[CH:7]=[N:8][C:9]([O:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[O:19][CH:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:17][CH2:16]3)=[CH:10][CH:11]=1)=[O:4]
Reactant: O=C(CCl)Nc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Reactant: OCCNCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=C(CN(CCO)CCO)Nc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Temperature: 25 °C

Procedure:
To a solution of 2-chloro-N-[6-(2-phenylchroman-6-yloxy)-pyridin-3-yl]acetamide (177 mg) in acetonitrile was added potassium carbonate (118 mg) and diethanolamine (65 μl). The mixture was stirred at room temperature. Water was added to the reaction mixture. Solution was extracted with ethyl acetate. Organic extract was dried and evaporated. 2-[Bis(2-hydroxyethyl)amino]-N-[6-(2-phenyl-chroman-6-yloxy)pyridin-3-yl]acetamide was purified by column chromatography using 10% methanol in methylenechloride as eluant. 1H-NMR (400 MHz; d6-DMSO) δ: 10.1 (s, 1H), 8.31 (d, 1H, J 2.7 Hz), 8.07 (dd, 1H, J 2.7, 8.8 Hz), 7.46-7.31 (m, 5H), 6.95 (d, 1H, J 8.8 Hz), 6.86-6.84 (m, 3H), 5.11 (dd, 1H, J 2.1, 10.0 Hz), 4.71 (t, 2H, J 5.4 Hz), 3.50 (q, 4H, J 5.4 Hz), 2.97-2.92 (m, 1H), 2.74-2.70 (m, 1H), 2.67 (t, 4H, J 5.4 Hz), 2.18-2.14 (m, 1H), 2.02-1.97 (m, 1H).
Reaction SMILES: CC1(C)C[O:5][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[CH:18]=[CH:17][C:16]([CH2:19][OH:20])=[CH:15][CH:14]=2)=N1.Cl.C([OH:25])C>>[OH:20][CH2:19][C:16]1[CH:17]=[CH:18][C:13]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:4]([OH:5])=[O:25])=[CH:14][CH:15]=1
Reactant: CC1(C)COC(c2ccccc2-c2ccc(CO)cc2)=N1
Reactant: CCO
Agent: Cl
Product: O=C(O)c1ccccc1-c1ccc(CO)cc1
Temperature: 25 °C
Yield: 81 %

Procedure:
2.0 g (7.11 mmol) of 4,4-dimethyl-2-(4'-hydroxymethylbiphenyl-2-yl)oxazoline was dissolved in ethanol (30 ml). 2N hydrochloric acid (10 ml) was added thereto, followed by heating under reflux for 3 hours. After the reaction liquid was cooled and concentrated, a saturated aqueous solution of sodium hydrogencarbonate (100 ml) was added thereto, followed by the extraction with chloroform. After the organic phase was washed with water and dried, it was subjected to vacuum concentration. A 20% aqueous solution of sodium hydroxide (20 ml) and ethanol (20 ml) were added to the residue, followed by heating under reflux for 8 hours. After the reaction liquid was cooled to room temperature and adjusted to pH 6 with hydrochloric acid, it was extracted with chloroform. After the organic phase was washed with water and dried, it was subjected to vacuum concentration. The residue was purified by silica gel column chromatography (a chloroform/methanol system) to give 1.31 g of the title compound (yield 81%).
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][C:12]2[CH:13]=[C:14]([CH:26]3[CH2:28][CH2:27]3)[C:15]3[O:22][C:19]4([CH2:21][CH2:20]4)[CH2:18][C:17]([CH3:24])([CH3:23])[C:16]=3[CH:25]=2)=[CH:6][C:5]=1[F:29].CO.[OH-].[Na+].O>C(#N)C>[CH:26]1([C:14]2[C:15]3[O:22][C:19]4([CH2:20][CH2:21]4)[CH2:18][C:17]([CH3:23])([CH3:24])[C:16]=3[CH:25]=[C:12]([C:11]#[C:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:30])=[O:2])=[C:5]([F:29])[CH:6]=3)[CH:13]=2)[CH2:27][CH2:28]1
Reactant: COC(=O)c1ccc(C#Cc2cc(C3CC3)c3c(c2)C(C)(C)CC2(CC2)O3)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC#N
Solvent: O
Product: CC1(C)CC2(CC2)Oc2c(C3CC3)cc(C#Cc3ccc(C(=O)O)c(F)c3)cc21

Procedure:
Following general procedure L and using 4-[(8-cyclopropyl-3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane]-6yl)ethynyl]-2-fluoro-benzoic acid methyl ester (Compound 53, 0.01 g, 0.047 mmol), 5 mL of methanol and 1M sodium hydroxide solution (2 mL) followed by preparative reverse phase HPLC using 10% water in acetonitrile as the mobile phase, the title compound was obtained as a solid (0.01 g, 56%).
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][C@H:10]2[CH2:15][CH2:14][Si@H:13]([CH2:16][CH2:17][CH3:18])[CH2:12][CH2:11]2)[CH2:4][CH2:3]1.[CH2:19]([C:22]1[CH:27]=[CH:26][C:25]([Mg]Br)=[CH:24][CH:23]=1)[CH2:20][CH3:21].Cl[SiH]1CCC(CC[C@H]2CC[C@H](CCCCC)CC2)CC1.FC1C=C([Mg]Br)C=CC=1F>>[CH2:19]([C:22]1[CH:27]=[CH:26][C:25]([C@H:2]2[CH2:7][CH2:6][C@H:5]([CH2:8][CH2:9][C@H:10]3[CH2:15][CH2:14][Si@H:13]([CH2:16][CH2:17][CH3:18])[CH2:12][CH2:11]3)[CH2:4][CH2:3]2)=[CH:24][CH:23]=1)[CH2:20][CH3:21]
Reactant: CCCc1ccc([Mg]Br)cc1
Reactant: CCC[Si@H]1CC[C@H](CCC2CCC(Br)CC2)CC1
Agent: CCCCC[C@H]1CC[C@H](CCC2CC[SiH](Cl)CC2)CC1
Agent: Fc1ccc([Mg]Br)cc1F
Product: CCCc1ccc([C@H]2CC[C@H](CC[C@H]3CC[Si@H](CCC)CC3)CC2)cc1

Procedure:
The preparation was conducted in the same manner as in Example 33, except that 2.6 g (7.9 mmol) of 1-bromo-4-(2-(trans-4-n-propyl-4-silacyclohexyl)ethyl)cyclohexane and p-n-propylphenylmagnesium bromide were used instead of 2.5 g (7.9 mmol) of 1-chloro-4-(2-(trans-4-n-pentylcyclohexyl) ethyl)-1-silacyclohexane and 3,4-difluorophenylmagnesium bromide.