Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([NH:42][C:43](=[O:45])[CH3:44])[CH:37]=2)=[CH:32][CH:31]=1)([C:6]1[N:7]=[CH:8][N:9](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4].Cl.N1C=CC=CC=1>>[OH:1][C:2]([C:30]1[CH:31]=[CH:32][C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([NH:42][C:43](=[O:45])[CH3:44])[CH:37]=2)=[CH:34][CH:35]=1)([C:6]1[N:7]=[CH:8][NH:9][CH:10]=1)[CH:3]([CH3:5])[CH3:4]
Reactant: CC(=O)Nc1cccc(-c2ccc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)cc2)c1
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)Nc1cccc(-c2ccc(C(O)(c3c[nH]cn3)C(C)C)cc2)c1
Yield: 47.8 %

Procedure:
By the reaction in the same manner as in Example 4-(iii) using N-{4′-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl][1,1′-biphenyl]-3-yl}acetamide (978 mg) and pyridine hydrochloride (310 mg), the title compound (276 mg) was obtained as a colorless amorphous powder.
Reaction SMILES: [CH:1]([Mg]Cl)=[CH2:2].[Br:5][C:6]1[CH:19]=[CH:18][C:17]2[O:16][C:15]3[C:10](=[CH:11][C:12]([I:20])=[CH:13][CH:14]=3)[C:9](=[O:21])[C:8]=2[CH:7]=1>C1COCC1>[Br:5][C:6]1[CH:19]=[CH:18][C:17]2[O:16][C:15]3[C:10](=[CH:11][C:12]([I:20])=[CH:13][CH:14]=3)[C:9]([CH:1]=[CH2:2])([OH:21])[C:8]=2[CH:7]=1
Reactant: O=c1c2cc(Br)ccc2oc2ccc(I)cc12
Reactant: C=C[Mg]Cl
Solvent: C1CCOC1
Product: C=CC1(O)c2cc(Br)ccc2Oc2ccc(I)cc21
Temperature: -10 °C
Yield: 100 %

Procedure:
To a solution of vinylmagnesium chloride (6.86 mL, 10.97 mmol) at −78° C. under nitrogen atmosphere was added drop wise a solution of 2-bromo-7-iodo-9H-xanthen-9-one (2.00 g, 4.99 mmol) in THF (30 mL). The reaction mixture was allowed to slowly warm to −10° C., then the reaction was quenched with saturated NH4Cl. The mixture was extracted with EtOAc followed by a solvent mixture of CHCl3: i-PrOH (3:1). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude material was purified by filtration over silica gel (10% EtOAc/hexane) to give 2.14 g of 2-bromo-7-iodo-9-vinyl-9H-xanthen-9-ol as a white solid.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([Cl:22])[CH:16]=2)[CH2:9]1)(OC(C)(C)C)=O.[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29]O)[CH:24]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>ClCCl>[Cl:22][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][C:18]=1[O:21][CH2:29][C:25]1[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=1)[CH2:14][C@H:10]1[O:11][CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](Cc2ccc(O)c(Cl)c2)C1
Reactant: OCc1cccnc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Solvent: ClCCl
Product: Clc1cc(C[C@@H]2CNCCO2)ccc1OCc1cccnc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
N-BOC-(R)-2-(3-chloro-4-hydroxybenzyl)morpholine, example 7, intermediate (a) (53 mg, 0.16 mmol), was dissolved in dichloromethane (4 mL) with 3-pyridinyl carbinol (35 mg, 0.32 mmol) shaken at room temperature for 20 mins and diisopropylazodicarboxylate (65 mg, 0.32 mmol) added in one portion. dichloromethane (6 mL) was added to solvate the polymer. The reaction mixture was shaken for 24 hrs then filtered. Polymer supported toluenesulfonyl chloride (0.18 g, 2.82 mmol/g) and MP-carbonate (0.39 g, 2.62 mmol/g) were added to the liquor and the mixture shaken for 6 hrs. The reaction was filtered and evaporated under a high flow of nitrogen. The crude residue was dissolved in TFA (20% v/v solution in dichloromethane, 2.0 mL) and shaken for 3 hrs at room temperature. The reaction mixture was added directly to an SCX-2 column (2 g) and washed with dichloromethane (2 mL×2) and methanol (2 mL×2). The SCX-2 column was then washed with ammonia (2N in methanol, 3×2 mL). Combined ammonia washes were concentrated in vacuo and the residue purified by preparative HPLC to yield the desired morpholine example 44 as a colorless oil (9 mg).
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:7])[CH2:4][CH2:5]Cl.C(=O)([O-])[O-].[K+].[K+].[N+:14]([C:17]1[CH:18]=[N:19][NH:20][CH:21]=1)([O-:16])=[O:15]>CC(C)=O>[CH3:2][N:3]([CH3:7])[CH2:4][CH2:5][N:19]1[CH:18]=[C:17]([N+:14]([O-:16])=[O:15])[CH:21]=[N:20]1
Reactant: O=[N+]([O-])c1cn[nH]c1
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CN(C)CCn1cc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Dimethylaminoethyl chloride hydrochloride (955 mg, 6.63 mmol), potassium carbonate (1.83 g, 8.84 mmol) and 4-nitro-1H-pyrazole (750 mg, 6.63 mmol) were combined in acetone (30 ml) and the reaction was stirred overnight at reflux. After cooling to room temperature, the crude reaction mixture was filtered to remove inorganics, and the filtrate was concentrated to give the product.
Reaction SMILES: [I:1]I.[Cl:3][C:4]1[CH:9]=[C:8]([C:10]([O:12][CH3:13])=[O:11])[CH:7]=[CH:6][C:5]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1.CO.CCOC(C)=O>CO.S([O-])([O-])(=O)=O.[Ag+2]>[Cl:3][C:4]1[CH:9]=[C:8]([C:10]([O:12][CH3:13])=[O:11])[CH:7]=[CH:6][C:5]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([I:1])[CH:15]=1
Reactant: II
Reactant: COC(=O)c1ccc(-c2ccc(OC)cc2)c(Cl)c1
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1ccc(-c2ccc(OC)c(I)c2)c(Cl)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a mixture of silver sulfate (0.97 g, 3.11 mmol) and iodine (0.79 g, 3.11 mmol) in MeOH (20 ml) at room temperature, a solution of methyl 2-chloro-4′-methoxybiphenyl-4-carboxylate (0.86 g, 3.11 mmol) in 1:1 mixture of MeOH/EtOAc (10 ml) was added. The mixture was stirred at room temperature for 6 h until color of the reaction turned to pale. The solid was filtered off and the filtrate was concentrated. The title compound was obtained after flash column using EtOAc:hexane/5:95 as the eluant. 1H NMR (CDCl3, 500 MHz): δ 8.15 (d, J=1.5 Hz, 1H), 7.97 (dd, J=8, 2 Hz, 1H), 7.89 (d, J=2 Hz, 1H), 7.46 (dd, J=8.5, 2 Hz, 1H), 7.40 (d, J=8 Hz, 1H), 6.91 (d, J=8 Hz, 1H), 3.98 (s, 6H).
Reaction SMILES: [H-].[Na+].[CH:3](OCC)=[O:4].[C:8]([C:11]1[S:12][C:13]([S:23][CH3:24])=[C:14]2[C:19](=[O:20])[CH2:18][C:17]([CH3:22])([CH3:21])[CH2:16][C:15]=12)(=[O:10])[CH3:9].CO>C1COCC1.O>[CH3:22][C:17]1([CH3:21])[CH2:16][C:15]2=[C:11]([C:8](=[O:10])[CH:9]=[CH:3][OH:4])[S:12][C:13]([S:23][CH3:24])=[C:14]2[C:19](=[O:20])[CH2:18]1
Reactant: CCOC=O
Reactant: CSc1sc(C(C)=O)c2c1C(=O)CC(C)(C)C2
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CSc1sc(C(=O)C=CO)c2c1C(=O)CC(C)(C)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
To a suspension of sodium hydride (149 mg of a 60% dispersion in oil. 3.7 mmol) in THF (7 mL) was added ethyl formate (0.75 mL, 9.3 mmol) at 0° C., under nitrogen. After addition a solution of 1-acetyl-6,6-dimethyl-3-methylthio-4,5,6,7-tetrahydrobenzo [c]thiophen-4-one (0.5 g, 1.9 mmol) in THF (7 mL) was added. The mixture was stirred overnight at room temperature. Methanol (0.5 mL) and water (0.5 mL) were then added to the mixture and the solvent removed in vacuo. The residue was dissolved in water and acidified using 1M HCl. The resultant solid was collected by filtration then partitioned between EtOAc (30 mL) and water (30 mL). The organic layer was separated, dried (Na2SO4) and evaporated. The residue was triturated with ether and the title compound (0.4 g, 80%) was isolated as a yellow solid. 1H NMR (360 MHz, CDCl3) δ 1.09 (6H, s), 2.43 (2H, s), 2.63 (3H, s), 3.08 (2H, s), 5.85 (1H, d, J=5.1 Hz), 7.77 (1H, d, J=5.1 Hz), 14.90 (1H, br s). MS (ES+) 297 (M+1).
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[C:8]#[N:9].Br[CH2:14][CH2:15][O:16][CH3:17]>O1CCCC1>[CH3:17][O:16][CH2:15][CH2:14][O:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[C:8]#[N:9]
Reactant: COCCBr
Reactant: N#Cc1cccc(CO)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCOCc1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride (55% in mineral oil, 1.76 g, 40.5 mmol) was suspended in 100 mL tetrahydrofurane. 3-(Hydroxymethyl)benzonitrile (5.0 g, 36.5 mmol), dissolved in 200 mL tetrahydrofuran was added dropwise. The reaction mixture was stirred at room temperature for 1 h. 2-Bromoethylmethylether (7.0 mL, 76 mmol) was added and the reaction mixture was refluxed overnight. The reaction mixture was quenched with 3 mL 2N sodium carbonate solution and the solvent was evaporated. The residue was taken up in 100 mL water and extracted three times with ethyl acetate (100 mL each). The organic phases ware pooled, dried with sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 100:0->50:50 gradient). 3-(2-Methoxy-ethoxymethyl)-benzonitrile was obtained as a yellow liquid (2.63 g, 38%).
Reaction SMILES: C[O:2][C:3]1[CH:23]=[CH:22][C:6]([C:7]([C:9]2[CH:19]=[CH:18][C:12]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[C:11]([Cl:20])[C:10]=2[Cl:21])=[O:8])=[CH:5][CH:4]=1.I>CCOCC>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([C:9]2[CH:19]=[CH:18][C:12]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[C:11]([Cl:20])[C:10]=2[Cl:21])=[O:8])=[CH:22][CH:23]=1
Reactant: COc1ccc(C(=O)c2ccc(OCC(=O)O)c(Cl)c2Cl)cc1
Agent: I
Solvent: CCOCC
Product: O=C(O)COc1ccc(C(=O)c2ccc(O)cc2)c(Cl)c1Cl
Reaction time: 1 h

Procedure:
A mixture of 4-(4-methoxybenzoyl)-2,3-dichlorophenoxy acetic acid (3.55 g., 0.01 mole) and hydriodic acid (7.5 ml.) was refluxed at 180°-190° C. for 4 hours. The reaction mixture was concentrated and the solid residue was stirred with water for one hour and filtered. The solid obtained was dissolved in ether and dried (MgSO4). The solvent was removed in vacuo and the residue was recrystallized from ether--pet. ether mixture to give 2 g. (60%) of the product; m.p. 218°-219° C.
Reaction SMILES: [C:1]([NH:7][C:8]1[C:9](=[CH:13][C:14]([I:17])=[CH:15][CH:16]=1)[C:10](O)=[O:11])(=O)[CH2:2][CH2:3][CH2:4][CH3:5].ClC(OCC)=O.C(=O)=O.[OH-].[NH4+:28]>CN(C)C=O.O.C(N(CC)CC)C>[CH2:2]([C:1]1[NH:28][C:10](=[O:11])[C:9]2[C:8](=[CH:16][CH:15]=[C:14]([I:17])[CH:13]=2)[N:7]=1)[CH2:3][CH2:4][CH3:5]
Reactant: [NH4+]
Reactant: CCCCC(=O)Nc1ccc(I)cc1C(=O)O
Agent: CCOC(=O)Cl
Agent: O=C=O
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCc1nc2ccc(I)cc2c(=O)[nH]1
Temperature: 25 °C
Yield: 56.7 %

Procedure:
To a mixture of 1500 g of N-valeryl-5-iodoanthranilic acid in 14.5 L of N,N-dimethylformamide is added under nitrogen, 660 mL of triethylamine. The resulting solution is cooled to 0° to 5° C. and 432 mL of ethyl chloroformate added over 10 minutes at a rate to maintain the temperature below 10° C. The reaction mixture is heated to 35° to 50° C. for 2 hours until the evolution of carbon dioxide ceases. Analysis of a small aliquot of the reaction mixture by GC/MS indicates 93.7% (area %) conversion. The reaction mixture is cooled to 10°-15° C. and 5.0 L of concentrated ammonium hydroxide added over 10 minutes. The resulting slurry is then heated at 60°-70° C. for 14 hours. To the reaction mixture is added 10 L of water and the resulting slurry cooled to ambient temperature and filtered. The recovered solid is washed with 3 L of a 1:1 water-N,N-dimethylformamide solution followed by two 3 L water washes. The solid is dried at 50° C. to give 803 g (56.7%) of the desired product. The purity is 100% as analyzed by GC/MS.
Reaction SMILES: [N:1]([C:4]1[CH:14]=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=1)=[C:2]=[O:3].[Cl:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][C:17]=1[C:23]([F:26])([F:25])[F:24]>C(Cl)Cl>[Cl:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:2]([NH:1][C:4]2[CH:14]=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=2)=[O:3])=[CH:18][C:17]=1[C:23]([F:24])([F:25])[F:26]
Reactant: Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: CCOC(=O)c1ccc(N=C=O)cc1
Solvent: ClCCl
Product: CCOC(=O)c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1
Reaction time: 8 h
Yield: 93.5 %

Procedure:
To a solution of ethyl 4-isocyanatobenzoate (3.14 g, 16.4 mmol) in CH2Cl2 (30 mL) was added 4-chloro-3-(trifluoromethyl)aniline (3.21 g, 16.4 mmol), and the solution was stirred at room temp. overnight. The resulting slurry was diluted with CH2Cl2 (50 mL) and filtered to afford N-(4-chloro-3-(trifluoromethyl)phenyl)-N′-(4-ethoxycarbonylphenyl) urea as a white solid (5.93 g, 97%): TLC (40% EtOAc/60% hexane) Rf 0.44.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[NH2:19])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([CH3:15])[CH:9]=1)=[O:6].[CH3:20][C:21]1[C:28]([CH3:29])=[CH:27][CH:26]=[CH:25][C:22]=1[CH:23]=O.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Yb+3]>CS(C)=O>[CH3:15][C:10]1[CH:9]=[C:8]([NH:7][C:5]([C:4]2[CH:16]=[CH:17][C:18]3[N:19]=[C:23]([C:22]4[CH:25]=[CH:26][CH:27]=[C:28]([CH3:29])[C:21]=4[CH3:20])[NH:1][C:2]=3[CH:3]=2)=[O:6])[CH:13]=[CH:12][C:11]=1[CH3:14]
Reactant: Cc1ccc(NC(=O)c2ccc(N)c(N)c2)cc1C
Reactant: Cc1cccc(C=O)c1C
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CS(C)=O
Product: Cc1ccc(NC(=O)c2ccc3nc(-c4cccc(C)c4C)[nH]c3c2)cc1C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 3,4-diamino-N-(3,4-dimethylphenyl)-benzamide (71 mg) and 2,3-dimethylbenzaldehyde (34 mg) in DMSO (1 mL) was added Yb(OTf)3 and the mixture was stirred at room temperature for 4 h. Additional Yb(OTf)3 was added and stirring was continued until starting material was consumed. Water was added and the mixture was extracted with EtOAc. The organic phase was washed with water and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by flash chromatography using CH2Cl2/EtOAc (2:1) as eluent to furnish 2-(2,3-dimethylphenyl)-3H-benzoimidazole-5-carboxylic acid (3,4-dimethylphenyl)-amide as a beige solid, MS (m/z) 370 (M−1).
Reaction SMILES: [CH:1]1([CH:7]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]3[CH:32]=[CH:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]=3)[CH:18]=2)[O:8][NH:9][C:10](=[O:16])[C:11]([O:13]CC)=[O:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl>C(O)C>[CH:1]1([CH:7]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]3[CH:32]=[CH:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]=3)[CH:18]=2)[O:8][NH:9][C:10](=[O:16])[C:11]([OH:13])=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)C(=O)NOC(c1cccc(-c2ccc3ccccc3n2)c1)C1CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C(=O)NOC(c1cccc(-c2ccc3ccccc3n2)c1)C1CCCCC1
Reaction time: 2 h

Procedure:
A solution of Example 4A (70 mg, 0.162 mmol) in ethanol (2 mL) at room temperature was treated with 2M NaOH (1 mL), stirred for 2 hours, adjusted to pH 1 with 1M HCl, and extracted with ethyl acetate. The extract was dried (Na2SO4), filtered, and concentrated to provide the desired product. MS (ESI(+)) m/z 405 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ11.96 (br s, 1H), 8.49 (d, 1H), 8.23-8.17 (m, 3H), 8.06 (d, 1H), 8.02 (d, J=8.2 Hz, 1H), 7.80 (dt, 1H), 7.61 (dt, 1H), 7.53 (t, 1H), 7.43 (d, 1H), 4.82 (d, 1H), 2.08 (m, 1H), 1.82-1.70 (m, 2H), 1.60 (m, 2H), 1.48-1.10 (m, 6H).
Reaction SMILES: [CH2:1]([C:3]1[CH:14]=[C:13]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:12]=[CH:11][C:4]=1[O:5][CH2:6][CH:7]([OH:10])[CH2:8][OH:9])[CH3:2].[C:29](Cl)([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.N1C=CC=CC=1>C(Cl)(Cl)Cl>[CH2:1]([C:3]1[CH:14]=[C:13]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:12]=[CH:11][C:4]=1[O:5][CH2:6][CH:7]([OH:10])[CH2:8][O:9][C:29]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[CH3:2]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCCCCCCCCCCCc1ccc(OCC(O)CO)c(CC)c1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCc1ccc(OCC(O)COC(c2ccccc2)(c2ccccc2)c2ccccc2)c(CC)c1
Reaction time: 72 h
Yield: 95.3 %

Procedure:
A mixture of 11.68 g of 3-(2-ethyl-4-tetradecylphenoxy)-1,2-propanediol, 14.95 g of trityl chloride and 40 ml pyridine was stirred for 72 hours, then diluted with chloroform, washed with two 100 ml portions of aqueous sodium bicarbonate, then water and dried. The solvents were evaporated under reduced pressure and the residue evaporated with toluene. This residue was then diluted with hexanes and the solid which formed collected giving 18 g of the desired compound.
Reaction SMILES: C(N(CC)CC)C.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH2:31]([O:33][C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][C:42]=1[C:43]1[CH:44]=[N:45][N:46]([CH3:48])[CH:47]=1)[C:37]([OH:39])=O)[CH3:32].Cl.[NH:50]1[C:54]([C:55]2[CH:56]=[C:57]3[C:67](=[CH:68][CH:69]=2)[O:66][C:60]2([CH2:65][CH2:64][NH:63][CH2:62][CH2:61]2)[CH2:59][C:58]3=[O:70])=[N:53][N:52]=[N:51]1>O.CN(C)C=O>[CH2:31]([O:33][C:34]1[CH:35]=[C:36]([C:37]([N:63]2[CH2:64][CH2:65][C:60]3([CH2:59][C:58](=[O:70])[C:57]4[C:67](=[CH:68][CH:69]=[C:55]([C:54]5[NH:53][N:52]=[N:51][N:50]=5)[CH:56]=4)[O:66]3)[CH2:61][CH2:62]2)=[O:39])[CH:40]=[CH:41][C:42]=1[C:43]1[CH:44]=[N:45][N:46]([CH3:48])[CH:47]=1)[CH3:32]
Reactant: CCOc1cc(C(=O)O)ccc1-c1cnn(C)c1
Reactant: O=C1CC2(CCNCC2)Oc2ccc(-c3nnn[nH]3)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4nnn[nH]4)ccc2O3)ccc1-c1cnn(C)c1
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
Triethylamine (136 μL, 0.97 mol), 1-hydroxybenzotriazole hydrate (99.0 mg, 0.73 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (140 mg, 0.73 mol) were added to an N,N-dimethylformamide solution (4.0 mL) of 3-ethoxy-4-(1-methyl-1H-pyrazol-4-yl)benzoic acid (120 mg, 0.49 mmol) and 6-(tetrazol-5-yl)spiro[chroman-2,4′-piperidin]-4-one hydrochloride (204 mg, 0.63 mol), and then stirred at 90° C. for 30 minutes. The reaction liquid was cooled to room temperature, and water was added thereto. The formed solid was taken out through filtration, and dried overnight at 75° C. under reduced pressure to obtain the title compound as a white solid. 1H-NMR (400 MHz, DMSO-d6) δ: 8.41 (1H, d, J=2.2 Hz), 8.23 (1H, dd, J=8.5, 2.2 Hz), 8.12 (1H, s), 7.93 (1H, br s), 7.63 (1H, d, J=8.0 Hz), 7.32 (1H, d, J=8.8 Hz), 7.03 (1H, br s), 6.97 (1H, dd, J=7.9, 1.6 Hz), 4.14 (2H, q, J=6.9 Hz), 3.87 (3H, s), 3.31-3.28 (4H, m), 2.97 (2H, s), 1.92-1.79 (4H, m), 1.43 (3H, t, J=7.0 Hz). MS [M+H]+=514.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([S:12][CH3:13])[CH:9]=[CH:8][C:4]=1[C:5](O)=[O:6].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C1COCC1.O>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([S:12][CH3:13])[CH:9]=[CH:8][C:4]=1[CH2:5][OH:6]
Reactant: COc1cc(SC)ccc1C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(SC)ccc1CO
Temperature: 60 °C
Yield: 50.2 %

Procedure:
2-Methoxy-4-methylsulfanyl-benzoic acid (2 g, 10.09 mmol) was dissolved in dry THF (20 mL) and the solution was stirred while heated to 60° C. under nitrogen and then borane-methylsulfide complex (1.7 eq, 1.7 mL, 17.5 mmol) was added very slowly dropwise via a syringe. The progress of the reaction was followed by both TLC and analytical HPLC and when complete (3 hours) the mixture was allowed to cool to room temperature, diluted with water (10 mL) added extremely slowly dropwise under nitrogen. Potassium carbonate (1 g) was added and after stirring the mixture for 30 minutes ethyl acetate (50 ml) was added. The organic layer was separated, washed with water, 2 N hydrochloric acid, water and brine, dried over Na2SO4 and then concentrated to a near colorless oil. The residue was triturated with hexane and product was purified from the resulting crystals by flash column chromatography to provide (2-methoxy-4-methylsulfanyl-phenyl)-methanol (934 mg, 51%) as colorless crystals. LCMS: M−182.8.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.[NH2:9][CH:10]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]1.C(O[Na])(C)(C)C.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.O.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]>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([NH:9][CH:10]2[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]2)=[N:3][CH:4]=1
Reactant: NC1CCC(O)CC1
Reactant: Cc1ccc(Cl)nc1
Agent: [Pd]
Agent: CC(C)(C)O[Na]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(NC2CCC(O)CC2)nc1
Temperature: 85 °C
Yield: 37.3 %

Procedure:
A mixture of 2-Chloro-5-methyl-pyridine (0.1 g, 0.78 mmol), 4-amino-cyclohexanol (0.117 g, 0.78 mmol), Pd2(dba)3 (0.057 g, 0.0624 mmol), t-BuONa (0.262 g, 2.73 mmol) and Binap (0.076 g, 0.1248 mmol) in toluene (10 mL) was stirred at 85° C. until TLC analysis confirmed the absence of starting materials. Then the mixture was diluted with water (10 mL), and extracted with EtOAc (3×20 mL). The combined organic extracts were washed with water (5 mL) and brine (10 mL), dried over Na2SO4, and filtered. The filtrate was evaporated in vacuo and the residue was purified by column chromatography (EtOAc:Petrol ether=1:2) to provide 4-(5-methyl-pyridin-2-ylamino)-cyclohexanol (0.06 g, yield 60%) as a solid.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8][C:9]#[CH:10])=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:5][C:4](=O)[CH:3]=1.Cl.[NH2:19][OH:20].NC1C=C(C)C=CN=1>>[OH:20][N:19]1[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:7]([CH2:8][C:9]#[CH:10])[C:2]([CH3:1])=[CH:3][C:4]1=[O:5]
Reactant: NO
Reactant: C#CCc1c(C)cc(=O)oc1-c1ccccc1
Agent: Cc1ccnc(N)c1
Agent: Cl
Product: C#CCc1c(C)cc(=O)n(O)c1-c1ccccc1
Yield: 76.9 %

Procedure:
1 g of 4-methyl-5-propargyl-6-phenyl-2-pyrone, 1.5 g of hydroxylamine hydrochloride and 3 g of 2-amino-4-methyl-pyridine were heated for 9 hours to 80° C. After the usual working up, there were obtained 0.82 g (77 %) of 1-hydroxy-4-methyl-5-propargyl-6-phenyl-2-pyridone melting at 200° C (Calc.: 5.9 % N, found: 5.8 % N).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=O)[CH2:2][CH3:3].[OH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)=O)=[CH:14][CH:13]=1>>[OH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)=[C:1]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:2][CH3:3])=[CH:14][CH:13]=1
Reactant: CCC(=O)c1ccccc1
Reactant: O=C(c1ccc(O)cc1)c1ccc(O)cc1
Product: CCC(=C(c1ccc(O)cc1)c1ccc(O)cc1)c1ccccc1
Yield: 88 %

Procedure:
Following general procedure of McMurry reaction as described in example 1, step B, propiophenone (1.9 g, 3.0 eq) was reacted with bis(4-hydroxyphenyl)-methanone (1.0 g, 1.0 eq) to give 1.3 g desired product (88% yield).
Reaction SMILES: [CH:1](=[N:8][OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClCCl.ClN1[C:18](=[O:19])[CH2:17][CH2:16]C1=O.C(O)C#C>C(N(CC)CC)C>[C:2]1([C:1]2[CH:16]=[C:17]([CH2:18][OH:19])[O:9][N:8]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: ON=Cc1ccccc1
Agent: C#CCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: OCc1cc(-c2ccccc2)no1
Yield: 76.8 %

Procedure:
10.0 mmol of Benzaldehyde oxime and 30 ml of dry dichloromethane were added into a 250 ml single-necked round-bottom flask. After the addition of 1.60 g (12.0 mmol) of N-chlorosuccinimide (NCS) under stirring, the mixture was slightly heated until NCS was completely dissolved. 0.56 g (10.0 mmol) of 2-propyn-1-ol was added dropwise, and then 20 ml solution of triethylamine in dichloromethane containing 10.1 g (10.0 mmol) of triethylamine was slowly added dropwise. After the addition was complete, the system was refluxed. After the completion of the reaction monitored by TLC, the mother liquor was washed with water, dried over anhydrous sodium sulfate and was separated on column (Vpetroleum ether:Vethyl acetate=5:1-2:1) to give 3-phenyl-5-hydroxymethyl-isoxazole in 76.8% yield.