Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([N+:11]([O-:13])=[O:12])[CH:7]=[CH:8][C:9]=1F.[CH3:14][C:15]1[O:19][C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:17][C:16]=1[CH2:26][OH:27].Cl>CN(C)C=O>[F:3][C:4]1[CH:5]=[C:6]([N+:11]([O-:13])=[O:12])[CH:7]=[CH:8][C:9]=1[O:27][CH2:26][C:16]1[N:17]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:19][C:15]=1[CH3:14]
Reactant: Cc1oc(-c2ccccc2)nc1CO
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc([N+](=O)[O-])cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.7 %

Procedure:
Sodium hydride (60% in oil, 2.2 g) was added portionwise, at 0° C., to a solution of 3,4-difluoronitrobenzene (8.8 g) and 5-methyl-2-phenyl-4-oxazolyl methanol (10.0 g) in N,N-dimethylformamide (DMF) (100 ml). The mixture was stirred for 3 hours at room temperature. The reaction mixture was poured into ice-water, which was acidified with 2N HCl. Then, resulting crystalline precipitate was collected by filtration, which was recrystallized from dichloromethane-methanol to give 3-fluoro-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)nitrobenzene (14.0 g, 81%) as colorless prisms, m.p.155-156° C.
Reaction SMILES: [CH2:1]([N:4]1[CH2:8][CH2:7][CH2:6][C@H:5]1[C:9]([O:11]CC=C)=O)[CH:2]=[CH2:3].[C-]#[N:16].[Na+]>N.CO>[CH2:1]([N:4]1[CH2:8][CH2:7][CH2:6][C@H:5]1[C:9]([NH2:16])=[O:11])[CH:2]=[CH2:3]
Reactant: [C-]#N
Reactant: C=CCOC(=O)[C@@H]1CCCN1CC=C
Agent: N
Agent: [Na+]
Solvent: CO
Product: C=CCN1CCC[C@H]1C(N)=O
Yield: 81 %

Procedure:
Allyl (S)-1-allyl-2-pyrrolidinecarboxylate (2.5 g, 12.8 mmol; and NaCN (64 mg, 1.3 mmol) in 50 ml 9M ammonia in methanol were stirred at 35° C. for 27 h. GLC showed a complete conversion. After evaporation the residue was dissolved in Et2O and washed with brine. Drying (Na2SO4), evaporation and recrystallization gave 1.6 g (81%) of the title amide identical with the one made in Example 8A.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]2[NH:6][C:7](=[O:12])[O:8][C:9]([CH3:11])([CH3:10])[C:4]=2[CH:3]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1>>[CH3:15][O:16][C:17]1[CH:22]=[C:21]([C:2]2[CH:14]=[CH:13][C:5]3[NH:6][C:7](=[O:12])[O:8][C:9]([CH3:11])([CH3:10])[C:4]=3[CH:3]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: CC1(C)OC(=O)Nc2ccc(Br)cc21
Product: COc1cccc(-c2ccc3c(c2)C(C)(C)OC(=O)N3)c1

Procedure:
6-(3-Methoxy-phenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one was prepared, according to the procedure of Example 4 from 6-bromo-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one and 3-methoxyphenyl boronic acid, as a yellow solid: mp 164-165° C.; 1H-NMR (DMSO-d6) δ10.3 (s, 1H), 7.56 (m, 2H), 7.36 (t, 1H, J=7.89Hz), 7.20 (m, 2H), 6.96 (d, 1H, J=8.88 Hz), 6.91 (dd, 1H, J=8.13, 2.35 Hz), 3.8 (s, 3H), 1.7 (s, 6H), MS (ESI) m/z 284 ([M+H]+, 30%); Anal. Calc. For C17H17NO3; C, 72.07; H, 6.05; N, 4.94. Found: C, 70.58; H, 5.73; N, 4.67.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([OH:13])[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11].Cl[C:15]1[CH:20]=[CH:19][N:18]=[C:17]([S:21][CH3:22])[N:16]=1>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[O:13][C:15]1[CH:20]=[CH:19][N:18]=[C:17]([S:21][CH3:22])[N:16]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1Cl
Reactant: CSc1nccc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1nccc(Oc2ccc([N+](=O)[O-])c(Cl)c2)n1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 64.1 %

Procedure:
160 mg (6.34 mmol) 95% sodium hydride was given to a solution of 1.00 g (5.76 mmol) 3-chloro-4-nitrophenol in 15 ml DMF. Stirring was continued for 30 min. at room temperature. 925 mg (5.76 mmol) 4-chloro-2-methylsulfanyl-pyrimidine was added and the mixture heated to 80° C. for 16 h. The reaction mixture was evaporated, taken up with water and extracted with ethyl acetate. The organic phase was extracted with water, dried (sodium sulphate) and evaporated. The obtained material was dissolved in ethyl acetate and purified by chromatography over silica (ethyl acetate/n-heptane) to give 1.10 g (64%) 4-(3-chloro-4-nitro-phenoxy)-2-methylsulfanyl-pyrimidine.
Reaction SMILES: [H-].[Na+].[OH:3][C@@H:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][C@H:5]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[CH3:23]I.O>CN(C=O)C>[CH3:23][O:3][C@@H:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][C@H:5]1[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)[C@H](c2ccccc2)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CO[C@@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1c1ccccc1
Temperature: 22 °C
Reaction time: 0.5 h
Yield: 101.8 %

Procedure:
Add sodium hydride (2.19 g, 54.75 mmol) in one portion to a solution of (−)trans-tert-butyl 4-hydroxy-3-phenyl-piperidine-1-carboxylate (11.8 g, 42.12 mmol) in DMF (168.5 mL) at 0° C. under a nitrogen atmosphere. Stir the mixture for 30 min and then add methyl iodide (3.15 mL, 50.54 mmol) dropwise. Stir the mixture at 0° C. for 1 minute and warm to 22° C. for 1 hour. Add additional sodium hydride (303 mg, 12.6 mmol), stir for 15 min, and then add methyl iodide (0.52 mL, 8.4 mmol) slowly. Stir the mixture at 22° C. for 1 hour, cool to 0° C. for 1 hour and add water (118 mL) carefully. Filter the resulting suspension, rinse the solid with water and dry the solid in the vacuum oven (45° C., 60 mbar) to obtain the title compound as a white solid (12.5 g, 99%). MS (m/z): 192 (M-Boc+1), 236 (M-tBu+1).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)[CH3:6])=[O:4].C(C1(C2C=CC(OC)=C(C=2)[CH:25]=[O:26])CC1)#N>>[CH3:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([CH:5]([C:3]([O:2][CH3:1])=[O:4])[CH3:6])=[CH:12][C:11]=1[CH:25]=[O:26]
Reactant: COc1ccc(C2(C#N)CC2)cc1C=O
Reactant: COC(=O)C(C)c1ccc(OC)cc1
Product: COC(=O)C(C)c1ccc(OC)c(C=O)c1

Procedure:
This compound was prepared from Compound 32 in the same manner of Compound 2.
Reaction SMILES: [CH:1]([Si:4]([CH:36]([CH3:38])[CH3:37])([CH:33]([CH3:35])[CH3:34])[O:5][C@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]2[N:16]3[CH:17]=[C:18]([O:21][C@H:22]4[C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[C@@H:25]([NH2:32])[CH2:24][CH2:23]4)[CH:19]=[CH:20][C:15]3=[N:14][N:13]=2)[CH2:7]1)([CH3:3])[CH3:2].ClC(Cl)(Cl)C[O:42][C:43](=O)[NH:44][C:45]1[N:46]([C:54]2[CH:59]=[CH:58][C:57]([CH3:60])=[CH:56][CH:55]=2)[N:47]=[C:48]([C:50]([CH3:53])([CH3:52])[CH3:51])[CH:49]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:50]([C:48]1[CH:49]=[C:45]([NH:44][C:43]([NH:32][C@@H:25]2[C:26]3[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=3)[C@H:22]([O:21][C:18]3[CH:19]=[CH:20][C:15]4[N:16]([C:12]([N:8]5[CH2:9][CH2:10][CH2:11][C@H:6]([O:5][Si:4]([CH:1]([CH3:3])[CH3:2])([CH:33]([CH3:35])[CH3:34])[CH:36]([CH3:38])[CH3:37])[CH2:7]5)=[N:13][N:14]=4)[CH:17]=3)[CH2:23][CH2:24]2)=[O:42])[N:46]([C:54]2[CH:59]=[CH:58][C:57]([CH3:60])=[CH:56][CH:55]=2)[N:47]=1)([CH3:53])([CH3:51])[CH3:52]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Reactant: CC(C)[Si](O[C@H]1CCCN(c2nnc3ccc(O[C@@H]4CC[C@H](N)c5ccccc54)cn23)C1)(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCC[C@H](O[Si](C(C)C)(C(C)C)C(C)C)C5)n4c3)c3ccccc32)cc1
Yield: 60 %

Procedure:
A solution of Intermediate 63c (140 mg, 0.261 mmol) and (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic Communications, 2009, 39, 3999-4009, which is incorporated herein by reference in its entirety; 106 mg, 0.261 mmol) in 1,4-dioxane (3 mL) and DIPEA (70 μL, 0.4 mmol) was stirred at 90° C. for 3 h. The cooled mixture was concentrated in vacuo. The residue was purified by FCC, using 0-10% MeOH in DCM, to give the title compound as a pale brown gum (124 mg, 60%). LCMS (Method 3): Rt 5.43 min, m/z 791 [MH+].
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH:13]=[CH:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.CN([CH:35]=[O:36])C.[NH4+].[Cl-]>C1COCC1>[C:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:20])=[O:19])[C:13]([CH:35]=[O:36])=[CH:12]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(c1ccccc1)n1ccc2cc(OCc3ccccc3)ccc21
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=Cc1cc2cc(OCc3ccccc3)ccc2n1S(=O)(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 76.9 %

Procedure:
To a solution of 5-[(phenylmethyl)oxy]-1-(phenylsulfonyl)-1H-indole (1.5 g, 4.12 mmol) in THF (20 mL), under N2, at −78° C., was added n-BuLi (2.5M solution in hexane, 2.15 mL, 5.37 mmol) dropwise. After stirring at −78° C. for 30 min, anhydrous DMF (0.54 g, 7.42 mmol) was added. After 5 min, the −78° C. bath was replaced with an ice bath. After 45 min, sat'd NH4Cl solution (20 mL) was added and the mixture was partitioned between Et2O and water. The organic phase was washed with water and sat'd brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography (20-70% CH2Cl2-hexanes gradient) to afford the title compound (1.24 g, 77% yield): 1H NMR (400 MHz, CDCl3) δ 10.5 (s, 1H), 8.14 (d, J=9.3 Hz, 1H), 7.74 (d, J=7.6 Hz, 2H), 7.53 (t, J=7.6 Hz, 1H), 7.43-7.31 (m, 8H), 7.22 (dd, J=9.3, 2.4 Hz, 1H), 7.06 (d, J=2.4 Hz, 1H), 5.06 (s, 2H); MS (ES) m/z 392 (M+1).
Reaction SMILES: [C:1]([NH:8][C@@H:9]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[CH:35][CH:34]=1)[C@@H:10]([OH:31])[CH2:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:19][CH:18]=1)[C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:47]([Si:51]([CH3:54])([CH3:53])Cl)([CH3:50])([CH3:49])[CH3:48].N1C=CN=C1>CN(C=O)C>[C:1]([NH:8][C@@H:9]([CH2:32][C:33]1[CH:34]=[CH:35][C:36]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[CH:37][CH:38]=1)[C@@H:10]([O:31][Si:51]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:54])[CH3:53])[CH2:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[CH:19][CH:18]=1)[C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)[C@@H](O)C[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)[C@H](C[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.44 g (3.90 mmol) of 5(S)-(Boc-amino)-4(S)-hydroxy-6-(p-benzyloxyphenyl)-2(R)-[(p-benzyloxyphenyl)methyl]-hexanoic acid in 14 ml of DMF are stirred, under an N2 atmosphere, together with 2.70 g (17.6 mmol) of tert-butyldimethylchlorosilane and 2.18 g (32 mmol) of imidazole at RT for 18 h. The reaction mixture is poured onto ice-water, and this mixture is extracted with 3 portions of ethyl acetate; the organic phases are washed with 10% citric acid solution, H2O and saline, dried with Na2SO4 and evaporated. The resulting oil is taken up in 30 ml of methanol/THF/H2O 3:1:1, and this solution is treated with 3.2 g of K2CO3 and stirred at RT for 1 h. The reaction mixture is partially evaporated, and the aqueous residue is poured onto 10% citric acid solution and ice, and this mixture is extracted 3× with ethyl acetate; the organic phases are washed twice with H2O and, finally, with saline, dried with Na2SO4 and evaporated. Column chromatography (SiO2, hexane/ethyl acetate 2:1→1:1) of the crude product affords the title compound: TLC Rf (C)=0.53; FAB-MS (M+H)+ =740.
Reaction SMILES: C([C:3]([CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:7](O)=O)[C:4]([OH:6])=[O:5])C.N1CCC[CH2:20][CH2:19]1.C=O>>[CH2:7]=[C:3]([CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:4]([O:6][CH2:19][CH3:20])=[O:5]
Reactant: CCC(CCc1ccccc1)(C(=O)O)C(=O)O
Reactant: C1CCNCC1
Agent: C=O
Product: C=C(CCc1ccccc1)C(=O)OCC
Temperature: 57.5 °C
Yield: 89 %

Procedure:
Monoethyl 2-[2-(phenyl)ethyl]malonic acid (47.2 g, 200 mole) was added to 40 mL round bottom flask fitted with a Teflon coated stirring bar. Piperidine (3 mL) and paraformaldehyde (8.4 g, 280 mmole) were added to the flask and the flask was heated to 55-60° C., until gas evolution ceased. TLC indicated that no starting material remained. The solution was worked up by removing the solvent under reduced pressure. Water (50 mL) and enough 12N HCl was added to the flask to acidify the mixture (pH>3). The mixture was extracted with ether (3×50 mL) and back extracted with brine. The solution was dried over MgSO4 and filtered. The reaction mixture was shown to be clean by NMR and TLC and used without further purification. Recovered 36.3 g material (89% yield).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4](Cl)[C:3]=1[CH2:10][C:11]([O:13][CH3:14])=[O:12].[OH:15][C:16]1[CH:17]=[C:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:19]=[CH:20][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:17]=2)[C:3]=1[CH2:10][C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)Cc1c(C)nc(Cl)nc1Cl
Reactant: Oc1cccc(-c2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)Cc1c(C)nc(Cl)nc1Oc1cccc(-c2ccccc2)c1

Procedure:
Methyl α-[6-methyl-2,4-dichloro-5-pyrimidinyl]-acetate (4 g, 18 mmol), 3-hydroxybiphenyl (3 g, 18 mmol) and potassium carbonate (11 g, 80 mmol) in dimethylformamide (50 ml) are stirred at +80° C. for 2 hours. Workup as for example 1a) gives pure methyl α-[6-methyl-2-chloro-4-(3-phenylphenoxy)-5-pyrimidinyl]-acetate. 1H (CDCl3):7.65-7.05 (m, 9H); 3.82 (s, 2H); 3.76 (s, 3H); 2.52 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[C:16]([O:22][CH3:23])[C:17]=1[O:18][CH2:19][C:20]#[CH:21])[C:6]([N:8]1[CH:14]2[CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13]2)=[O:7].[Cl-:24].[NH4+]>[Cl-].[Zn+2].[Cl-].C(Cl)(Cl)Cl>[Cl:24][CH:14]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[NH:8][C:6](=[O:7])[C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:17]([O:18][CH2:19][C:20]#[CH:21])=[C:16]([O:22][CH3:23])[CH:15]=1
Reactant: [Cl-]
Reactant: C#CCOc1c(OC)cc(C(=O)N2C3CCCCC32)cc1OC
Agent: [NH4+]
Agent: [Zn+2]
Solvent: ClC(Cl)Cl
Product: C#CCOc1c(OC)cc(C(=O)NC2CCCCC2Cl)cc1OC
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A mixture of 2 ml of chloroform and 258 mg of zinc (II) chloride was stirred at room temperature for 5 minutes. Thereafter, a mixture of 300 mg of 7-[3,5-dimethoxy-4-(2-propynyloxy)benzoyl]-7-azabicyclo[4.1.0]heptane and 2 ml of chloroform was added dropwise thereto at room temperature, and the resulting mixture was stirred at room temperature for 5 hours. Then, an aqueous saturated ammonium chloride solution was added to the reaction mixture, and this was extracted with chloroform. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.16 g of N-(2-chlorocyclohexyl)-3,5-dimethoxy-4-(2-propynyloxy)benzamide (hereinafter, described as the compound 109 of the present invention) represented by the formula:
Reaction SMILES: [O:1]=[C:2]([CH3:10])[CH2:3][CH2:4][CH2:5][CH2:6][C:7](O)=[O:8].S(Cl)([Cl:13])=O>CN(C)C=O.C1C=CC=CC=1>[O:1]=[C:2]([CH3:10])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([Cl:13])=[O:8]
Reactant: CC(=O)CCCCC(=O)O
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: CC(=O)CCCCC(=O)Cl

Procedure:
6-Oxo-heptanoic acid (20.1g; 0.14 mole), thionyl chloride (18.3g; 11.2 ml; 0.154 mole) and dry benzene (300 ml) together with dimethylformamide (three drops) were stirred at room temperature for 22 hours. The halogenating reagent and benzene were removed on the rotary evaporator. A further 100 ml of benzene was added and the solution was again evaporated under reduced pressure (to remove last traces of thionyl chloride). The quantitatively formed liquid acid chloride was used directly in step (b).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:17])[C:11](=[CH:15][CH:16]=2)[C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1.ClCCl.Cl[Si](C)(C)C.[C:26](Cl)(=[O:30])[C:27]([CH3:29])=[O:28]>C(N(CC)CC)C>[O:30]=[C:26]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:9][C:10](=[O:17])[C:11](=[CH:15][CH:16]=2)[C:12]([OH:14])=[O:13])=[CH:6][CH:7]=1)[C:27](=[O:28])[CH3:29]
Reactant: Nc1ccc(-c2ccc(C(=O)O)c(=O)[nH]2)cc1
Reactant: CC(=O)C(=O)Cl
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)C(=O)Nc1ccc(-c2ccc(C(=O)O)c(=O)[nH]2)cc1
Yield: 44 %

Procedure:
Using the method for the preparation of the side chain acid in Example 3, 11.5 g (50 mmol) of 6-(4-aminophenyl)-1,2-dihydro-2-oxonicotinic acid, 500 ml of dichloromethane, 21.0 ml (150 ml) of triethylamine, 20 ml (158 mmol) of chlorotrimethylsilane, and 8.0 g (75 mmol) of pyruvic acid chloride, [J. Org. Chem., 35, 3972 (1970)] gives 6.6 g of 6-[4(1,2-dioxopropylamino)phenyl]-1,2-dihydro-2-oxonicotinic acid after recrystallization from N,N-dimethylacetamide; mp>280°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:5]=1[OH:11].Br[CH2:14][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][CH2:28][CH2:29][CH2:30][CH3:31].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C=O)C>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH3:14])[C:5]=1[OH:11]
Reactant: COC(=O)c1cccc(O)c1O
Reactant: CCCCCCCCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCCCCCOc1cccc(C(=O)OC)c1O
Yield: 16 %

Procedure:
A mixture of 1.0 g (5.95 mmol) of 2,3-dihydroxybenzoic acid methyl ester, 1.98 g (5.95 mmol) of 1-bromooctadecane and 0.825 g (5.95 mmol) of potassium carbonate in 20 ml of acetone and 4 ml of DMF was stirred at reflux for 40 hours. The usual workup followed by purification by chromatography on 40 g of silica gel (230-400 mesh) using 50% toluene-hexane gave 0.40 g (16% yield, mp 57°-60°) of 2-hydroxy-3-(octadecyloxy)benzoic acid methyl ester. The structure was established by nmr and mass spectra.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1)(=O)[CH2:2][CH3:3].[ClH:11].[C:12]1([NH:18]N)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl>C(O)C>[ClH:11].[CH3:3][C:2]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:18][C:1]=1[C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1
Reactant: CCC(=O)c1cccnc1
Reactant: NNc1ccccc1
Agent: Cl
Solvent: CCO
Product: Cc1c(-c2cccnc2)[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3-Methyl-2-pyridin-3-yl-1H-indole hydrochloride is synthesized based on the method described in U.S. Pat. No. 3,468,894. A flask is charged with 3-propionylpyridine (1.004 g, 7.279 mmol), phenylhydrazine hydrochloride (1.010 g, 6.915 mmol) and ethanol (15 mL). The mixture is heated to reflux for 1 h and cooled to room temperature. To a portion of the reaction mixture (2.5 mL) is added HCl (4M in dioxane, 1 mL, 4 mmol) and the mixture is heated to reflux. After 3 h, the mixture is concentrated in vacuo. The solid is dissolved in the minimum amount of boiling methanol (17 mL) and allowed to cool slowly to room temperature. A solid precipitates and after cooling to 0° C. for 30 min, the yellow solid is filtered off, washed with portions of cold methanol and dried under high vacuum to give 3-methyl-2-pyridin-3-yl-1H-indole hydrochloride as yellow needles. 1H NMR (400 MHz, MeOD) δ ppm (HCl salt) 2.56 (s, 3H), 7.09-7.13 (m, 1H), 7.23-7.26 (m, 1H), 7.43 (d, J=8.1 Hz, 1H), 7.63 (d, J=8.1 Hz, 1H), 8.14-8.18 (m, 1H), 8.74 (d, J=5.8 Hz, 1H), 8.83-8.85 (m, 1H), 9.08 (s, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1/[CH:7]=[CH:8]/[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].ClC1C=CC=C(C(OO)=[O:24])C=1>C(OCC)(=O)C>[O-:24][N+:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1/[CH:7]=[CH:8]/[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]
Reactant: CC(C)(C)OC(=O)/C=C/c1ccccn1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)/C=C/c1cccc[n+]1[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.7 %

Procedure:
tert-Butyl (E)-3-(2-pyridyl)-2-propenoate (2.05 g, 10.0 mmol) was dissolved in ethyl acetate (10 ml), and 3-chloroperbenzoic acid (ca. 70%, 2.35 g, 10.5 mmol) was added thereto. The mixture was stirred at room temperature overnight. The reaction mixture was subjected to a silica gel (100 g) column chromatography. The fractions eluted with ethyl acetate-ethanol (5:1, v/v) were collected and concentrated to give the title compound (2.14 g, 96%).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH2:26][CH3:27])[CH2:23][CH2:22][C:21]([C:28]([NH:30][C:31]4[CH:32]=[N:33][C:34]([S:37][CH2:38][C:39]5[N:43]([CH2:44][CH2:45][CH3:46])[CH:42]=[N:41][CH:40]=5)=[CH:35][CH:36]=4)=[O:29])=[CH:20][C:19]=3[CH:47]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:56])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH2:26][CH3:27])[CH2:23][CH2:22][C:21]([C:28]([NH:30][C:31]4[CH:32]=[N:33][C:34]([S:37]([CH2:38][C:39]5[N:43]([CH2:44][CH2:45][CH3:46])[CH:42]=[N:41][CH:40]=5)=[O:56])=[CH:35][CH:36]=4)=[O:29])=[CH:20][C:19]=3[CH:47]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4cncn4CCC)nc2)CCN3CCC)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4cncn4CCC)nc2)CCN3CCC)cc1
Reaction time: 0.25 h
Yield: 23.4 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-1-propyl-N-[6-[[(1-propylimidazol-5-yl)methyl]sulfanyl]-3-pyridinyl]-2,3-dihydro-1-benzazepine-4-carboxamide (0.96 g) was dissolved in methylene chloride (29 ml), and a solution of m-chloroperbenzoic acid (0.38 g) in methylene chloride (14 ml) was added dropwise to the solution at −78° C. The mixture was stirred for 15 minutes, and an aqueous solution of saturated sodium thiosulfate was added to the mixture. The mixture was extracted with ethyl acetate, washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-1-propyl-N-[6-[[(1-propylimidazol-5-yl)methyl]sulfinyl]-3-pyridinyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 295) (0.23 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:3]=1.C(N(CC)CC)C.[C:19]([Si:21]([CH3:24])([CH3:23])[CH3:22])#[CH:20]>C1C=CC=CC=1.[Cu]I>[CH3:11][S:8]([C:4]1[CH:3]=[C:2]([C:20]#[C:19][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH:7]=[CH:6][CH:5]=1)(=[O:10])=[O:9]
Reactant: CS(=O)(=O)c1cccc(Br)c1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: C[Si](C)(C)C#Cc1cccc(S(C)(=O)=O)c1
Temperature: 70 °C
Yield: 95 %

Procedure:
To a solution of 0.23 g (1 mmol) of 1-bromo-3-methanesulfonyl-benzene in benzene (2 mL) was added 40 mg (0.1 mmol) of PdCl2(Ph3P)2, 30 mg (0.1 mmol) CuI, triethylamine (1 mL) and 0.3 mL of ethynyl-trimethyl-silane. The reaction mixture was heated at 70° C. for 3 h After removal of solvent, the residue was purified by column chromatography elution with hexanes/ethyl acetate (v/v=7:1 then 5:1) to give 0.24 g (95%) of (3-methanesulfonyl-phenylethynyl)-trimethylsilane. 1H NMR (CDCl3, 400 MHz): δ 8.4 (s, 1H), 7.88 (d, 1H), 7.70 (d, 1H), 7.52 (dd, 1H), 3.05 (s, 3H), 0.27 (s, 9H) ppm.