Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH3:7])=[N:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1.[C:16]([Cu])#[N:17].Cl>N1C=CC=CC=1>[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([C:3]2[N:4]=[C:5]([CH3:7])[S:6][C:2]=2[C:16]#[N:17])=[CH:9][CH:10]=1
Reactant: N#C[Cu]
Reactant: COc1ccc(-c2nc(C)sc2Br)cc1
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(-c2nc(C)sc2C#N)cc1
Temperature: 150 °C
Yield: 93.1 %

Procedure:
To a solution of 5-Bromo-4-(4-methoxy-phenyl)-2-methyl-thiazole (2.0 g, 7.0 mmol) in 15 ml of pyridine was added CuCN (3.10 g, 35.2 mmol) and the reaction mixture was heated to 150° C. in microwave for 2 h. After the completion of the reaction pH was adjusted to 3-4 with 1 N HCl solution and extracted with ethyl acetate (3×50 mL). The combined organics was washed with water, brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified over silica gel (60-120 M, 12% EtOAc-Hexane) to get the desired product (1.5 g, 92%) as a white solid.
Reaction SMILES: [CH:1]([CH:3]([CH2:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[C:12]([O:20][CH3:21])[CH:11]=1)[C:4](OCC)=O)=[O:2].[N+:22]([NH:25][C:26]([NH2:28])=[NH:27])([O-:24])=[O:23].C[O-].[Na+]>CO>[N+:22]([NH:25][C:26]1[NH:28][C:1](=[O:2])[C:3]([CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[C:12]([O:20][CH3:21])[CH:11]=2)=[CH:4][N:27]=1)([O-:24])=[O:23]
Reactant: CCOC(=O)C(C=O)Cc1cc(OC)c(OC)c(OC)c1
Reactant: N=C(N)N[N+](=O)[O-]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)cc(OC)c1OC
Yield: 13 %

Procedure:
Crude ethyl 2-formyl-3-(3,4,5-trimethoxyphenyl)propionate (7.41 g) was reacted with nitroguanidine (2.62 g) and sodium methoxide in refluxing methanol for 40 hours to give 2-nitroamino-5-(3,4,5-trimethoxybenzyl)-4-pyrimidone in 13% yield.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][C:15]([F:18])([F:17])[F:16])[CH2:10][C:11]([OH:13])=O)=[CH:5][C:4]=1[C:19]([F:22])([F:21])[F:20])#[N:2].[CH:23]1([NH2:29])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][C:15]([F:16])([F:18])[F:17])[CH2:10][C:11]([NH:29][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:13])=[CH:5][C:4]=1[C:19]([F:20])([F:21])[F:22])#[N:2]
Reactant: NC1CCCCC1
Reactant: N#Cc1ccc(N(CC(=O)O)CC(F)(F)F)cc1C(F)(F)F
Product: N#Cc1ccc(N(CC(=O)NC2CCCCC2)CC(F)(F)F)cc1C(F)(F)F

Procedure:
Synthesized as described in example 3 using N-[4-cyano-3-(trifluoromethyl)phenyl]-N-(2,2,2-trifluoroethyl)glycine and cyclohexylamine: 1H NMR (400 MHz, CDCl3) δ 7.68 (d, J=8.8 Hz, 1H), 7.03 (d, J=2.6 Hz, 1H), 6.92 (dd, J=8.8, 2.7 Hz, 1H), 5.81 (d, J=8.0 Hz, 1H), 4.12 (s, 2H), 4.10 (q, J=8.6 Hz, 2H), 3.80 (m, 1H), 1.83 (m, 2H), 1.63 (m, 3H), 1.32 (m, 2H), 1.08 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:23][O:24][CH3:25])[C:8]([NH:10][CH:11]2[C:21](=[O:22])[N:13]3[C:14]([C:18]([OH:20])=[O:19])=[CH:15][CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.C(=O)(O)[O-].[Na+:30]>>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:23][O:24][CH3:25])[C:8]([NH:10][CH:11]2[C:21](=[O:22])[N:13]3[C:14]([C:18]([O-:20])=[O:19])=[CH:15][CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+:30]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(N)n1
Agent: O=C([O-])O
Agent: [Na+]
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=CCS[C@H]12)c1csc(N)n1
Reaction time: 0.5 h
Yield: 83.7 %

Procedure:
7-[2-(2-Amino-4-thiazolyl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid(syn-isomer: 5 g.) was gradually added to an aqueous solution (30 ml.) of sodium bicarbonate (1.04 g.) at 35° to 40° C., and stirred at 50° to 53° C. for 30 minutes. After removing the insoluble substance from the resultant solution, the filtrate was treated with activated charcoal (0.3 g.), and filtered. The filtrate was lyophilized to give sodium 7-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn-isomer: 4.2 g.)
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=O.[CH:12]([NH2:15])([CH3:14])[CH3:13]>>[CH:12]([NH:15][C:4](=[O:6])[C:3]1[C:7]([CH3:11])=[CH:8][CH:9]=[CH:10][C:2]=1[CH3:1])([CH3:14])[CH3:13]
Reactant: CC(C)N
Reactant: Cc1cccc(C)c1C(=O)O
Product: Cc1cccc(C)c1C(=O)NC(C)C

Procedure:
Using Preparation Method 1, 2,6-dimethylbenzoic acid was reacted with isopropylamine. The resulting reaction mixture was purified using SiO2 with CH2Cl2/MeOH 99:1. A white crystalline solid was obtained (73%). NMR 1H (ppm, CDCl3): 7.15-7.10 (m, 1H), 6.99 (d, J3=7.57 Hz, 2H), 5.44 (br. s., 1H), 4.40-4.24 (m, 1H), 2.31 (s, 6H), 1.24 (d, J3=6.58 Hz, 6H).
Reaction SMILES: [CH3:1][CH:2]([C@H:4]([NH:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C:5]([OH:7])=O)[CH3:3].[NH:19]1[CH2:24][CH2:23][CH:22]([O:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:21][CH2:20]1>>[CH2:12]([O:11][C:9]([NH:8][C@H:4]([C:5]([N:19]1[CH2:20][CH2:21][CH:22]([O:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:24]1)=[O:7])[CH:2]([CH3:1])[CH3:3])=[O:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)COC1CCNCC1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC(OCC(=O)OC(C)(C)C)CC1
Yield: 96 %

Procedure:
By coupling 2.5 g of Z-L-valine with 2 g of t-butyl 4-piperidinyloxyacetate as described in Example 2b) there are obtained 4 g of t-butyl [[1-[N-[(benzyloxy)carbonyl]-L-valyl]-4-piperidinyl]oxy]acetate, MS (EI): 449 (M+H)+.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[SH:7][C:8]1[N:22]=[CH:21][CH:20]=[CH:19][C:9]=1[C:10]([NH:12][CH2:13][C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)=[O:11].Br[CH2:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1>CN(C=O)C>[F:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][CH2:25][CH2:24][S:7][C:8]2[C:9]([C:10]([NH:12][CH2:13][C:14]3[S:15][CH:16]=[CH:17][CH:18]=3)=[O:11])=[CH:19][CH:20]=[CH:21][N:22]=2)=[CH:28][CH:29]=1
Reactant: Fc1ccc(CCCBr)cc1
Reactant: O=C(NCc1cccs1)c1cccnc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(NCc1cccs1)c1cccnc1SCCCc1ccc(F)cc1
Reaction time: 1 h
Yield: 73.3 %

Procedure:
227 mg (1.65 mmol) of K2CO3 were added to a solution of 375 mg (1.5 mmol) of 2-mercapto-N-(thiophen-2-ylmethyl)nicotinamide in DMF (6 ml) and stirring was carried out for 1 h at RT. 325 mg (1.5 mmol) of 1-(3-bromopropyl)-4-fluorobenzene were then added and stirring was carried out for a further 16 h at RT. The mixture was then concentrated in vacuo and the residue was taken up in an EA/water mixture. The organic phase was separated off and the aqueous phase was extracted again with EA. The combined organic phases were dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by means of CC (EA/hex 1:2), yielding 428 mg (1.1 mmol, 74%) of 2-[3-(4-fluorophenyl)-propylsulfanyl]-N-(thiophen-2-yl-methyl)-pyridine-3-carboxylic acid amide. MS: m/z 3871 [M+H]+.
Reaction SMILES: C([O:4][CH2:5][C:6]1[N:19]=[C:9]2[N:10]=[C:11]([C:15]([O:17]C)=[O:16])[CH:12]=[C:13](Cl)[N:8]2[N:7]=1)(=O)C.NC(N)=[S:22]>C(O)C>[C:15]([C:11]1[CH:12]=[C:13]([SH:22])[N:8]2[N:7]=[C:6]([CH2:5][OH:4])[N:19]=[C:9]2[N:10]=1)([OH:17])=[O:16]
Reactant: COC(=O)c1cc(Cl)n2nc(COC(C)=O)nc2n1
Reactant: NC(N)=S
Solvent: CCO
Product: O=C(O)c1cc(S)n2nc(CO)nc2n1
Yield: 85.3 %

Procedure:
In 200 ml of ethanol was dissolved 12 g of 2-acetoxymethyl7-chloro-5-methoxycarbonyl-s-triazolo[1,5-a]pyrimidine under heating, and 8.36 g of thiourea was added to the solution and the mixture was stirred under reflux for 10 minutes. After cooling by allowed to stand, precipitates were collected by filteration, washed with ethanol and then dissolved in 100 ml of a 10% KOH, and the solution was stirred at room temperature for one hour. This solution was adjusted to pH 1 with 2N HCl under ice-cooling and stirring, and precipitates were collected by filtration, washed with water and then dried to obtain 8.13 g of the title compound.
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1([CH3:33])[CH2:9][CH2:8][N:7]([C:10]2[N:15]=[C:14]([C:16]([NH:18][C:19]3[C:29]([CH3:30])=[CH:28][C:22]([C:23]([O:25]CC)=[O:24])=[CH:21][C:20]=3[CH3:31])=[O:17])[C:13]([CH3:32])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1.CO>C1COCC1>[OH:3][C:4]1([CH3:33])[CH2:5][CH2:6][N:7]([C:10]2[N:15]=[C:14]([C:16]([NH:18][C:19]3[C:20]([CH3:31])=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:28][C:29]=3[CH3:30])=[O:17])[C:13]([CH3:32])=[CH:12][CH:11]=2)[CH2:8][CH2:9]1
Reactant: CCOC(=O)c1cc(C)c(NC(=O)c2nc(N3CCC(C)(O)CC3)ccc2C)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(N2CCC(C)(O)CC2)nc1C(=O)Nc1c(C)cc(C(=O)O)cc1C
Reaction time: 1 h
Yield: 0 %

Procedure:
A solution of aqueous 2N NaOH (5.00 ml) is added to a stirred solution of ethyl 4-[[6-(4-hydroxy-4-methyl-1-piperidyl)-3-methyl-pyridine-2-carbonyl]amino]-3,5-dimethyl-benzoate (0.27 g, 634.51 mmol) in THF:MeOH (10 ml:5 ml). After 1 hour at 50° C., the organic solvent is removed under reduced pressure and the residue is diluted with water, acidified to pH 6 with 5N HCl, and extracted with ethyl acetate. The organic layers are combined with aqueous layer and concentrated under reduced pressure. The solids are triturated with acetone/acetonitrile and filtered. The filtrate is dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford the title compound as an off-white solid (0.11 g, 43.6%). Mass spectrum (m/z): 398.2 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][CH2:9][N:10]1[C:18]2[C:17](Cl)=[N:16][CH:15]=[N:14][C:13]=2[CH:12]=[CH:11]1)([CH3:4])([CH3:3])[CH3:2].[CH3:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[O:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=1)[NH2:25].C(O)(C)C>C(OCC)(=O)C>[CH3:21][C:22]1[CH:23]=[C:24]([NH:25][C:17]2[C:18]3[N:10]([CH2:9][CH2:8][NH:7][C:6](=[O:20])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH:11]=[CH:12][C:13]=3[N:14]=[CH:15][N:16]=2)[CH:26]=[CH:27][C:28]=1[O:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:37])([F:38])[F:39])[CH:31]=1
Reactant: Cc1cc(N)ccc1Oc1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)NCCn1ccc2ncnc(Cl)c21
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: Cc1cc(Nc2ncnc3ccn(CCNC(=O)OC(C)(C)C)c23)ccc1Oc1cccc(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
A mixture of tert-butyl[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]carbamate (297 mg), 3-methyl-4-[3-(trifluoromethyl)phenoxy]aniline (401 mg) and isopropyl alcohol (2.97 mL) was stirred at 80° C. for 16 hrs. The reaction mixture was diluted with ethyl acetate (80 mL), and washed with aqueous sodium hydrogen carbonate (30 mL). The organic layer was separated, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10→0/100) to give the title compound (528 mg) as a white powder.
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.[Li]CCCC.CCCCCC.[B:26]([O-])([O-:28])[O-:27]>C1COCC1>[CH3:10][C:9]1([CH3:11])[C:4]2[CH:3]=[C:2]([B:26]([OH:28])[OH:27])[CH:14]=[CH:13][C:5]=2[NH:6][C:7](=[O:12])[O:8]1
Reactant: CC1(C)OC(=O)Nc2ccc(Br)cc21
Reactant: [O-]B([O-])[O-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC1(C)OC(=O)Nc2ccc(B(O)O)cc21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 81.2 %

Procedure:
To a solution of 6-bromo-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one (2 g, 7.8 mmol) in anhydrous THF (60 mL) was added a solution of n-BuLi in hexane (10 M, 2.4 mL, 24 mmol) at −78° C. under nitrogen. After stirring at −78° C. for 30 minutes, a slurry was obtained and treated with trisopropyl borate (6.5 mL, 28 mmol). The reaction medium was slowly warmed to ambient temperature and quenched with 1N aqueous hydrochloric acid solution (60 mL). Ethyl acetate (100 mL) was added and organic layer was separated, and aqueous layer was extracted with ethyl acetate (3×60 mL). The combined organic layer was washed with brine and dried with MgSO4. The solvent was removed in vacuo and the residue was purified by a silica gel flash chromatography (ethyl acetate:hexane/2:1) to afford (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid as a white solid (1.4 g, 81%): mp 249-250° C.; 1H-NMR (DMSO-d6) δ10.21 (s, 1H, D2O exchangeable), 7.90-7.95 (br s, 2H, D2O exchangeable), 7.67 (m, 2H), 6.79 (d, 1H, J=7.8 Hz), 1.61 (s, 6H); MS (ESI) m/z 222 ([M+H]+, 87%).
Reaction SMILES: [F:1][C:2]1[C:3]([O:13][CH2:14][CH2:15][CH2:16][CH:17]=O)=[N:4][C:5]2[NH:6][C:7](=[O:12])[CH2:8][CH2:9][C:10]=2[CH:11]=1.[CH2:19]1[C:27]2[C:22](=[C:23]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20]1>>[F:1][C:2]1[CH:11]=[C:10]2[C:5](=[N:4][C:3]=1[O:13][CH2:14][CH2:15][CH2:16][CH2:17][N:31]1[CH2:30][CH2:29][N:28]([C:23]3[CH:24]=[CH:25][CH:26]=[C:27]4[C:22]=3[CH2:21][CH2:20][CH2:19]4)[CH2:33][CH2:32]1)[NH:6][C:7](=[O:12])[CH2:8][CH2:9]2
Reactant: O=CCCCOc1nc2c(cc1F)CCC(=O)N2
Reactant: c1cc2c(c(N3CCNCC3)c1)CCC2
Product: O=C1CCc2cc(F)c(OCCCCN3CCN(c4cccc5c4CCC5)CC3)nc2N1

Procedure:
The title compound was prepared by reductive amination of 4-(3-fluoro-7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde with 1-indan-4-yl-piperazine according to the above procedure. MS: APCI: M+1: 439.2 (Exact Mass: 438.24).
Reaction SMILES: [CH2:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH2:4][CH2:3][CH:2]1[NH2:14].[C:15]1([CH3:24])[C:16]([C:21](Cl)=[O:22])=[CH:17][CH:18]=[CH:19][CH:20]=1.C(N(CC)CC)C>O1CCCC1>[CH3:24][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]([NH:14][C:2]1[CH:3]=[CH:4][C:5]2[O:6][C:7]3[CH2:13][CH2:12][CH2:11][CH2:10][C:8]=3[C:9]=2[CH:1]=1)=[O:22]
Reactant: Cc1ccccc1C(=O)Cl
Reactant: NC1CCc2oc3ccccc3c2C1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccccc1C(=O)Nc1ccc2oc3c(c2c1)CCCC3
Yield: 65.5 %

Procedure:
Following the procedure of Example 1, tetrahydro-dibenzofuran-2-ylamine (0.94 g, 5.0 mmol), o-toluoyl chloride (0.69 mL, 5.2 mmol), and triethylamine (2.1 mL, 15 mmol) in tetrahydrofuran (30 mL) provided 2-methyl-N-(6,7,8,9-tetrahydro-dibenzofuran-2-yl)-benzamide (1.0 g). Mp 209-210° C.;Anal. Calcd. for C20H19NO2: C, 78.66; H, 6.27; N, 4.59; Found: C, 78.52; H, 6.28; N, 4.67.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([S:30][CH3:31])=[CH:26][CH:25]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:4].ClC1C=CC=C(C(OO)=[O:40])C=1>ClCCl>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]([S:30]([CH3:31])=[O:40])=[CH:28][CH:29]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(SC)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(S(C)=O)cc1
Yield: 46.4 %

Procedure:
To a solution (6.7 ml) of 6-bromo-2-(4-methylsulfanylbenzyl)-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (334 mg) in dichloromethane was added m-chloro perbenzoic acid (200 mg) at 0° C. with stirring, and the mixture was stirred at room temperature for 2 hrs. The reaction mixture was washed with 1N sodium hydroxide and water, and the organic layer was dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1-1/4) to give the title compound (160 mg) as colorless crystals.
Reaction SMILES: [C:1]12([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(=O)([O-])[O-].[K+].[K+].Br[C:25]([CH3:31])([CH3:30])[C:26]([O:28][CH3:29])=[O:27]>CN(C)C=O.C(OCC)(=O)C>[C:1]12([C:11]3[CH:12]=[CH:13][C:14]([O:17][C:25]([CH3:31])([CH3:30])[C:26]([O:28][CH3:29])=[O:27])=[CH:15][CH:16]=3)[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: Oc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Reactant: COC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C(C)(C)Oc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 95.7 %

Procedure:
To a solution of 4-(adamantan-1-yl)phenol (0.8 g, 3.50 mmol) in N,N-dimethylformamide (8 mL) was added anhydrous potassium carbonate (1.45 g, 10.51 mmol) and methyl 2-bromo-2-methylpropanoate (1.15 g, 7.0 mmol), and stirred at room temperature for 12 hours. The reaction mixture was diluted with ethyl acetate and washed with aqueous sodium bicarbonate. The organic layer was dried over anhydrous magnesium sulfate. The solvent was filtered and evaporated under reduced pressure to afford a crude solid, which was purified by silica gel column chromatography to give methyl 2-(4-(adamantan-1-yl)phenoxy)-2-methylpropanoate as colorless oil (1.1 g, 94.1% yield).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=2[CH:13]=O)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH2:19]([NH2:27])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1(C)C=CC=CC=1>[N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=2[CH:13]=[N:27][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=Cc1ccccc1OCCCN1CCOCC1
Reactant: NCCc1ccccc1
Solvent: Cc1ccccc1
Product: C(=NCCc1ccccc1)c1ccccc1OCCCN1CCOCC1
Yield: 76.5 %

Procedure:
2-[3-(4-Morpholinyl)propoxy]benzaldehyde (31.7 g) is reacted with 15.8 g of phenethylamine in 130 ml of toluene following the procedure described in Example 1A to yield 34.3 g of product as an oil, boiling point 215°-219° C. at 0.2-0.3 mm of Hg.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:14]=[CH:13][C:6]2[S:7][C:8](C(O)=O)=[CH:9][C:5]=2[CH:4]=1.N12CCCN=C1CCCCC2>CC(N(C)C)=O.Cl>[F:16][C:2]([F:1])([F:15])[C:3]1[CH:14]=[CH:13][C:6]2[S:7][CH:8]=[CH:9][C:5]=2[CH:4]=1
Reactant: O=C(O)c1cc2cc(C(F)(F)F)ccc2s1
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: C1CCC2=NCCCN2CC1
Product: FC(F)(F)c1ccc2sccc2c1
Temperature: 200 °C
Yield: 74.3 %

Procedure:
A mixture of 5-trifluoromethyl-benzo[b]thiophene-2-carboxylic acid (2.00 g, 8.12 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (5.0 mL, 34 mmol) in DMA (13 mL) was heated via microwave irradiation at 200° C. for 1 h. The reaction was cooled to rt, diluted with HCl (1 N aq., 20 mL) and extracted with EtOAc (20 mL). The organic layer was washed with water (10 mL), dried (Na2SO4) and concentrated. The residue was taken up in Et2O (25 mL) and washed with water (25 mL). The aqueous layer was extracted with Et2O (10 mL×2). The combined Et2O layers were dried (Na2SO4) and concentrated. The crude material was purified (FCC) to yield the title compound (1.22 g, 74%).
Reaction SMILES: [C:1](Cl)(=O)[CH2:2][CH3:3].[CH2:6]([O:8][C:9](=[O:33])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([S:16][C:17]2[C:25]3[C:20](=[C:21]([F:27])[C:22]([Cl:26])=[CH:23][CH:24]=3)[N:19]([C:28](=[NH:31])[NH:29][OH:30])[C:18]=2[CH3:32])[CH:11]=1)[CH3:7]>N1C=CC=CC=1>[CH2:6]([O:8][C:9](=[O:33])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([S:16][C:17]2[C:25]3[C:20](=[C:21]([F:27])[C:22]([Cl:26])=[CH:23][CH:24]=3)[N:19]([C:28]3[N:31]=[C:1]([CH2:2][CH3:3])[O:30][N:29]=3)[C:18]=2[CH3:32])[CH:11]=1)[CH3:7]
Reactant: CCC(=O)Cl
Reactant: CCOC(=O)c1cccc(Sc2c(C)n(C(=N)NO)c3c(F)c(Cl)ccc23)c1
Solvent: c1ccncc1
Product: CCOC(=O)c1cccc(Sc2c(C)n(-c3noc(CC)n3)c3c(F)c(Cl)ccc23)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Propionyl chloride (0.042 mL, 0.48 mmol) was added to a solution of 3-[6-Chloro-7-fluoro-1-(N-hydroxycarbamimidoyl)-2-methyl-1H-indol-3-ylsulfanyl]-benzoic acid ethyl ester (0.12 g, 0.24 mmol) in pyridine (2 mL) at room temperature. The resulting mixture was heated to 80° C. and stirred for overnight, then cooled to room temeperature and subjected to standard aqueous workup. The crude residue was purified on silica gel (0-60% EtOAc in hexanes) to afford the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Si:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)([OH:15])[CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:4][CH:3]=1.Cl[Si:24]([CH3:27])([CH3:26])[CH3:25].C(N(CC)CC)C>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([Si:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)([O:15][Si:24]([CH3:27])([CH3:26])[CH3:25])[CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)Cl
Reactant: O[Si](Cn1cncn1)(c1ccc(F)cc1)c1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[Si](C)(C)O[Si](Cn1cncn1)(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1.5 g (0.0047 mol) of [bis(4-fluorophenyl)]hydroxy(1H-1,2,4-triazol-1-ylmethyl)silane in 20 ml of tetrahydrofuran was added 0.8 ml (0.0063 mol) of chlorotrimethylsilane. A solution of 0.8 ml (0.0057 mol) of triethylamine in 5 ml of tetrahydrofuran was added dropwise, giving a thick white precipitate. The mixture was stirred overnight at room temperature, then filtered and concentrated to an oil. The residue was taken up in ether, filtered, and the filtrate was evaporated to afford the title compound as a clear colorless oil: nmr (CDCl3) 0.1 (9H, s), 4.3 (2H, s), 7.2 (4H, t, J=9 Hz), 7.6 (4H, d of d, J=9,6 Hz), 8.0 (2H, s).
Reaction SMILES: [C:1]1([CH2:11][NH2:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[O:13]=[C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]([C:24](O)=[O:25])[CH2:16][CH2:15]1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]1([CH2:11][NH:12][C:24]([CH:17]2[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:14](=[O:13])[CH2:15][CH2:16]2)=[O:25])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: NCc1cccc2ccccc12
Reactant: O=C1CCC(C(=O)O)c2ccccc21
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C1CCC(C(=O)NCc2cccc3ccccc23)c2ccccc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 1-naphthalenemethylamine (1.37 g, 7.2 mmol), 4-oxo-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (1.13 g, 7.2 mmol) ECD (2.87 g, 15 mmol), and DMAP (1.83 g, 15 mmol) in CH2Cl2 (20 mL) was stirred at room temperature. After 12 h, the reaction mixture was concentrated and the residue was purified by flash column chromatography (2-5% MeOH in CH3Cl to yield the product (2.29 g, 97% liht yellow solid, m.p. 155-156° C.).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH2:16][O:17][CH3:18])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH:23][C:24](=[O:42])[CH2:25][C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]2[CH:39]=[CH:38][N:37]=[C:36]([C:40]#[N:41])[CH:35]=2)[CH:29]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:18][O:17][CH2:16][CH2:15][O:14][C:12]1[C:11]([C:19]([F:20])([F:21])[F:22])=[CH:10][C:9]2[NH:23][C:24](=[O:42])[CH2:25][C:26]([C:28]3[CH:29]=[C:30]([C:34]4[CH:39]=[CH:38][N:37]=[C:36]([C:40]#[N:41])[CH:35]=4)[CH:31]=[CH:32][CH:33]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: COCCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(C#N)c3)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCOc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccnc(C#N)c3)c1)=N2

Procedure:
The title compound was prepared from [2-{3-[3-(2-cyano-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-5-(2-methoxy-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M189) (278 mg, 0.46 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (185 mg, 84%).