Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][C:9](=[O:12])[N:8]([CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][CH:18]([NH:21]C(=O)OC(C)(C)C)[CH2:17][C:16]3=[O:29])[C:7]=2[CH:30]=1.FC(F)(F)C(O)=O.NC1CCN(CCN2C3C=C(OC)C=CC=3COC2=O)CC1>>[NH2:21][CH:18]1[CH2:19][CH2:20][N:15]([CH2:14][CH2:13][N:8]2[C:7]3[CH:30]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=3[O:11][CH2:10][C:9]2=[O:12])[C:16](=[O:29])[CH2:17]1
Reactant: COc1ccc2c(c1)N(CCN1CCC(NC(=O)OC(C)(C)C)CC1=O)C(=O)CO2
Agent: COc1ccc2c(c1)N(CCN1CCC(N)CC1)C(=O)OC2
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(c1)N(CCN1CCC(N)CC1=O)C(=O)CO2

Procedure:
tert-Butyl {1-[2-(6-methoxy-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]-2-oxopiperidin-4-yl}carbamate (Intermediate 115, 350 mg, 0.83 mmol) was reacted as described for Intermediate 106. The crude trifluoro acetate of the title compound was obtained as a black oil, 395 mg (quantitative), and used without further purification for the next step.
Reaction SMILES: C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1.[CH3:26][O:27][C:28]1[N:33]=[CH:32][C:31]([NH:34][CH:35]=[C:36]([C:42](=[O:44])[CH3:43])[C:37]([O:39]CC)=O)=[CH:30][CH:29]=1>>[OH:39][C:37]1[C:32]2[C:31](=[CH:30][CH:29]=[C:28]([O:27][CH3:26])[N:33]=2)[N:34]=[CH:35][C:36]=1[C:42](=[O:44])[CH3:43]
Reactant: CCOC(=O)C(=CNc1ccc(OC)nc1)C(C)=O
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COc1ccc2ncc(C(C)=O)c(O)c2n1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 98.2 %

Procedure:
To a flask containing Dowtherm™ A (500 mL) at 250° C. was added ethyl 2-[(6-methoxypyridin-3-ylamino)methylene]-3-oxobutanoate (75 g, 0.28 mol) portion wise over 3 to 5 min and the reaction mixture was stirred for an additional 30 to 60 min. The reaction mixture was removed from the heat source, cooled to room temperature and diluted with hexanes to facilitate precipitation. The solids were filtered, washed with hexanes and acetonitrile and dried under vacuum to afford the desired product (60 g, 46%) as an off-white solid: 1H NMR (500 MHz, DMSO-d6) δ 12.48 (bs, 1H), 8.45 (d, J=5.2 Hz, 1H), 8.00 (d, J=8.9 Hz, 1H), 7.40-7.37 (m, 1H), 7.21 (d, J=8.9 Hz, 1H), 7.01-6.99 (m, 1H), 3.96 (s, 3H), 2.61 (s, 3H); ESI MS m/z 219 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]=[CH:10][C:3]=12.[C:19]([CH2:21][C:22]1([N:33]2[CH:37]=[C:36](B3OC(C)(C)C(C)(C)O3)[CH:35]=[N:34]2)[CH2:25][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:23]1)#[N:20].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:19]([CH2:21][C:22]1([N:33]2[CH:37]=[C:36]([C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]=[CH:10][C:3]=34)[CH:35]=[N:34]2)[CH2:25][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:23]1)#[N:20]
Reactant: C[Si](C)(C)CCOCn1ccc2c(Br)ccnc21
Reactant: CC(C)(C)OC(=O)N1CC(CC#N)(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(CC#N)(n2cc(-c3ccnc4c3ccn4COCC[Si](C)(C)C)cn2)C1
Temperature: 90 °C
Reaction time: 2 h
Yield: 104.8 %

Procedure:
A mixture of 4-bromo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine (1.0 g, 3.0 mmol), tert-butyl 3-(cyanomethyl)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]azetidine-1-carboxylate (1.2 g, 3.0 mmol), tetrakis(triphenylphosphine)palladium(0) (200 mg, 0.2 mmol) and cesium carbonate (3.0 g, 9.2 mmol) in 1,4-dioxane (6 mL) and water (0.9 mL) was degassed and sealed. It was stirred at 90° C. for 2 h. After cooling it was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexane (0-50%) to afford the desired product (1.6 g). LCMS (M+H)+: m/z=509.3.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][NH2:6].Cl[C:9]1[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][C:10]=1[N+:20]([O-:22])=[O:21]>C(OCC)(=O)C>[CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][NH:6][C:9]1[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][C:10]=1[N+:20]([O-:22])=[O:21]
Reactant: CN(C)CCCN
Reactant: CCOC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(NCCCN(C)C)c([N+](=O)[O-])c1
Temperature: 125 °C
Reaction time: 12 h
Yield: 101.2 %

Procedure:
N,N-Dimethy-1,3-propanediamine (1.41 g) was added to ethyl 4-chloro-3-nitrobenzoate (1.59 g) and stirred for 12 hours at 125° C. The reaction mixture, with ethyl acetate added thereto, was washed with 1N sodium hydroxide aqueous solution, water, and saturated brine successively, dried over sodium sulfate anhydride, and concentrated, thereby yielding the entitled compound (2.07 g) as brown oil.
Reaction SMILES: [Br:1][C:2]1[N+:7]([O-])=[C:6]([CH3:9])[C:5]([F:10])=[CH:4][CH:3]=1.C([O-])([O-])=[O:12].[K+].[K+].O>C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>[Br:1][C:2]1[N:7]=[C:6]([CH2:9][OH:12])[C:5]([F:10])=[CH:4][CH:3]=1
Reactant: Cc1c(F)ccc(Br)[n+]1[O-]
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: OCc1nc(Br)ccc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.9 %

Procedure:
6-bromo-3-fluoro-2-methylpyridine 1-oxide (2.89 g, 14.02 mmol, 1 eq.) was dissolved in neat TFAA (10 ml) and stirred 30 min at room temperature and refluxed for 2 hrs. The solvent was evaporated and the residue diluted with DCM and basified with sat. aqueous Na2CO3. The organic layers was separated and washed with sat. aqueous Na2CO3, dried with MgSO4 and concentrated. The crude was dissolved in THF and MeOH (1 ml) was added followed by K2CO3 (4.8 g, 35.07 mmol, 2.5 eq.). After 30 min of stirring, water was added and the reaction was extracted with EtOAc. The organic layers were combined, dried over MgSO4 and concentrated. (6-bromo-3-fluoropyridin-2-yl)methanol (2.54 g, 79% yield) was obtained as a yellow solid.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3]([C:5]1[CH:6]=[CH:7][C:8]2[CH:12]=[C:11]([C:13]3[C:18]([CH3:19])=[CH:17][N:16]=[C:15](Cl)[N:14]=3)[S:10][C:9]=2[CH:21]=1)=[O:4].[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][CH:33]([CH2:36][CH2:37][NH2:38])[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].C(N(C(C)C)CC)(C)C>O1CCOCC1>[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][CH:33]([CH2:36][CH2:37][NH:38][C:15]2[N:14]=[C:13]([C:11]3[S:10][C:9]4[CH:21]=[C:5]([C:3](=[O:4])[N:2]([CH3:22])[CH3:1])[CH:6]=[CH:7][C:8]=4[CH:12]=3)[C:18]([CH3:19])=[CH:17][N:16]=2)[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]
Reactant: Cc1cnc(Cl)nc1-c1cc2ccc(C(=O)N(C)C)cc2s1
Reactant: CC(C)(C)OC(=O)N1CCC(CCN)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1cnc(NCCC2CCN(C(=O)OC(C)(C)C)CC2)nc1-c1cc2ccc(C(=O)N(C)C)cc2s1
Temperature: 97 °C

Procedure:
A stirred mixture of 2-(2-chloro-5-methylpyrimidin-4-yl)-benzo[b]thiophene-6-carboxylic acid dimethylamide (473 mg, 1.43 mmol), 4-(2-aminoethyl)-piperidine-1-carboxylic acid tert-butyl ester (814 mg, 3.56 mmol) and diisopropylethylamine (0.747 mL, 4.29 mmol) in 1,4-dioxane (5 mL) is heated at 97° C. under nitrogen for 2 days. At room temperature the mixture is concentrated and the crude product is chromatographed on silica gel, eluting with MeOH in dichloromethane 0-2%, to give 4-{2-[4-(6-dimethylcarbamoyl-benzo[b]thiophen-2-yl)-5-methylpyrimidin-2-ylamino]-ethyl}-piperidine-1-carboxylic acid tert-butyl ester. The intermediate is then subject to deprotection by dissolving in dichloromethane (20 mL) and treating with triethylsilane (0.9 mL) and TFA (4 mL). The resultant yellow solution is stirred at room temperature for 1 hour. After concentration and subsequent chromatography on silica gel, eluting with 2.0 M NH3/MeOH in dichloromethane 3-12%, the fractions containing the desired product are collected and concentrated to give yellow foam. This foam is dissolved in MeOH (20 mL), treated with 0.5 N LiOH (20 mL) then concentrated to give the crude product of the title compound as yellow foam. It is used for next reductive methylation without further purification.
Reaction SMILES: [H-].[Na+].CI.[Cl:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[CH:12]=[C:13]([C:15]([N:17]3[CH2:21][CH2:20][CH:19]([CH2:22][NH:23][C:24](=O)OC(C)(C)C)[CH2:18]3)=[O:16])[S:14][C:7]=12>C1COCC1>[Cl:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[CH:12]=[C:13]([C:15]([N:17]3[CH2:21][CH2:20][CH:19]([CH2:22][NH:23][CH3:24])[CH2:18]3)=[O:16])[S:14][C:7]=12
Reactant: CC(C)(C)OC(=O)NCC1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CNCC1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1
Temperature: 25 °C
Yield: 134.3 %

Procedure:
NaH (0.033 g, 0.82 mmole) and CH3I (0.064 ml, 1.02 mmole) were added to a solution of tert-butyl {1-[(7-chlorothieno[3,2-b]pyridin-2-yl)carbonyl]pyrrolidin-3-yl}methyl-carbamate 43 (0.271 g, 0.68 mmole) in THF at 0° C. The reaction mixture was stirred and warmed to room temperature overnight and partitioned between H2O (50 ml) and EtOAc (2×50 ml). The combined organic layers were dried over MgSO4 and concentrated. The residue was purified by flash column chromatography eluting with 0-2% CH3OH in CH2Cl2 to give a yellow solid (0.283 g, 82%). 1H NMR (300 MHz, CDCl3) δ8.62 (1H, d, J=5.1 Hz), 7.85 (1H, s), 7.34 (1H, d, J=5.1 Hz), 4.72 (1H, s), 3.99 (1H, m), 3.77 (2H, m), 3.50 (1H, m), 3.19 (2H, m), 2.88 (3H, d, J=12.06 Hz), 2.62 (1H, m), 2.14 (1H, m), 1.83 (1H, m); ESIMS (MH+): 310.10.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[C:5](=[CH:10][C:11]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[I:29])=[C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[I:21])[CH:13]=1)[C:6]([O:8]C)=O.[NH3:31]>C(O)CO.[Cl-].[Na+].O>[I:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[NH:22][C:11]1[CH:10]=[C:5]2[C:6](=[O:8])[NH:31][C:3](=[O:2])[C:4]2=[CH:13][C:12]=1[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[I:21]
Reactant: COC(=O)c1cc(Nc2ccccc2I)c(Nc2ccccc2I)cc1C(=O)OC
Reactant: N
Agent: [Cl-]
Agent: [Na+]
Solvent: OCCO
Solvent: O
Product: O=C1NC(=O)c2cc(Nc3ccccc3I)c(Nc3ccccc3I)cc21

Procedure:
Analogously to Example 1, 1.48 g (2.36 mmol) of 4,5bis(2-iodoanilino)phthalic acid dimethyl ester in 25 ml of ethylene glycol are heated at 120° and, with stirring, ammonia gas is passed through the mixture for 19 hours. The reaction mixture is cooled, diluted with brine and extracted with ethyl acetate. The ethyl acetate phases are washed in succession three times with water and once with saturated sodium chloride solution, dried with sodium sulfate and concentrated by evaporation. The residue obtained after concentration by evaporation is filtered through silica gel with dichloromethane and the product fractions are combined and concentrated by evaporation. The residue obtained after concentration by evaporation is crystallized from boiling dichloromethane, yielding the title compound in the form of yellow crystals, m.p. 108°-110° C., FAB-MS: 582 [M+ +H].
Reaction SMILES: [C:1]([C:3]1[CH:26]=[CH:25][C:6]([C:7]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][CH:15]([O:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:14][CH2:13]2)=[O:11])=[O:8])=[CH:5][CH:4]=1)#[N:2].N1C=CC=CC=1.[SH2:33]>C(N(CC)CC)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]([N:12]2[CH2:13][CH2:14][CH:15]([O:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:16][CH2:17]2)=[O:11])=[O:8])=[CH:25][CH:26]=1)(=[S:33])[NH2:2]
Reactant: S
Reactant: CCOC(=O)COC1CCN(C(=O)NC(=O)c2ccc(C#N)cc2)CC1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CCOC(=O)COC1CCN(C(=O)NC(=O)c2ccc(C(N)=S)cc2)CC1

Procedure:
In a similar manner to Example 1, starting material step (b), the product from step (c) (1.2 g), pyridine (84 ml), triethylamine (7 ml) and H2S gas were reacted to give ethyl N-[N-(4-thiocarbamoylbenzoyl)carbamoyl]piperidin-4-yloxyacetate (0.74 g) as a yellow gum: NMR Spectrum (DMSO-d6) 1.20 (3H, t), 1.50 (2H, m), 1.87 (2H, m), 3.20 (2H, m), 3.66 (3H, m), 4.12 (2H, q), 4.15 (2H, s), 7.90 (4H, m), 9.63 (1H, br s), 10.00 (1H, br s); Mass Spectrum m/Z 394 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[NH:10][C:9](=[O:12])[C:8](=[O:13])[NH:7][C:6]=2[S:5][CH:4]=1)[CH3:2].C([O-])(=O)C.[Na+].[Br:19]Br.S(S([O-])=O)([O-])=O.[Na+].[Na+]>C(O)(=O)C>[Br:19][C:4]1[S:5][C:6]2[NH:7][C:8](=[O:13])[C:9](=[O:12])[NH:10][C:11]=2[C:3]=1[CH2:1][CH3:2]
Reactant: CCc1csc2[nH]c(=O)c(=O)[nH]c12
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCc1c(Br)sc2[nH]c(=O)c(=O)[nH]c12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 51.3 %

Procedure:
A suspension of 7-ethylthieno[2,3-b]pyrazine-2,3(1H,4H)-dione (1.0 g, 5.1 mmol) and sodium acetate (0.84 g, 10.2 mmol) in 225 ml of acetic acid was stirred at 10°-15° C. under a dry nitrogen atmosphere. A solution of bromine (0.26 ml, 5.1 mmol) in 2 ml of acetic acid was added during 0.5 h. Stirring was continued for further 0.5 h at room temperature and the reaction mixture was poured into ice water. The reddish mixture was decolourized by the addition of a small amount of aqueous sodium dithionite. The precipitate was filtered off, washed with water, resuspended in alcohol, filtered and washed with ether. Drying at 60° C. in vacuo afforded 720 mg (51%) of the title compound. M.p. 295°-297° C. 1H-NMR (DMSO-D6, δ): 1.04 (t, 3H), 2.62 (q, 2H), 12.01 (s, 1H), 12.19 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][N+:12]([O-:14])=[O:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:22](Cl)(=[O:26])[CH2:23][CH2:24][CH3:25]>O1CCCC1>[C:22]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][N+:12]([O-:14])=[O:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1)(=[O:26])[CH2:23][CH2:24][CH3:25]
Reactant: CCCC(=O)Cl
Reactant: Nc1ccc(S(=O)(=O)C[N+](=O)[O-])cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCC(=O)Nc1ccc(S(=O)(=O)C[N+](=O)[O-])cc1
Reaction time: 2 h
Yield: 7.5 %

Procedure:
(4-Aminophenylsulphonyl)nitromethane (1.62 g, 7.5 mmol) was dissolved in dry tetrahydrofuran (35 ml) under an atmosphere of argon. Triethylamine (1.14 g, 11.25 mmol) was added, followed by butyryl chloride (0.88 g, 8.25 mmol). The mixture was stirred for 2 hours. The precipitated triethylamine hydrochloride was removed by filtration and the filtrate concentrated in vacuo. The brown oil obtained was purified by MPLC, eluting with dichloromethane/methanol (99:1 v/v) to give (4-butyramidophenylsulphonyl)nitromethane (0.16 g, 7.5% yield) as a solid, m.p. 155 156° C.; microanalysis, found: C, 45.8; H, 4.8; N, 9.6%; C11H14N2O5S requires: C, 46.1; H, 4.9; N, 9.8%.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([CH2:10][S:11][C:12]2[CH:20]=[CH:19][C:15]([CH2:16][CH2:17][NH2:18])=[CH:14][CH:13]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:21]([Si:25]([O:38][C:39]1[CH:44]=[CH:43][C:42]([O:45][CH2:46][C@@H:47]2[CH2:49][O:48]2)=[CH:41][CH:40]=1)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([CH3:24])([CH3:23])[CH3:22]>>[Si:25]([O:38][C:39]1[CH:44]=[CH:43][C:42]([O:45][CH2:46][C@@H:47]([OH:48])[CH2:49][NH:18][CH2:17][CH2:16][C:15]2[CH:14]=[CH:13][C:12]([S:11][CH2:10][C:7]3[N:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[O:9][N:8]=3)=[CH:20][CH:19]=2)=[CH:41][CH:40]=1)([C:21]([CH3:22])([CH3:24])[CH3:23])([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CC(C)(C)c1nc(CSc2ccc(CCN)cc2)no1
Reactant: CC(C)(C)[Si](Oc1ccc(OC[C@@H]2CO2)cc1)(c1ccccc1)c1ccccc1
Product: CC(C)(C)c1nc(CSc2ccc(CCNC[C@H](O)COc3ccc(O[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)cc3)cc2)no1
Yield: 12.9 %

Procedure:
Following the procedure described in Example 14 using the amine of Example 30 (0.481 g, 1.565 mmol) and tert-butyl{4-[(2S)oxiranylmethoxy]phenoxy}diphenylsilane (0.697 g, 1.721 mmol) afforded 0.140 g of the title compound.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:19][CH2:20][CH:21]([CH3:28])[CH2:22][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26]>O1CCCC1.CN(C)C=O>[CH3:28][CH:21]([CH2:22][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])[CH2:20][CH2:19][N:11]1[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[N:8]=[C:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)=CCCC(C)CCBr
Reactant: c1ccc(-c2nc3ccccc3[nH]2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)=CCCC(C)CCn1c(-c2ccccc2)nc2ccccc21
Temperature: 25 °C

Procedure:
In a flask equipped with a stirrer, condenser and nitrogen inlet tube, there is added 90 ml. of anhydrous tetrahydrofuran, 30 ml. of anhydrous dimethylformamide and 9.7 g. (0.05 mole) of 2-phenylbenzimidazole. The resulting system is then blanketed with nitrogen, stirring is initiated and 2.2 g. (0.053 mole) of 57% sodium hydride mineral oil dispersion is added in one portion. The mixture is then heated to 50° for about 2 hours. After cooling to room temperature, a solution of 12.0 g. (0.053 mole) of (±) 1-bromo-3,7-dimethyl-6-octene in 50 ml. of dry tetrahydrofuran is added dropwise. The resulting mixture is stirred overnight at room temperature and the resultant salts are removed by filtration. The filtrate is concentrated in vacuo. The resultant oil is dissolved in chloroform and chromatographed on silica gel using methylenechloride as the eluant to give (±)1-(3,7-dimethyl-6-octen-1-yl)-2-phenylbenzimidazole, NMR (CDCl3) δ0.72-2.18 (16H, complex multiplet, ##EQU1## 4.23 (2H, triplet, J=7cps, CH2N), 5.00 (1H, triplet, J=7cps, HC=C), 7.13-7.95 (9H, multiplet, C6H5 and C6H4). Anal. Calcd. for C23H28N2 :C, 83.1; H, 8.5; N, 8.4. Found:C, 83.3; H, 8.8; N, 8.0.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([CH2:18]O)[C:13]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:23])=O.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl>[CH2:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([CH2:18][Cl:23])[C:13]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1c(OCCOCc2ccccc2)ccnc1CO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1c(OCCOCc2ccccc2)ccnc1CCl
Temperature: 25 °C
Reaction time: 7 h
Yield: 111.4 %

Procedure:
5.3 g of 4-(2-benzyloxyethoxy)-2-hydroxymethyl-3-methylpyridine was dissolved in 60 ml of chloroform to obtain a solution. A solution of 5.8 g of thionyl chloride in 40 ml of chloroform was dropwise added to the above solution under cooling with ice. The obtained mixture was stirred at a room temperature for 7 hours and distilled under a reduced pressure to obtain a residue. 200 ml of a 2N aqueous solution of sodium carbonate was added to the residue. The obtained mixture was extracted with chloroform and the extract was dried over magnesium sulfate and distilled to remove the chloroform. 6.3 g of the title compound was obtained.
Reaction SMILES: Cl[C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][CH:15]=[N:16]3)=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1>>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:2]2[CH:20]=[CH:19][C:5]([C:6]([NH:8][C:9]3[CH:18]=[C:17]4[C:12]([CH:13]=[CH:14][CH:15]=[N:16]4)=[CH:11][CH:10]=3)=[O:7])=[CH:4][N:3]=2)=[CH:24][CH:23]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: O=C(Nc1ccc2cccnc2c1)c1ccc(Cl)nc1
Product: O=C(Nc1ccc2cccnc2c1)c1ccc(-c2ccc(Cl)cc2)nc1

Procedure:
Using the procedure outlined in Example 100, the title compound was prepared from 6-chloro-N-quinolin-7-yl-nicotinamide (D70) (40 mg, 0.14 mmol) and 4-chlorophenylboronic acid (27 mg, 0.17 mmol) as a pale yellow solid. 1H NMR (250 MHz, CDCl3) δ (ppm): 9.25 (dd, 1H), 8.82 (dd, 1H), 8.43 (dd, 1H), 8.33 (dd, 1H), 8.22 (br.d, 1H), 8.11 (d, 1H), 8.00 (d, 2H), 7.89 (d, 1H), 7.87 (d, 1H), 7.51 (d, 2H), 7.40 (dd, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:13][CH2:12][C@:11]([CH:17]([CH3:19])[CH3:18])([C:14]([OH:16])=O)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[F:21][C:22]([F:37])([F:36])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1([OH:35])[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>C(Cl)Cl>[OH:35][C:29]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[C:22]([F:37])([F:21])[F:36])[CH2:34][CH2:33][N:32]([C:14]([C@@:11]2([CH:17]([CH3:19])[CH3:18])[CH2:12][CH2:13][C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10]2)=[O:16])[CH2:31][CH2:30]1
Reactant: CC(C)[C@]1(C(=O)O)CC[C@@H](NC(=O)OC(C)(C)C)C1
Reactant: OC1(c2ccccc2C(F)(F)F)CCNCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)[C@]1(C(=O)N2CCC(O)(c3ccccc3C(F)(F)F)CC2)CC[C@@H](NC(=O)OC(C)(C)C)C1
Reaction time: 2.5 h

Procedure:
To a solution of (1S,3R)-3-[(tert-butoxycarbonyl)amino]-1-isopropylcyclopentanecarboxylic acid (150 mg, 0.55 mmol), 4-[2-(trifluoromethyl)phenyl]piperidin-4-ol hydrochloride (170 mg, 0.60 mmol), and triethylamine (0.17 g, 1.6 mmol) in methylene chloride (3 mL) was added (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (0.31 g, 0.60 mmol). After being stirred for 2.5 h, the reaction was quenched by addition of a saturated NaHCO3 solution. The resulting solution was extracted with methylene chloride three times. The combined extracts were dried (MgSO4), filtered, and concentrated. The crude product was carried on to the next step without purification. MS calculated for C26H37F3N2O4: (M+H) 499; found 499.2.
Reaction SMILES: [CH:1]1[C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=[C:3]([I:10])[CH:2]=1.[CH3:11][Si](C=[N+]=[N-])(C)C.CCCCCC>CO>[CH3:11][O:8][C:7](=[O:9])[C:6]1[CH:5]=[CH:4][C:3]([I:10])=[CH:2][CH:1]=1
Reactant: O=C(O)c1ccc(I)cc1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: CCCCCC
Product: COC(=O)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
p-iodobenzoic acid (500 mg, 2.02 mmol) was dissolved in methanol (30 ml), to which was added 2M trimethylsilyl diazomethane/hexane solution (13 ml) and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to yield a crude product (500 mg) of the title compound. This was used as a raw material in the subsequent reaction without purification.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH2:11]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:21]2[CH2:22][CH2:23][N:18]([CH2:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:19][CH2:20]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(N2CCN(Cc3ccccc3)CC2)cc1

Procedure:
To a solution of 48.67 g (0.35 mol) of 1-fluoro-4-nitrobenzene and 67.15 g (0.38 mol) of 1-benzylpiperazine in 600 mL of acetonitrile, add 52.65 g (0.381 mol) of anhydrous potassium carbonate. Heat the reaction mixture to reflux for 20h under nitrogen. After this time, add 300 mL of water and concentrate mixture to 500 mL volume. Extract the mixture with 3×500 mL of methylene chloride. Remove the solvent of the combined organic layers in vacuo. Triturate the resulting crystalline residue with 1000 mL of diethyl ether and filter to obtain title compound.