Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([OH:43])=O)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:47]([NH:51][CH:52]([CH3:54])[CH3:53])[CH2:48][CH2:49][CH3:50]>>[CH2:47]([N:51]([CH:52]([CH3:54])[CH3:53])[C:41](=[O:43])[CH2:40][CH:37]1[CH2:38][CH2:39][N:34]([C:32]([N:12]2[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=[C:11]2[C:8]2[CH:9]=[N:10][C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])=[CH:6][C:7]=2[O:44][CH2:45][CH3:46])=[O:33])[CH2:35][CH2:36]1)[CH2:48][CH2:49][CH3:50]
Reactant: CCCCNC(C)C
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Product: CCCCN(C(=O)CC1CCN(C(=O)N2C(c3cnc(C(C)(C)C)cc3OCC)=N[C@@](C)(c3ccc(Cl)cc3)[C@@]2(C)c2ccc(Cl)cc2)CC1)C(C)C

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was coupled with n-butyl isopropyl amine (ChemBridge) to give the title compound. HR-MS (ES, m/z) calculated for C43H58Cl2N5O3 [(M+H)+] 762.391 1, observed 762.3908.
Reaction SMILES: N#C[Cl:3].C[N:5](C)[C:6]([N:8](C)C)=[NH:7].N>O>[NH2:7][C:6]([NH2:8])=[NH:5].[ClH:3].[NH2:7][C:6]([NH2:8])=[NH:5]
Reactant: N#CCl
Reactant: CN(C)C(=N)N(C)C
Agent: N
Solvent: O
Product: Cl
Product: N=C(N)N

Procedure:
Besides it is known that in the action of cyanogen chloride on dimethylamine under pressure at a temperature of 130° to 180° C. in a water nonmiscible organic solvent 1,1,3,3-tetramethyl guanidine is formed (German Pat. No. 1,958,095). If it is attempted to react cyanogen chloride in a corresponding manner with ammonia to produce guanidine or guanidine hydrochloride there are not obtained satisfactory yields.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:24]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[N:23][CH:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1)=[O:11].[C:31](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C=O)C.CO>[CH3:31][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:13]=[CH:14][C:15]([O:18][C:19]2[C:24]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[N:23][CH:22]=[CH:21][N:20]=2)=[CH:16][CH:17]=1)=[O:11]
Reactant: O=C(c1ccc(Oc2nccnc2N2CCOCC2)cc1)c1nc2ccccc2[nH]1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: CO
Product: Cn1c(C(=O)c2ccc(Oc3nccnc3N3CCOCC3)cc2)nc2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of (1H-benzo[d]imidazol-2-yl)(4-(3-morpholinopyrazin-2-yloxy)-phenyl)methanone as prepared according to Scheme 3, (0.2 g, 0.5 mmol) in DMF (1 mL) was added cesium carbonate (0.2 g, 0.7 mmol) and iodomethane (0.04 mL, 0.6 mmol). The resulting mixture was stirred at RT overnight. LC/MS showed complete conversion. Compound crashed out in MeOH. Filtered the resulting orange solid and rinse with copious amounts of MeOH. Solids were dried by vacuum pump overnight to afford (1-methyl-1H-benzo[d]imidazol-2-yl)(4-(3-morpholinopyrazin-2-yloxy)phenyl)methanone. MS (ESI, pos. ion) m/z: 416.1. (M+1). IC50 (uM) ++++.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C@H:4]([NH:17][C:18]1[CH:23]=[C:22]([CH3:24])[C:21]([F:25])=[C:20]([CH3:26])[CH:19]=1)[CH2:5][CH2:6][CH2:7][CH2:8][NH:9]C(OC(C)(C)C)=O.FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3](=[O:27])[C@H:4]([NH:17][C:18]1[CH:23]=[C:22]([CH3:24])[C:21]([F:25])=[C:20]([CH3:26])[CH:19]=1)[CH2:5][CH2:6][CH2:7][CH2:8][NH2:9]
Reactant: COC(=O)[C@@H](CCCCNC(=O)OC(C)(C)C)Nc1cc(C)c(F)c(C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@@H](CCCCN)Nc1cc(C)c(F)c(C)c1
Temperature: 25 °C
Reaction time: 19 h
Yield: 81.2 %

Procedure:
To a solution of (R)-6-tert-butoxycarbonylamino-2-(4-fluoro-3,5-dimethyl-phenylamino)-hexanoic acid methyl ester (2.000 g, 5.232 mmol) in 10 mL of dichloromethane, was added trifluoroacetic acid (10 mL). After stirring at room temperature for 19 h, the reaction mixture was concentrated under reduced pressure, and dried in vacuum for overnight. The crude product (1.200 g, 81% yield) was used directly in the next step without further purification. LC-MS: tR=4.8 min; m/z 283 (M+H)+.
Reaction SMILES: C([Sn](=[O:10])CCCC)CCC.C1(C[C:18]2[CH:23]=CC=CC=2)C=CC=CC=1.C([C:26](O)([CH2:30][CH3:31])[C:27]([O-:29])=[O:28])C>C(O)C>[CH2:23]([O:29][C:27](=[O:28])[CH2:26][CH:30]([OH:10])[CH3:31])[CH3:18]
Reactant: c1ccc(Cc2ccccc2)cc1
Reactant: CCC(O)(CC)C(=O)[O-]
Reactant: CCCC[Sn](=O)CCCC
Solvent: CCO
Product: CCOC(=O)CC(C)O
Temperature: 180 °C

Procedure:
Ethyl-3-hydroxybutyrate was prepared from a PHA (poly 3-hydroxybutyrate) as follows. A solution of 1.0 g of poly 3-hydroxybutyrate (94% purity) in 4.0 ml of absolute ethanol was prepared in a glass pressure bottle. The PHA was derived from biomass. 10.5 mg of di-butyl tin oxide and 0.5 ml of diphenylmethane were added as a catalyst and as an internal gas chromatographic standard, respectively. The mixture was heated to 180° C. with magnetic stirring. After 2.0 hours the percent yield of ethyl-hydroxybutyrate from the PHA was 77.8%, and after 4.0 hours the percent yield of ethyl-hydroxybutyrate from the PHA was 92%.
Reaction SMILES: [OH-].[K+].[C:3]([OH:11])(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CN(C=O)C.Cl[CH:18]([C:22](=[O:24])[CH3:23])[C:19](=[O:21])[CH3:20]>O>[C:3]([O:11][CH:18]([C:22](=[O:24])[CH3:23])[C:19](=[O:21])[CH3:20])(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(O)c1ccccc1
Reactant: CC(=O)C(Cl)C(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)C(OC(=O)c1ccccc1)C(C)=O
Temperature: 50 °C
Reaction time: 8 h
Yield: 96.1 %

Procedure:
A flask was charged with powdered potassium hydroxide (21.89 g, 390.2 mmol), benzoic acid (47.65 g, 390.2 mmol), and DMF (500 mL). The mixture was heated at 50° C. for 1 hour. 3-Chloropentane-2,4-dione (52.5 g, 390.2 mmol) was added and the reaction was stirred at 50° C. overnight. The reaction was cooled to ambient temperature, diluted in water (1.5 L) and extracted with ether (3×500 mL). The combined organic layers were washed with water, saturated NH4Cl and brine. The organic layer was dried over sodium sulfate and concentrated in vacuo to afford 2,4-dioxopentan-3-yl benzoate (82.59 g, 96.12% yield) as yellow oil.
Reaction SMILES: [CH:1](=[N:8]/[CH2:9][CH:10]1[CH2:15][CH2:14][CH:13]=[CH:12][CH2:11]1)\[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C=O)CCC=CC1.C(N)C1C=CC=CC=1>>[CH:10]1(/[CH:9]=[N:8]/[CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:15][CH2:14][CH:13]=[CH:12][CH2:11]1
Reactant: C1=CCC(C/N=C/c2ccccc2)CC1
Agent: O=CC1CC=CCC1
Solvent: NCc1ccccc1
Product: C1=CCC(/C=N/Cc2ccccc2)CC1

Procedure:
Kimpe et al., Tetrahedron, Vol. 53, No. 31, pg. 10803-10816 (1997) shows synthesis of (E)-N-benzylidene-1-(cyclohex-3-en-1-yl)methanamine by condensing cyclohex-3-enecarbaldehyde with benzylamine to give (E)-N-(cyclohex-3-en-1-ylmethylene)-1-phenylmethanamine, followed by an isomerization reaction using potassium tert-butoxide in THF. Resulting isomerized imine is useful as an intermediate for synthesis of agriculture compounds.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)[CH:7]=[CH:6][C:5]=1[OH:22])[CH:2]=[CH2:3].[H][H]>C(O)C.Cl.[Pd]>[CH2:1]([C:4]1[CH:9]=[C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)[CH:7]=[CH:6][C:5]=1[OH:22])[CH2:2][CH3:3]
Reactant: [H][H]
Reactant: C=CCc1cc(N2CCN(c3ccncc3)CC2)ccc1O
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCCc1cc(N2CCN(c3ccncc3)CC2)ccc1O
Yield: 94 %

Procedure:
The product from Example 134, step (ii) (0.74 g) in ethanol (25 ml) and 1N hydrochloric acid (2.5 ml) was hydrogenated at room temperature and atmospheric pressure over 10% palladium charcoal (0.15 g) until uptake of hydrogen was complete. Catalyst was removed by filtration through diatomaceous earth and the filtrate evaporated. The residue was triturated with a mixture of ethyl acetate (25 ml) and saturated sodium bicarbonate solution (25 ml) and the insoluble solid was filtered and washed with water and ethyl acetate. The aqueous layer of the filtrate was extracted twice with dichloromethane and the combined organic extracts evaporated. The residue was combined with the ethyl acetate-insoluble material and treated with boiling ethanol (40 ml), unsoluble material being removed by filtration. Evaportion of the filtrate gave 2-n-propyl-4-[4-(4-pyridyl)piperazin-1-yl]phenol (0.7 g) as a solid NMR (d6DMSO) δ8.84-8.68(1H,m), 8.18(2H,d), 6.82(2H,m), 6.7(3H,m), 4.1(1H,m), 3.42(4H,t), 3.17(3H,s), 3.05(4H,t), 2.48(DMSO), 1.55(2H,m), 0.89(3H,t).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[S:10][CH2:11][CH2:12][CH2:13][O:14]C1CCCCO1>CO>[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[S:10][CH2:11][CH2:12][CH2:13][OH:14]
Reactant: Fc1ccc(SCCCOC2CCCCO2)c(F)c1
Agent: Cl
Solvent: CO
Product: OCCCSc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 94.7 %

Procedure:
1M Hydrochloric acid (10 mL) was added to a solution of 2-({3-[(2,4-difluorophenyl)thio]propyl}oxy)tetrahydro-2H-pyran (610 mg, 2.12 mmol) in methanol (10 mL) and stirred at RT for 40 minutes. The methanol was removed in vacuo and the residue adjusted to pH 6 then extracted into ethyl acetate (3×50 mL). The combined organics were washed with brine (50 mL), dried (MgSO4), filtered and reduced in vacuo to give the desired compound as a colourless oil (410 mg). 1H NMR δ (CDCl3): 1.38 (t, 1H), 1.83 (quintet, 2H), 2.97 (t, 2H), 3.77 (q, 2H), 6.81-6.87 (m, 2H), 7.38-7.45 (m, 1H)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][OH:10]>C(Cl)Cl.O=[Mn]=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]=[O:10]
Reactant: OCc1cc(F)ccc1Br
Agent: O=[Mn]=O
Solvent: ClCCl
Product: O=Cc1cc(F)ccc1Br
Temperature: 25 °C
Reaction time: 48 h
Yield: 92.1 %

Procedure:
To the solution of (2-bromo-5-fluoro-phenyl)methanol (0.852 g, 4.156 mmol) in DCM (15 ml) was added MnO2 (4.254 g, 85%, 41.56 mmol). The mixture was stirred at room temperature for two days, and then filtered and washed with DCM. The filtrate was concentrated to afford 777 mg 2-bromo-5-fluoro-benzaldehyde (92% yield). The newly made aldehyde (0.777 g, 3.828 mmol) was then dissolved in anhydrous THF (10 ml) and cooled to 0° C. Trifluoromethyl trimethylsilane (1.13 ml, 7.656 mmol) was added, and followed by tetrabutyl ammonium fluoride (0.020 g, 0.076 mmol). The temperature was then allowed to warm to room temperature. The mixture was stirred for 5 h at room temperature, then diluted with ethyl acetate, washed with water, brine and dried by MgSO4. The solvent was removed under reduced pressure to give 2-bromo-5-fluoro-phenyl)2,2,2-trifluoro-ethanol, 1.1 g (90% purity) as a crude product, which was used for the next step without further purification.
Reaction SMILES: C[O:2][C:3](=[O:27])[C@@H:4]([N:9]1[CH2:13][C:12]2=[CH:14][C:15]3[C:16]([O:24][CH3:25])=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[C:20]=3[O:21][CH:11]2[C:10]1=[O:26])[CH2:5][CH:6]([CH3:8])[CH3:7].O.[OH-].[Li+].O1C[CH2:34][CH2:33][CH2:32]1.O>>[CH:6]1([CH2:5][C@H:4]([N:9]2[CH2:13][C:12]3[CH2:14][C:15]4[C:16]([O:24][CH3:25])=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[C:20]=4[O:21][C:11]=3[C:10]2=[O:26])[C:3]([OH:2])=[O:27])[CH2:8][CH2:34][CH2:33][CH2:32][CH2:7]1
Reactant: C1CCOC1
Reactant: COC(=O)[C@H](CC(C)C)N1CC2=Cc3c(OC)ccc(OC)c3OC2C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(OC)c2c1CC1=C(O2)C(=O)N([C@@H](CC2CCCCC2)C(=O)O)C1
Yield: 71.4 %

Procedure:
A solution of (S)-2-(5,8-dimethoxy-3-oxo-3,3a-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-4-methyl pentanoic acid methyl ester (0.58 g, 1.39 mmol) and lithium hydroxide monohydrate (0.64 g, 5.22 mmol) was stirred at 25° C. for 2 hours in tetrahydrofuran-water (3:1) mixture (25 mL). The reaction mixture was concentrated in vacuo to remove tetrahydrofuran, and the residue was acidified with 2N hydrochloric acid, and diluted with water. The resulting solution was extracted with ethyl acetate (3×). The combined organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed in vacuo to afford (S)-3-cyclohexyl-2-(5,8-dimethoxy-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-propionic acid (0.4 g, 71.4%).
Reaction SMILES: [CH2:1]([N:8]([CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])=[CH:15][CH:14]=1)CC)[C:2]1C=CC=CC=1>C(O)C.[Pd]>[CH2:1]([NH:8][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])=[CH:15][CH:14]=1)[CH3:2]
Reactant: CCN(CCc1ccc(NS(C)(=O)=O)cc1)Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCNCCc1ccc(NS(C)(=O)=O)cc1

Procedure:
N-Benzyl-N-ethyl-4-methanesulphonamidophenethylamine (4.3 g, 12.9 mmole) was stirred under a hydrogen atmosphere (50 p.s.i.=344.7 kPa) in ethanol (50 ml) containing 10% Pd/C (0.5 g) for 5 hours. The mixture was then filtered, evaporated and the residue triturated with ether to give the title compound, yield 2.6 g, m.p. 125°-128°.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])=[C:6]([O:13][CH3:14])[CH:5]=[CH:4][C:3]=1[C:15](=[O:26])[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:34][C:35]([O:37][CH3:38])=[O:36]>CC(C)=O>[CH3:14][O:13][C:6]1[CH:5]=[CH:4][C:3]([C:15](=[O:26])[CH2:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=2)=[C:2]([O:1][CH2:34][C:35]([O:37][CH3:38])=[O:36])[C:7]=1[CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11]
Reactant: COC(=O)CBr
Reactant: COc1ccc(CCC(=O)c2ccc(OC)c(CCC(C)C)c2O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1c(C(=O)CCc2ccc(OC)cc2)ccc(OC)c1CCC(C)C
Reaction time: 0.5 h
Yield: 80.9 %

Procedure:
Then, 21.5 g of 1-(2-hydroxy-4-methoxy-3-isopentylphenyl)-3-(4-methoxyphenyl)-1-propanone was dissolved in 150 ml of anhydrous acetone, and 41.6 g of anhydrous potassium carbonate was added to the solution and the mixture was stirred for 30 minutes. Then, 18.4 g of methyl α-bromoacetate was added to the reaction mixture, and the mixture was stirred at room temperature for 5 days to effect reaction. After the reaction, the reaction mixture was extracted with diethyl ether and the solvent was removed from the extract, and the obtained residue was subjected to the silica gel chromatography (eluting solvent: n-hexane/ethyl acetate=8/1) to obtain 20.9 g (yield=80.9%) of 1-(4-methoxy-2-methoxycarbonylmethoxy-3-isopentylphenyl)-3-(4-methoxyphenyl)-1-propanone in the form of a colorless oil.
Reaction SMILES: [Na].[CH3:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][OH:9].[Br:10][CH2:11][CH2:12][CH2:13][CH2:14]Br>>[Br:10][CH2:11][CH2:12][CH2:13][CH2:14][O:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4][O:3][CH3:2]
Reactant: COCCOCCO
Reactant: BrCCCCBr
Agent: [Na]
Product: COCCOCCOCCCCBr

Procedure:
This compound is prepared in a way similar to that in paragraph 1/ of example 1) by reacting the sodium salt of diethylene glycol monomethyl ether with an excess of 1,4-dibromobutane. Column purification gives a yellow-colored oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:12][O:13][C:14]2[CH:15]=[N:16][C:17]([CH:21]3[CH2:23][CH2:22]3)=[C:18]([Cl:20])[CH:19]=2)=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].[CH3:24][N:25]([C:27](ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.CN[N:59](NC)[SH:60](=[O:62])=[O:61]>ClCCl>[CH2:15]([NH:16][CH2:17][CH3:18])[CH3:14].[Cl:1][C:2]1[C:3]([CH2:12][O:13][C:14]2[CH:15]=[N:16][C:17]([CH:21]3[CH2:23][CH2:22]3)=[C:18]([Cl:20])[CH:19]=2)=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([NH:59][S:60]([N:25]([CH3:27])[CH3:24])(=[O:62])=[O:61])=[O:8]
Reactant: CNN(NC)[SH](=O)=O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1cc(Cl)c(COc2cnc(C3CC3)c(Cl)c2)cc1F
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCNCC
Product: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(COc2cnc(C3CC3)c(Cl)c2)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 18.7 %

Procedure:
To a stirred solution of 5-chloro-4-(((5-chloro-6-cyclopropylpyridin-3-yl)oxy)methyl)-2-fluorobenzoic acid (Preparation 27, 200 mg, 0.56 mmol) in dichloromethane (20 mL) was added HATU (256 mg, 0.67 mmol) and diisopropylethylamine (0.30 mL, 1.79 mmol). The reaction mixture was stirred at room temperature for 15 minutes before the addition of N,N-dimethylamino sulphonamide (209 mg, 1.68 mmol). The reaction mixture was stirred under nitrogen at room temperature for 18 hours. Upon completion the reaction mixture was washed with aqueous NH4Cl (15 mL) and brine (15 mL). The organic extracts were dried (MgSO4) and evaporated under vacuum to give the crude product as an orange oil, which was purified by column chromatography on silica (eluting with 1:1 cyclohexane/EtOAc). The partially purified product was dissolved in DMSO (2 mL) and purified by reverse phase chromatography (0-90% acetonitrile/water containing 0.1% formic acid) to afford the title compound as a beige solid (28 mg, 11%).
Reaction SMILES: [CH3:1][O:2][S:3]([F:6])(=[O:5])=[O:4].[C:7]([C:15]1[C:16](=[O:27])[O:17][C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[C:20]([O:25][CH3:26])[CH:19]=2)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[N:10][CH:9]=1>ClCCl>[S:3]([F:6])([O-:5])(=[O:4])=[O:2].[CH3:26][O:25][C:20]1[CH:19]=[C:18]2[C:23]([CH:24]=[C:15]([C:7]([C:8]3[CH:9]=[N+:10]([CH3:1])[CH:11]=[CH:12][CH:13]=3)=[O:14])[C:16](=[O:27])[O:17]2)=[CH:22][CH:21]=1
Reactant: COS(=O)(=O)F
Reactant: COc1ccc2cc(C(=O)c3cccnc3)c(=O)oc2c1
Solvent: ClCCl
Product: COc1ccc2cc(C(=O)c3ccc[n+](C)c3)c(=O)oc2c1
Product: O=S(=O)([O-])F

Procedure:
Two milliliters of methylfluorosulfonate was added to a stirred solution of 1.5 g 3-nicotinoyl-7-methoxycoumarin in 120 ml dichloromethane.
Reaction SMILES: FC(F)(F)S(C1C=CC(N)=CC=1)(=O)=O.C(N(CC)CC)C.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.[F:34][C:35]([F:50])([F:49])[S:36]([C:39]1[CH:44]=[CH:43][C:42]([NH:45][C:46](Cl)=[O:47])=[CH:41][CH:40]=1)(=[O:38])=[O:37].[CH3:51][Si:52]([CH3:72])([CH3:71])[CH2:53][CH2:54][O:55][CH2:56][N:57]1[C:61]2=[N:62][CH:63]=[CH:64][CH:65]=[C:60]2[C:59]([CH2:66][NH:67][CH:68]([CH3:70])[CH3:69])=[CH:58]1>>[CH3:70][CH:68]([N:67]([CH2:66][C:59]1[C:60]2[C:61](=[N:62][CH:63]=[CH:64][CH:65]=2)[N:57]([CH2:56][O:55][CH2:54][CH2:53][Si:52]([CH3:71])([CH3:51])[CH3:72])[CH:58]=1)[C:46]([NH:45][C:42]1[CH:43]=[CH:44][C:39]([S:36]([C:35]([F:50])([F:49])[F:34])(=[O:38])=[O:37])=[CH:40][CH:41]=1)=[O:47])[CH3:69]
Reactant: CC(C)NCc1cn(COCC[Si](C)(C)C)c2ncccc12
Reactant: O=C(Cl)Nc1ccc(S(=O)(=O)C(F)(F)F)cc1
Agent: Nc1ccc(S(=O)(=O)C(F)(F)F)cc1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)N(Cc1cn(COCC[Si](C)(C)C)c2ncccc12)C(=O)Nc1ccc(S(=O)(=O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 38 %

Procedure:
To a solution of 4-[(trifluoromethyl)sulfonyl]aniline (180 mg, 0.80 mmol) in 2 mL dichlroethane at 0° C. was added triethylamine (0.250 mL, 1.76 mmol) and triphosgene (71 mg, 0.24 mmol). The solution was allowed to stir at ambient temperature for 10 min. To the crude reaction mixture of {4-[(trifluoromethyl)sulfonyl]phenyl}carbamic chloride was added N-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]propan-2-amine (256 mg, 0.80 mmol) and the reaction was allowed to stir at ambient temperature for 16 h. The mixture was concentrated and partitioned between saturated NaHCO3 and ethylacetate. The organics were washed with water and brine, then dried over Na2SO4, filtered and concentrated. The filtrate was concentrated and purified by silica gel chromatography to give 1-propan-2-yl-3-{4-[(trifluoromethyl)sulfonyl]phenyl}-1-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]urea (38%). LCMS [M+H]+=571.2.
Reaction SMILES: [CH:1]1([N:4]([CH3:16])[CH:5]2[CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6]2)[CH2:3][CH2:2]1.O1CCOCC1>C(Cl)Cl.Cl>[CH:1]1([N:4]([CH3:16])[CH:5]2[CH2:8][NH:7][CH2:6]2)[CH2:3][CH2:2]1
Reactant: CN(C1CC1)C1CN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CN(C1CC1)C1CNC1
Temperature: 20 °C
Reaction time: 21 h

Procedure:
Combine a solution of tert-butyl 3-(cyclopropyl(methyl)amino)azetidine-1-carboxylate (73 mg, 0.323 mmol) in methylene chloride (3 mL) and 4 M HCl in dioxane (0.323 mL, 1.290 mmol) and the solution stirred at 20° C. for 4 hours then added 4 M HCl in dioxane (0.323 mL, 1.290 mmol) and stirred at 20° C. for 21 h. The solution was then concentrated in vacuo to give the title compound as a hydrochloride salt which was used without further purification.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][NH:17][C:18]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]#[N:28])[CH:22]=2)=[O:19])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:29][CH2:30][C:31]([O:33][CH3:34])=[O:32]>CC(C)=O>[Br-:29].[CH2:1]([CH:8]1[CH2:9][CH2:10][N+:11]([CH2:30][C:31]([O:33][CH3:34])=[O:32])([CH2:14][CH2:15][CH2:16][NH:17][C:18]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]#[N:28])[CH:22]=2)=[O:19])[CH2:12][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1cccc(NC(=O)NCCCN2CCC(Cc3ccccc3)CC2)c1
Reactant: COC(=O)CBr
Solvent: CC(C)=O
Product: COC(=O)C[N+]1(CCCNC(=O)Nc2cccc(C#N)c2)CCC(Cc2ccccc2)CC1
Product: [Br-]
Reaction time: 16 h
Yield: 71 %

Procedure:
4-benzyl-1-[3-(3-cyanophenylaminocarbonylamino)prop-1-yl]piperidine (50 mg, 0.133 mmol, 1 eq), was dissoved in acetone at 25° C. under N2 then methyl bromoacetate (13 μL, 0.133 mmol, 1 eq),was added. After 16 hours, the solvent was removed in vacuo and the residue was purified over silica gel in 100% EtOAc to 8:2 chloroform/MeOH to yield 50 mg of white solids as product. NMR (300 MHz, CD3OD) δ8.00-7.80 (m, 1H) ; 7.65-7.45 (m, 1H); 7.45-7.33 (m, 1H); 7.33-7.05 (m, 6H); 4.50-4.25 (m, 2H); 4.00-3.60 (m, 5H); 3.50-3.20 (m, 6H); 2.70-2.50 (m, 2H); 2.10-1.60 (m, 7H).
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[C:7]([O:16]C(OC(C)(C)C)=O)[C:6]([C:24]([F:27])([F:26])[F:25])=[CH:5][CH:4]=1.[Cl:28][C:29]1[N:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1>>[Cl:28][C:29]1[N:34]=[CH:33][C:32]([O:35][CH2:2][C:3]2[C:8]([C:9]([O:11][C:12]([CH3:15])([CH3:13])[CH3:14])=[O:10])=[C:7]([OH:16])[C:6]([C:24]([F:25])([F:26])[F:27])=[CH:5][CH:4]=2)=[CH:31][CH:30]=1
Reactant: CC(C)(C)OC(=O)Oc1c(C(F)(F)F)ccc(CBr)c1C(=O)OC(C)(C)C
Reactant: Oc1ccc(Cl)nc1
Product: CC(C)(C)OC(=O)c1c(COc2ccc(Cl)nc2)ccc(C(F)(F)F)c1O
Yield: 84 %

Procedure:
According to a method similar to Example (2-3) and Example (33-5), from tert-butyl 6-(bromomethyl)-2-[(tert-butoxycarbonyl)oxy]-3-(trifluoromethyl)benzoate (6.22 g, 13.7 mmol) obtained in Example (28-5) and 6-chloro-3-pyridinol (1.77 g, 13.7 mmol), tert-butyl 6-{[(6-chloro-3-pyridinyl)oxy]methyl}-2-hydroxy-3-(trifluoromethyl)benzoate was obtained (4.61 g, two-step total yield: 84%).