Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][N:2]([C:7]([O:9][CH2:10][C:11]#[CH:12])=[O:8])[CH2:3][C:4]([OH:6])=[O:5].N12CCCN=C1CCCCC2.[CH2:24](Br)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>C(#N)C>[CH2:24]([O:5][C:4](=[O:6])[CH2:3][N:2]([C:7]([O:9][CH2:10][C:11]#[CH:12])=[O:8])[I:1])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: C#CCOC(=O)N(I)CC(=O)O
Reactant: CCCCCCCCBr
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: C#CCOC(=O)N(I)CC(=O)OCCCCCCCC
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
N-Iodopropargyloxycarbonyl glycine (compound 1, 6.50 g., 22.97 mmole) was dissolved in anhydrous acetonitrile (100 ml.), treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (3.5 ml., 23.40 mmole) and stirred at room temperature for 5 minutes. n-Octylbromide (4.00 ml., 23.16 mmole) was added and the reaction mixture was stirred at room temperature for 17 hours, then heated at reflux temperature for 6 hours. The reaction mixture was concentrated under reduced pressure and the resultant residue was dissolved in ethyl acetate. The ethyl acetate solution was washed with water, 5% aqueous citric acid, saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, dried over magnesium chloride, filtered and concentrated under reduced pressure. The resultant residue was purified utilizing column chromatography (silica gel, 200 g.) and eluted with ethyl acetate/hexane (1:10) to afford N-Iodopropargyloxycarbonyl glycine n-octyl ester (Compound 3) as a clear colorless liquid which crystallized on standing. m.p. 43°-46° C. Elemental Analysis: C14H22NO4 l: Calc'd. C: 42.55, H: 5.61, N: 3.54. Found: C: 43.73, H: 5.62, N: 3.54. (Ethyl acetate was present in 0.5 mole %). 1H-NMR (200 MHz, CDCl3) δppm =0.89, m, 3H (--CH3), 1.30, m, 10H (--(CH2)5 --CH3), 1.64, m, 2H (--CH2 --), 4.0,d, J=3.4 Hz., 2H (--N--CH2 --), 4.1-4.2, m, 2H (--CH2 --), 4.86, s, 2H (C--CH2 --O), 5.32, m, 1H (--NH--). IR (neat) 3460, 2920, 2850, 2200, 1740, 1560, 1480, 1400, 1360, 1200, 1060, 980 cm-1.
Reaction SMILES: [CH3:1][CH:2]1[O:7][CH:6]([CH3:8])[CH2:5][NH:4][CH2:3]1.[CH2:9]1[O:12][CH:10]1[CH3:11]>>[CH3:8][CH:6]1[O:7][CH:2]([CH3:1])[CH2:3][N:4]([CH2:9][CH:10]([OH:12])[CH3:11])[CH2:5]1
Reactant: CC1CNCC(C)O1
Reactant: CC1CO1
Product: CC(O)CN1CC(C)OC(C)C1

Procedure:
The compound 2,6-dimethyl-N-(2-hydroxypropyl) morpholine was prepared by the method of Example 1 from 100.56 grams 2,6-dimethylmorpholine (0.87 moles) and 50.53 grams of propylene oxide (0.87 moles). Distillation of the reaction mixture gave 116.1 grams (76.8%) of the alcohol as a pale yellow oil, bp 70°-72° C. at 0.25 mm of Hg. The following elemental analysis was obtained: calc. 62.4 C, 11.1 H, 8.1 N; found 62.0 C, 10.8 H, 8.0 N.
Reaction SMILES: [N+:1]([C:4]([N+:13]([O-:15])=[O:14])([N+:10]([O-:12])=[O:11])[CH2:5][O:6][CH2:7][CH:8]=[CH2:9])([O-:3])=[O:2].ClC1C=C(C=CC=1)C(OO)=[O:21]>C(Cl)(Cl)Cl>[N+:1]([C:4]([N+:10]([O-:12])=[O:11])([N+:13]([O-:15])=[O:14])[CH2:5][O:6][CH2:7][CH:8]1[O:21][CH2:9]1)([O-:3])=[O:2]
Reactant: C=CCOCC([N+](=O)[O-])([N+](=O)[O-])[N+](=O)[O-]
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])C(COCC1CO1)([N+](=O)[O-])[N+](=O)[O-]
Temperature: 70 °C
Yield: 60.5 %

Procedure:
A solution of allyl trinitroethyl ether (111 g, 502 mmol) in chloroform (100 ml) was added to the mechanically stirred mixture of m-chloroperoxybenzoic acid (102 g, 590 mmol) and chloroform (450 ml). The mixture was refluxed at 70° C. for 6 h under nitrogen. The mixture was cooled with an ice bath for 30 min and filtered. The filtrate was concentrated and additional precipitate was filtered out. The filtrate was diluted with methylene chloride, washed with 10% sodium thiosulfate, saturated sodium bicarbonate, water and dried. Solvent was removed under vacuum. The golden yellow liquid residue (109 g) was chromatographed in portions using silica gel and methylene chloride to give 72 g (60% yield) of glycidyl trinitroethyl ether: 1HNMR (CDCl3) 2.64 (d of d, 1H), 2.87 (t, 1H), 3.22 (m, 1H), 3.53 (d of d, 1H), 4.15 (d of d, 1H), 4.85 (AB quartet, 2H) ppm; IR (neat): 3067 (w), 3006 (m), 2932 (m), 1591 (br, vs), 1454 (m), 1340 (m), 1305 (s), 1254 (m), 1161 (m), 1138 (s), 1082 (m), 1032 (w), 988 (w), 945 (w), 900 (m), 880 (m), 855 (m), 804 (s), 782 (m) cm−1.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5](COCC[Si](C)(C)C)[C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[CH3:26])[CH:22]=[C:21]([C:29]#[N:30])[CH:20]=2)[C:12]=1[F:31])=[O:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]2[CH:24]=[C:23]([C:25]([F:27])([F:28])[CH3:26])[CH:22]=[C:21]([C:29]#[N:30])[CH:20]=2)[C:12]=1[F:31])=[O:8]
Reactant: CC(F)(F)c1cc(C#N)cc(Oc2c(Cl)ccc(CNC(=O)c3c(Cl)ncn3COCC[Si](C)(C)C)c2F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(F)(F)c1cc(C#N)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]cnc3Cl)c2F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.2 %

Procedure:
To a solution of 4-chloro-N-[(4-chloro-3-{[3-cyano-5-(1,1-difluoroethyl)phenyl]oxy}-2-fluorophenyl)methyl]-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (59 mg, 0.098 mmol) in DCM (6 ml) was added TFA (2.0 mL) and the reaction mixture was stirred at RT for 3 hours. The reaction mixture was purified via reverse phase HPLC to give 4-chloro-N-[(4-chloro-3-{[3-cyano-5-(1,1-difluoroethyl)phenyl]oxy}-2-fluorophenyl)methyl]-1H-imidazole-5-carboxamide (28 mg, 0.060 mmol, 61% yield). 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.72 (s, 1H), 7.63 (s, 1H), 7.30-7.42 (m, 3H), 7.28 (s, 1H), 4.63 (s, 2H), 1.90 (t, 3H). LC-MS (ES+) m/z 469.08, [M+H].
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[C:8]([C:10]#[C:11][C:12]2[N:13]=[C:14]([CH3:17])[NH:15][CH:16]=2)[CH:7]=[CH:6][N:5]=1.Br.Br[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1.O>C1COCC1>[N:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[CH2:20][N:15]1[CH:16]=[C:12]([C:11]#[C:10][C:8]2[CH:7]=[CH:6][N:5]=[C:4]([CH3:3])[CH:9]=2)[N:13]=[C:14]1[CH3:17]
Reactant: Cc1cc(C#Cc2c[nH]c(C)n2)ccn1
Reactant: BrCc1ccccn1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C#Cc2cn(Cc3ccccn3)c(C)n2)ccn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (69 mg, 55%, 1.59 mmol) was suspended in 2 mL dry THF. A solution of 2-methyl-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine (95 mg, 0.48 mmol) in 8 mL dry THF was added and the reaction mixture was stirred at room temperature for 30 min. 2-(Bromomethyl)pyridine hydrobromide (162 mg, 0.63 mmol) was added and stirring was continued overnight. The reaction mixture was poured into 70 mL water and extracted three times with ethyl acetate (70 mL each). The combined organic extracts were dried with sodium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (dichloromethane/methanol 100:0→90:10 gradient) and a mixture of two regioisomers was obtained. This mixture could be separated by crystallization from diethylether and the desired compound was obtained as a white solid (35 mg, 25%), MS: m/e=289.1 (M+H30).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:13][CH:12]=[CH:11][CH2:10][CH2:9][CH:8]=[CH:7][CH2:6][CH:5]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[N:4]=[CH:3]1.S(O)(O)(=O)=O.[NH2:26][OH:27].Cl>O>[CH3:1][C:2]([CH3:20])([CH2:13][CH:12]=[CH:11][CH2:10][CH2:9][CH:8]=[CH:7][CH2:6][CH:5]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[NH2:4])[CH:3]=[N:26][OH:27]
Reactant: CCCCCCC1CC=CCCC=CCC(C)(C)C=N1
Reactant: NO
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: O
Product: CCCCCCC(N)CC=CCCC=CCC(C)(C)C=NO
Yield: 200.5 %

Procedure:
The procedure described in Example (1b) is repeated, except that 113 g (0.41 mol) of 3,3-dimethyl-12-hexyl-1-aza-1,5,9-cyclododecatriene, 33 g (0.202 mol) of hydroxylamine sulfate, 50 g of concentrated hydrochloric acid and 250 ml of water are used. Working up yields 125 g (0.405 mol) of 2,2-dimethyl-11-n-hexyl-11-amino-undeca-4,8-dienal oxime; yield 99% of theory.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:33]=[CH:32][C:7]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=3)=[O:16])[CH2:11][CH2:10]2)=[CH:6][CH:5]=1.C([Si]([O:51][C:52]1[CH:57]=[CH:56][C:55]([O:58][CH2:59][CH:60]2[CH2:62][O:61]2)=[CH:54][CH:53]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>C(Cl)(Cl)Cl.CO>[CH3:31][O:30][C:24]1[CH:23]=[C:22]([CH2:21][CH2:20][CH2:19][CH2:18][NH:17][C:15]([N:12]2[CH2:13][CH2:14][CH:9]([NH:8][C:7]3[CH:32]=[CH:33][C:4]([CH2:3][CH2:2][NH:1][CH2:62][CH:60]([OH:61])[CH2:59][O:58][C:55]4[CH:56]=[CH:57][C:52]([OH:51])=[CH:53][CH:54]=4)=[CH:5][CH:6]=3)[CH2:10][CH2:11]2)=[O:16])[CH:27]=[CH:26][C:25]=1[O:28][CH3:29]
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccc(CCCCNC(=O)N2CCC(Nc3ccc(CCN)cc3)CC2)cc1OC
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1ccc(CCCCNC(=O)N2CCC(Nc3ccc(CCNCC(O)COc4ccc(O)cc4)cc3)CC2)cc1OC
Yield: 52.8 %

Procedure:
4-[4-(2-Aminoethyl)anilino]-N-[4-(3,4-dimethoxyphenyl)butyl]-1-piperidinecarboxamide (0.79 g, 1.42 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.36 g, 0.89 mmol) according to Procedure G (eluant: 20:1 chloroform-methanol) to give the title compound (0.40 g, 0.47 mmol).
Reaction SMILES: [CH:1](=[C:3]1[C:9](=[O:10])[N:8]2[CH:4]1[CH2:5][C:6]([S:24][CH2:25][CH2:26][NH:27]C(OCC1C=CC([N+]([O-])=O)=CC=1)=O)=[C:7]2[C:11]([O:13]CC1C=CC([N+]([O-])=O)=CC=1)=[O:12])[CH3:2].C1COCC1>O=[Pt]=O.CCO>[CH2:1]([CH:3]1[C:9](=[O:10])[N:8]2[CH:4]1[CH2:5][C:6]([S:24][CH2:25][CH2:26][NH2:27])=[C:7]2[C:11]([OH:13])=[O:12])[CH3:2]
Reactant: CC=C1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SCCNC(=O)OCc3ccc([N+](=O)[O-])cc3)CC12
Agent: O=[Pt]=O
Solvent: C1CCOC1
Solvent: CCO
Product: CCC1C(=O)N2C(C(=O)O)=C(SCCN)CC12
Reaction time: 2.5 h

Procedure:
A mixture of p-nitrobenzyl 6-ethylidene-3-[2-(p-nitrobenzyloxycarbonylamino)ethylthio]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (37 mg), PtO2 (40 mg), THF (4 ml) and EtOH (2 ml) is hydrogenated at 50 psi and 25° C., for 2.5 hrs. The catalyst is filtered off and washed thoroughly with 0.1 M pH 7 phosphate buffer (5 ml). The combined filtrate and washings are concentrated in vacuo to remove most of the organic solvents. The aqueous residue is chromatographed on a column of Dowex-50×4 (Na Form) ion-exchange resin; the product being eluted with deionized H2O. The appropriate fractions are combined and lyophilized to afford 6-ethyl-3-(2-aminoethyl)thio-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([N+:9]([O-])=O)[C:3]=1[CH3:12].N1CCC[CH2:14]1.CC(O)=O.[OH-].[Na+]>O1CCOCC1.[Fe]>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]2[C:3]=1[CH:12]=[CH:14][NH:9]2
Reactant: Cc1c(Br)cc(F)cc1[N+](=O)[O-]
Reactant: C1CCNC1
Agent: [Fe]
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: Fc1cc(Br)c2cc[nH]c2c1
Temperature: 100 °C
Yield: 27 %

Procedure:
To a solution of 1-bromo-5-fluoro-2-methyl-3-nitrobenzene (4.69 g, 20 mmol) in 1,4-dioxane (25 mL) at RT was slowly added DMF dimethylacetal (13.3 mL) and pyrrolidine (1.7 mL). The solution was heated at 100° C. for 18 h, then concentrated in vacuo to give a dark residue. To the residue was added HOAc (30 mL) and iron powder (11 g, 200 mmol) then the mixture was heated to reflux for 1 h, cooled to RT, neutralized by addition of 50% aq. NaOH and extracted with EtOAc (2×200 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by SiO2 chromatography eluting with an EtOAc/petroleum ether gradient (5 to 30% EtOAc) to afford 1.16 g (27%) of 4-bromo-6-fluoro-1H-indole (224)—as brown solid: MS (ESI) m/z=213.9 [M+1]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH3:17])[CH3:15])[C:11]([Cl:18])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28](=[O:48])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N:35]2[C:39]([CH2:40][O:41][CH:42]3[CH2:47][CH2:46][CH2:45][CH2:44][O:43]3)=[CH:38][N:37]=[N:36]2)[CH:30]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH3:17])[CH3:15])[C:11]([Cl:18])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28](=[O:48])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N:35]2[C:39]([CH2:40][O:41][CH:42]3[CH2:47][CH2:46][CH2:45][CH2:44][O:43]3)=[CH:38][N:37]=[N:36]2)[CH:30]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2nncc2COC2CCCCO2)c1
Product: CCN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3nncc3COC3CCCCO3)c2)cc1Cl

Procedure:
The title compound was prepared from [2-amino-4-chloro-5-(ethyl-methyl-amino)-phenyl]-carbamic acid tert-butyl ester (Example J7) (300 mg, 1.0 mmol) and (RS)-3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionic acid tert-butyl ester (Example K5) (402 mg, 1.0 mmol) according to the general procedure M. Obtained as a yellow foam (500 mg).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH3:5][C:6]([C:9]1[C:14]([OH:15])=[C:13]([C:16]([CH3:19])([CH3:18])[CH3:17])[N:12]=[C:11]([C:20](=[O:24])[CH:21](Br)[CH3:22])[N:10]=1)([CH3:8])[CH3:7]>O.CC(C)=O>[N:1]([CH:21]([CH3:22])[C:20]([C:11]1[N:10]=[C:9]([C:6]([CH3:5])([CH3:8])[CH3:7])[C:14]([OH:15])=[C:13]([C:16]([CH3:19])([CH3:18])[CH3:17])[N:12]=1)=[O:24])=[N+:2]=[N-:3]
Reactant: CC(Br)C(=O)c1nc(C(C)(C)C)c(O)c(C(C)(C)C)n1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CC(N=[N+]=[N-])C(=O)c1nc(C(C)(C)C)c(O)c(C(C)(C)C)n1
Reaction time: 2 h
Yield: 96.2 %

Procedure:
A solution of 1.2 g (18 mmol) of sodium azide in 9.0 mL of water was added dropwise to a solution of 5.5 g (16 mmol) of 1-[4,6-bis(1,1-dimethylethyl)-5-hydroxy-2-pyrimidinyl]-2-bromo-1-propanone in 35 mL of acetone. The mixture was stirred for 2 hours then added to 100 mL of water and extracted with ethyl acetate. The organic layers were washed with brine, dried (anhydrous sodium sulfate), and evaporated to yield 4.7 g (96%) of the azide product, mp 91° C.-92° C., suitable for further synthesis.
Reaction SMILES: FC(F)(F)C([O:5][CH2:6][CH:7]1[CH:11]([CH2:12][N:13]2[CH:17]=[C:16]([C:18]3[CH:23]=[C:22]([CH3:24])[CH:21]=[C:20]([NH:25][C:26]4[N:31]=[C:30]([CH:32]([F:34])[F:33])[CH:29]=[CH:28][N:27]=4)[CH:19]=3)[CH:15]=[N:14]2)[O:10][C:9](=[O:35])[NH:8]1)=O.C(=O)([O-])[O-].[K+].[K+]>CO.O>[F:34][CH:32]([F:33])[C:30]1[CH:29]=[CH:28][N:27]=[C:26]([NH:25][C:20]2[CH:19]=[C:18]([C:16]3[CH:15]=[N:14][N:13]([CH2:12][CH:11]4[O:10][C:9](=[O:35])[NH:8][CH:7]4[CH2:6][OH:5])[CH:17]=3)[CH:23]=[C:22]([CH3:24])[CH:21]=2)[N:31]=1
Reactant: Cc1cc(Nc2nccc(C(F)F)n2)cc(-c2cnn(CC3OC(=O)NC3COC(=O)C(F)(F)F)c2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1cc(Nc2nccc(C(F)F)n2)cc(-c2cnn(CC3OC(=O)NC3CO)c2)c1

Procedure:
A solution of (5-{[4-(3-{[4-(difluoromethyl)pyrimidin-2-yl]amino}-5-methylphenyl)-1H-pyrazol-1-yl]methyl}-2-oxo-1,3-oxazolidin-4-yl)methyl trifluoroacetate (80 mg, 0.15 mmol) and potassium carbonate (80 mg, 0.58 mmol) in methanol (3 mL) was stirred at 25° C. for 30 minutes. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford the crude product residue. The crude product residue was purified by prep-TLC (ethyl acetate) to give racemic 5-{[4-(3-{[4-(difluoromethyl)pyrimidin-2-yl]amino}-5-methylphenyl)-1H-pyrazol-1-yl]methyl}-4-(hydroxymethyl)-1,3-oxazolidin-2-one. MS ESI calc'd. for C20H21F2N6O3 [M+H]+ 431. found 431.
Reaction SMILES: [CH:1]1([CH2:6][C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15]O)=[CH:11][CH:10]=2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:19])=O.C([O-])([O-])=O.[K+].[K+]>C1C=CC=CC=1>[Cl:19][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([C:7](=[O:8])[CH2:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:10][CH:11]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(CC1CCCC1)c1ccc(CO)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Product: O=C(CC1CCCC1)c1ccc(CCl)cc1
Yield: 58.1 %

Procedure:
The product of Example F (450 mg, 0.002 mole) was dissolved in 5 mls of benzene and 250 mg of thionyl chloride was added. The mixture was refluxed for one hour. After cooling, the solution was poured into dilute K2CO3 and extracted with ethyl acetate. The organic phase was dried over Na2SO4, stripped and chromatographed on silica gel using 5% ethyl acetate/hexane as the eluent to give 275 mg of the title compound as an oil (56% yield).
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3](=[O:15])[C@@H:4]([CH2:12][O:13][CH3:14])[NH:5][C:6]1[CH2:10][S:9][C:8](=[O:11])[N:7]=1.[F:17][C:18]([F:39])([F:38])[C:19]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][C:20]=1[CH2:21][N:22]1[CH2:27][CH2:26][CH:25]([CH:28]=O)[CH2:24][CH2:23]1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:39][C:18]([F:17])([F:38])[C:19]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][C:20]=1[CH2:21][N:22]1[CH2:27][CH2:26][CH:25](/[CH:28]=[C:10]2/[C:6]([NH:5][C@@H:4]([C:3]([N:2]([CH3:1])[CH3:16])=[O:15])[CH2:12][O:13][CH3:14])=[N:7][C:8](=[O:11])[S:9]/2)[CH2:24][CH2:23]1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Reactant: COC[C@@H](NC1=NC(=O)SC1)C(=O)N(C)C
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: COC[C@@H](NC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1)C(=O)N(C)C
Temperature: 60 °C
Reaction time: 8 h
Yield: 45.1 %

Procedure:
To a solution of N,N,O-trimethyl-N2-(2-oxo-2,5-dihydro-1,3-thiazol-4-yl)-D-serinamide (736 mg) and 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (1018 mg) in 2-propanol (10 mL) was added piperidinium acetate (436 mg). The reaction mixture was stirred at 60° C. overnight, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) and recrystallized from ethyl acetate/heptane to give the title compound (766 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:12][CH2:11][C:10]3[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:9]=3[CH:8]([N:18]3[CH2:23][CH2:22][N:21]([C:24](=[O:32])[CH2:25][CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[CH2:20][CH2:19]3)[C:5]2=[N:6][CH:7]=1.[C:33]([N:37]=[C:38]=[O:39])([CH3:36])([CH3:35])[CH3:34]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:12][CH2:11][C:10]3[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:9]=3[CH:8]([N:18]3[CH2:19][CH2:20][N:21]([C:24](=[O:32])[CH2:25][CH:26]4[CH2:31][CH2:30][N:29]([C:38]([NH:37][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:39])[CH2:28][CH2:27]4)[CH2:22][CH2:23]3)[C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)N=C=O
Reactant: O=C(CC1CCNCC1)N1CCN(C2c3ccc(Cl)cc3CCc3cc(Br)cnc32)CC1
Solvent: ClCCl
Product: CC(C)(C)NC(=O)N1CCC(CC(=O)N2CCN(C3c4ccc(Cl)cc4CCc4cc(Br)cnc43)CC2)CC1
Temperature: 25 °C
Reaction time: 47 h
Yield: 85.5 %

Procedure:
1-(3-Bromo-8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)-4-[(4-piperidinyl)acetyl]piperazine (Preparative Example 10) (500 mg, 0.8 mmoles) was dissolved in anhydrous dichloromethane (5 ml) and tert-butyl isocyanate (383.8 mg, 3.2 mmoles) was added. The mixture was stirred under argon at 25° C. for 47 h. Additional tert-butyl isocyanate (191.4 mg, 1.6 mmoles) was added and the reaction was stirred for a total of 144 h. The solution was heated at 74° C. for 5 h and the stirred at 25° C. for an additional 24 h. The solution was chromatographed on silica gel using 2% (10% conc. NH4OH in methanol) dichloromethane as the eluant to give 421.8 mg of the title compound (Yield: 71%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@:10]([C:15]#[C:16][C:17]([O:19]CC)=O)([OH:14])[C@@H:9]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:28]([SnH:32]([CH2:37][CH2:38][CH2:39][CH3:40])[CH2:33][CH2:34][CH2:35][CH3:36])[CH2:29][CH2:30][CH3:31]>C1(C)C=CC=CC=1.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:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@:10]2([O:14][C:17](=[O:19])[C:16]([Sn:32]([CH2:33][CH2:34][CH2:35][CH3:36])([CH2:37][CH2:38][CH2:39][CH3:40])[CH2:28][CH2:29][CH2:30][CH3:31])=[CH:15]2)[C@@H:9]1[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: CCOC(=O)C#C[C@]1(O)CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCCC[Sn](CCCC)(CCCC)C1=C[C@@]2(CCCN(C(=O)OC(C)(C)C)[C@H]2c2ccccc2)OC1=O
Temperature: 23 °C
Reaction time: 2 h
Yield: 62.1 %

Procedure:
A mixture of (2S,3R)-ethyl 3-(1-tert-butoxycarbonyl-3-hydroxy-2-phenylpiperidin-3-yl)propynoate (Description 9, 524 mg, 1.4 mmol) and tetrakis(triphenylphosphine)palladium (0) (50 mg) in toluene (10 ml) was degassed with nitrogen for 30 min. Tributyl tin hydride (0.405 mM, 1.5 mmol) was added dropwise and the resulting mixture was stirred at 23° C. for 2 h. The solvent was evaporated under reduced pressure and the residue was taken up in ethyl acetate (50 ml). The mixture was washed with saturated aqueous sodium hydrogen carbonate (50 ml), dried (Na2SO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give the title compound as a gum (538 mg, 0.87 mmol, 62%). 1H NMR (250 MHz, CDCl3) δ7.63 (1H, s), 7.30 (5H, m), 5.11 (1H, m, 310 (1H, m) 2.19 (1H, m), 1.80 (3H, m), 1.30-150 (12H, m), 1.40 (9H), s), 1.02 (6H), m), and 0.88 (9H), t, J 7.22 Hz), m/z (ES+) 619 (M+1)
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]#[C:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C:15]#[N:16])[CH:10]=2)[N:6]=1.[Cl:17][C:18]1[N:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1>>[Cl:17][C:18]1[N:23]=[CH:22][C:21]([N:3]2[CH:4]=[C:5]([C:7]#[C:8][C:9]3[CH:14]=[CH:13][N:12]=[C:11]([C:15]#[N:16])[CH:10]=3)[N:6]=[C:2]2[CH3:1])=[CH:20][CH:19]=1
Reactant: OB(O)c1ccc(Cl)nc1
Reactant: Cc1nc(C#Cc2ccnc(C#N)c2)c[nH]1
Product: Cc1nc(C#Cc2ccnc(C#N)c2)cn1-c1ccc(Cl)nc1

Procedure:
The title compound, MS: m/e=320.0, 322.1 (M+H+), was prepared in accordance with the general method of example 7 from 4-(2-Methyl-1H-imidazol-4-ylethynyl)-pyridine-2-carbonitrile and 6-chloro-3-pyridinyl-boronic acid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:17][O:18][C:19]1[CH:24]=[C:23]([B:25]2[O:29][C:28]([CH3:31])([CH3:30])[C:27]([CH3:33])([CH3:32])[O:26]2)[CH:22]=[CH:21][C:20]=1[OH:34]>CN(C=O)C>[CH3:17][O:18][C:19]1[CH:24]=[C:23]([B:25]2[O:29][C:28]([CH3:31])([CH3:30])[C:27]([CH3:33])([CH3:32])[O:26]2)[CH:22]=[CH:21][C:20]=1[O:34][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1O
Reactant: ClCCCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1OCCCN1CCOCC1
Temperature: 25 °C

Procedure:
A solution of 4-(3-Chloro-propyl)-morpholine (460 mg, 2.75 mmol), Cs2CO3 (493 mg, 1.515 mmol) and 2-Methoxy-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol (703 mg, 2.75 mmol) in dry DMF (15 ml) are heated at 80° C. under argon for 24 h and then allowed to cool to RT. DMF is removed under HV and the residue is re-taken in EtOAc and washed with de-ionized water. The aqueous phase is re-extracted with EtOAc and the combined organic extracts are washed with saturated brine, dried over Na2SO4, filtered and concentrated under vacuum to dryness. After drying under HV, the title compound is obtained as a solid, Rt=0.878 min (Acquity HPLC BEH C18, 2.1×50 mm, 1.7 micron, detection 215 nM, 0.1 min 2% CH3CN in H2O, 2% to 100% CH3CN in H2O in 1.5 min, 0.4 min 100% CH3CN+0.1% TFA, flow rate 1.0 ml/min); MS: 378 (M+1)+.