Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][S:2]([OH:5])(=[O:4])=[O:3].[CH:6]1([CH2:9][CH2:10][CH2:11][CH2:12][OH:13])[CH2:8][CH2:7]1.[CH3:14][C:15]([CH3:17])=[O:16].OS(O)(=O)=O.[O:23]=[Cr:24](=[O:26])=[O:25].[CH3:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>O.CC(C)=O.CC(O)=O.CCOC(C)=O>[CH3:14][C:15]([CH3:17])=[O:16].[OH:4][S:2]([OH:5])(=[O:3])=[O:1].[O:23]=[Cr:24](=[O:26])=[O:25].[CH:29]1([CH2:30][CH2:31][CH2:32][C:15]([O:13][CH2:12][CH2:11][CH2:10][CH2:9][CH:6]2[CH2:8][CH2:7]2)=[O:16])[CH2:27][CH2:28]1
Reactant: CCCCCC
Reactant: OCCCCC1CC1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: O
Product: O=C(CCCC1CC1)OCCCCC1CC1
Temperature: 23 °C

Procedure:
Jones reagent is prepared by carefully adding H2SO4 (321 mL) to a cold solution of CrO3 (366 g) in H2O (600 mL) over a period of 0.5 h. In a 5-L 3-neck flask, equipped with mechanical stirrer, internal thermometer, and 1-L addition funnel is placed a solution of 4-cyclopropylbutan-1-ol (127.0 g) in acetone (300 mL). Stirring is commenced, and the solution is cooled below -10° C. with an ice/MeOH bath. The Jones reagent is added at a rate such that the temperature of the reaction mixture never exceeds +10° C. The reaction mixture becomes dark green and heterogenous. 300 mL of Jones reagent is added over 3.5 h and the reaction appears to be complete by TLC (hexane:EtOAc:HOAc, 3:1:0.05). An additional 50 mL Jones reagent is added, and the red color of the reagent persists. The reaction is quenched by the addition of isopropanol (80 mL), and the mixture is allowed to warm to 23° C. A small amount of green precipitate is filtered off, rinsed with acetone (3×200 mL), and discarded. The filtrate is evaporated to a biphasic mixture, poured onto 1.8 kg ice/water, and made alkaline to indicator paper with 50 wt % NaOH (133 g) added in portions. The resulting green solution is filtered to remove a small amount of solids which are discarded. The filtrate is extracted with Et20 (2×40 mL), and the Et20 layers are dried and evaporated to yield 4-cyclopropylbutyl 4-cyclopropylbutanoate. The aqueous layer is cooled in ice while it is acidified with 12N HCl (139 g). The resulting solution is extracted with EtOAc (3×1 L). The aqueous layer is discarded. The organic phases are combined, dried over MgSO4, filtered through paper and evaporated to yield 4-cyclopropylbutanoic acid as a faint green oil. This can be further purified by filtration through Celite and distillation at reduced pressure (0.2-0.4 mbar, 60°-90° C.).
Reaction SMILES: C(N)(C)C.FC1C(F)=C(F)C(F)=CC=1C(=O)C[C:17]([O:19]CC)=[O:18].[F:23][C:24]1[CH:25]=[C:26]2[C:31](=[C:32]([F:35])[C:33]=1[F:34])[N:30]([CH:36]([CH3:38])[CH3:37])[CH:29]=[C:28](C(O)=O)[C:27]2=[O:42]>>[F:23][C:24]1[CH:25]=[C:26]2[C:31](=[C:32]([F:35])[C:33]=1[F:34])[N:30]([CH:36]([CH3:37])[CH3:38])[C:29]([C:17]([OH:19])=[O:18])=[CH:28][C:27]2=[O:42]
Reactant: CC(C)n1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Reactant: CCOC(=O)CC(=O)c1cc(F)c(F)c(F)c1F
Solvent: CC(C)N
Product: CC(C)n1c(C(=O)O)cc(=O)c2cc(F)c(F)c(F)c21

Procedure:
Using the procedure of Example VV with isopropyl amine, 3.0 g (11.33 mmol) of 2,3,4,5-tetrafluoro-β-oxo-benzeneproprionic acid, ethyl ester was converted to 1.21 g of 6,7,8-trifluoro-1,4-dihydro-1-(1-methylethyl)-4oxo-3-quinolinecarboxylic acid, mp 256°-260° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH2:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:40])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:37]=[C:36]([CH3:38])[N:35]=[C:34]([CH3:39])[CH:33]=2)[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:38][C:36]1[CH:37]=[C:32]([C:28]2[CH:27]=[C:26]([C:24]3[CH2:23][C:22](=[O:40])[NH:21][C:9]4[CH:10]=[C:11]([C:17]([F:18])([F:20])[F:19])[C:12]([CH2:14][CH2:15][CH3:16])=[CH:13][C:8]=4[N:7]=3)[CH:31]=[CH:30][CH:29]=2)[CH:33]=[C:34]([CH3:39])[N:35]=1
Reactant: CCCc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cc(C)nc(C)c3)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3cc(C)nc(C)c3)c1)=N2

Procedure:
The title compound was prepared from (2-{3-[3-(2,6-Dimethyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-5-propyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M209) (295 mg, 0.52 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (197 mg, 84%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([CH3:18])[N:15]=[C:14]3[S:19][C:20]([C:30]#[C:31][CH2:32][N:33]4[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C:13]=23)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1>[Pd].C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([CH3:18])[N:15]=[C:14]3[S:19][C:20]([CH2:30][CH2:31][CH2:32][N:33]4[CH2:34][CH2:35][O:36][CH2:37][CH2:38]4)=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C:13]=23)(=[O:9])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cccc(-c2c(C#CCN3CCOCC3)sc3nc(C)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Agent: [Pd]
Solvent: CCO
Product: COc1cccc(-c2c(CCCN3CCOCC3)sc3nc(C)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 27.7 %

Procedure:
A mixture of 3-chloro-N-{6-methyl-3-[3-(methyloxy)phenyl]-2-[3-(4-morpholinyl)-1-propyn-1-yl]thieno[2,3-b]pyridin-4-yl}benzenesulfonamide (Example 86) (6.8 mg, 0.012 mmol) and palladium on carbon (2.55 mg, 2.394 μmol) in ethanol (2.0 mL) was stirred under an atmosphere of hydrogen at RT for 20 h. The mixture was then filtered through celite, washing with ethanol, and evaporated to dryness. The residue was purified on silica, eluting with a gradient of 0-10% MeOH in DCM to afford the title compound (1.9 mg). 1H NMR (MeOD, 400 MHz) δ ppm: 1.76 (2H, m), 2.27-2.40 (6H, m), 2.54 (3H, s), 2.69 (2H, m), 3.61 (4H, m), 3.84 (3H, s), 6.76-6.81 (2H, m), 7.04-7.10 (1H, m), 7.27 (1H, s), 7.39-7.48 (3H, m), 7.52-7.60 (2H, m).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]=[O:8])=[C:5]([B:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]2)[CH:4]=[N:3]1.[BH4-].[Na+]>CO>[CH3:1][N:2]1[C:6]([CH2:7][OH:8])=[C:5]([B:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]2)[CH:4]=[N:3]1
Reactant: Cn1ncc(B2OC(C)(C)C(C)(C)O2)c1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cn1ncc(B2OC(C)(C)C(C)(C)O2)c1CO
Temperature: 25 °C
Reaction time: 2 h
Yield: 32.2 %

Procedure:
To a solution of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-5-carbaldehyde (Preparation 142, 80 mg, 0.339 mmol) in MeOH (4 mL) at room temperature was added NaBH4 (25.6 mg, 0.678 mmol). The resulting solution was stirred at room temperature for 2 hours before concentrating in vacuo. EtOAc (10 mL) and water (0.5 mL) were added to the residue and the mixture was dried over Na2SO4 and concentrated in vacuo to afford the title compound as a white solid (26 mg, 32%).
Reaction SMILES: [CH2:1]([C:3]1[NH:4][CH:5]=[CH:6][N:7]=1)[CH3:2].Br[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:13]([O:12][C:10](=[O:11])[CH2:9][N:4]1[CH:5]=[CH:6][N:7]=[C:3]1[CH2:1][CH3:2])[CH3:14]
Reactant: CCc1ncc[nH]1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)Cn1ccnc1CC
Yield: 30.4 %

Procedure:
2-Ethyl-imidazole (10.0 g, 104 mmol) was dissolved in acetone (80 mL) and then ethyl bromoacetate (17.4 g, 104 mmol) and potassium carbonate (2.6 g, 18.7 mmol) was added and the resulting mixture was heated under reflux for 12 h. After filtration and evaporation the residue was extracted with water and dichloromethane. The organic phase was dried over sodium sulfate and evaporated to afford the title compound as a light yellow solid (5.76 g, 30%). MS: m/e=183.1 [M+H]+.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].Br[C:18]1[S:22][N:21]=[CH:20][C:19]=1[N+:23]([O-:25])=[O:24]>O1CCOCC1.C(OCC)(=O)C>[N+:23]([C:19]1[CH:20]=[N:21][S:22][C:18]=1[O:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1)([O-:25])=[O:24]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: O=[N+]([O-])c1cnsc1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2sncc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 44.7 %

Procedure:
To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (1B2) (464 mg, 2.3 mmol) in dioxane (10 mL) at room temperature was added NaH (114 mg, 2.8 mmol). The mixture was stirred for 20 min and 5-bromo-4-nitroisothiazole (P) (400 mg, 1.9 mmol) was added. The mixture was stirred at 65° C. for 5 hours, cooled to room temperature, diluted with ethyl acetate (100 mL), washed with brine, dried over Na2SO4, and concentrated in vacuo at room temperature (25° C.). The residue was purified with flash column (eluent: 10-30% ethyl acetate/petroleum ether) to afford the product tert-butyl 4-(4-nitroisothiazol-5-yloxy)piperidine-1-carboxylate (1C3) (280 mg, 0.85 mmol).
Reaction SMILES: CN(C)C=O.Br[C:7]1[CH:8]=[C:9]([Cl:30])[C:10]([C:13]2[N:14]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:17]=2)=[N:11][CH:12]=1.[CH3:31][C:32]1[C:37](B2OC(C)(C)C(C)(C)O2)=[CH:36][N:35]=[C:34]([O:47][CH2:48][C:49]2([C:53]([O:55][CH2:56][CH3:57])=[O:54])[CH2:52][CH2:51][CH2:50]2)[CH:33]=1.C(=O)([O-])[O-].[Na+].[Na+]>O>[Cl:30][C:9]1[CH:8]=[C:7]([C:37]2[CH:36]=[N:35][C:34]([O:47][CH2:48][C:49]3([C:53]([O:55][CH2:56][CH3:57])=[O:54])[CH2:52][CH2:51][CH2:50]3)=[CH:33][C:32]=2[CH3:31])[CH:12]=[N:11][C:10]=1[C:13]1[N:14]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:17]=1
Reactant: C[Si](C)(C)CCOCn1cc(C(F)(F)F)nc1-c1ncc(Br)cc1Cl
Reactant: CCOC(=O)C1(COc2cc(C)c(B3OC(C)(C)C(C)(C)O3)cn2)CCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1(COc2cc(C)c(-c3cnc(-c4nc(C(F)(F)F)cn4COCC[Si](C)(C)C)c(Cl)c3)cn2)CCC1
Temperature: 65 °C
Reaction time: 2 h
Yield: 63.7 %

Procedure:
N,N-dimethylformamide (3 mL) was added to 5-bromo-3-chloro-2-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]pyridine (365 mg), ethyl 1-({[4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]-oxy}methyl)cyclobutanecarboxylate (300 mg) and palladium chloride (dppf) methylene chloride complex (33 mg), and after adding 2N aqueous sodium carbonate solution (1.2 mL) to the mixture, the atmosphere was replaced with nitrogen and the mixture was stirred at 65° C. for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated brine, concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=100:0 to 90:10) to obtain ethyl 1-[({5′-chloro-4-methyl-6′-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]-3,3′-bipyridin-6-yl}oxy)methyl]cyclobutanecarboxylate (318 mg).
Reaction SMILES: Cl.[CH2:2]([NH:5][C:6](=[O:26])[C@@H:7]([CH3:25])[NH:8][C:9](=[O:24])[C@H:10]([CH2:20][C:21](=[O:23])[OH:22])[NH:11][C:12](=[O:19])[C@H:13]([CH2:15][CH2:16][S:17][CH3:18])[NH2:14])[CH2:3][CH3:4].[C:27]([O:31][C:32]([NH:34][C@H:35]([C:46](N[C@H](C(N[C@H](C(N[C@@H](C(N)=O)C)=O)CC(=O)O)=O)CCSC)=[O:47])[CH2:36][C:37]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[NH:39][CH:38]=1)=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[CH2:2]([NH:5][C:6](=[O:26])[C@@H:7]([CH3:25])[NH:8][C:9](=[O:24])[C@H:10]([CH2:20][C:21](=[O:22])[OH:23])[NH:11][C:12](=[O:19])[C@H:13]([CH2:15][CH2:16][S:17][CH3:18])[NH:14][C:46](=[O:47])[C@H:35]([CH2:36][C:37]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[NH:39][CH:38]=1)[NH:34][C:32]([O:31][C:27]([CH3:30])([CH3:28])[CH3:29])=[O:33])[CH2:3][CH3:4]
Reactant: CCCNC(=O)[C@@H](C)NC(=O)[C@H](CC(=O)O)NC(=O)[C@@H](N)CCSC
Reactant: CSCC[C@H](NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(=O)O)C(=O)N[C@H](C)C(N)=O
Agent: Cl
Product: CCCNC(=O)[C@@H](C)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CCSC)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C

Procedure:
When an equivalent quantity of L-methionyl-L-aspartyl-D-alanine n-propylamide hydrochloride is substituted for the L-methionyl-L-aspartyl-D-alanine amide hydrochloride of Example 6, and the procedure detailed therein substantially repeated, there is obtained N-t-butoxycarbonyl-L-tryptophanyl-L-methionyl-L-aspartyl-D-alanine n-propylamide. This compound melts at about 143.5°-148° C. with decomposition and is represented by the following formula.
Reaction SMILES: IC1C=CC=CC=1S([O-])(=O)=O.[Na+].OOS([O-])=O.[K+].S([O-])([O-])(=O)=O.[Na+].[Na+].[CH3:26][C:27]1([CH3:39])[CH2:32][O:31][C:30]2([CH2:37][CH2:36][CH:35]([OH:38])[CH2:34][CH2:33]2)[O:29][CH2:28]1>C(OCC)(=O)C>[CH3:26][C:27]1([CH3:39])[CH2:28][O:29][C:30]2([CH2:37][CH2:36][C:35](=[O:38])[CH2:34][CH2:33]2)[O:31][CH2:32]1
Reactant: CC1(C)COC2(CCC(O)CC2)OC1
Agent: O=S(=O)([O-])[O-]
Agent: O=S(=O)([O-])c1ccccc1I
Agent: O=S([O-])OO
Solvent: CCOC(C)=O
Product: CC1(C)COC2(CCC(=O)CC2)OC1
Temperature: 70 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
6.1 mg (0:02 mmol) of sodium 2-iodobenzenesulfonate prepared by Preparation Example 4, 0.49 g (0.8 mmol) of powdered Oxone (registered trademark), 0.5 g (3.5 mmol) of anhydrous sodium sulfate and 200 mg (1 mmol) of 3,3-dimethyl-1,5-dioxaspiro[5.5]undecan-9-ol were added to 5 ml of ethyl acetate, and the mixture was heated at 70° C. while being stirred under a nitrogen for eight hours. The later treatment was carried out in the same way as in Example 1, and then 3,3-dimethyl-1,5-dioxaspiro[5.5]undecan-9-one was obtained. The yield of the obtained 3,3-dimethyl-1,5-dioxaspiro[5.5]undecan-9-one was determined and the result is shown in Table 2. (Yield 91%)
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:23])[C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:14]=2[CH:15]=[CH:16][CH:17]=[N:18]3)=[CH:8][CH:7]=1>O.O1CCCC1.CO>[N:18]1[C:19]2[C:14](=[C:13]([NH:12][C:9]3[CH:10]=[CH:11][C:6]([C:5]([OH:23])=[O:4])=[CH:7][CH:8]=3)[CH:22]=[CH:21][CH:20]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: COC(=O)c1ccc(Nc2cccc3ncccc23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(Nc2cccc3ncccc23)cc1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
A solution of sodium hydroxide (7 g, 0.18 mol) in water (100 ml) was added to a solution of the product from stage (a) in a mixture of tetrahydrofuran (100 ml) and methanol (350 ml). The reaction mixture was stirred at 50° C. for 3 h before the solvent was removed under reduced pressure. The resultant residue was purified by dissolving in water (1000 ml) adjusted to pH10 with 2M NaOH and precipitating the crude product by acidification to pH3 with 2N HCl. The precipitate so formed was collected by filtration and washed with water (250 ml). This purification procedure was repeated a further two times before the product was dried to give 12.3 g of an orange powder.
Reaction SMILES: I[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].[C:12](C1C=CC=CC=1N)#[CH:13]>>[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]#[CH:13])(=[O:4])[CH3:2]
Reactant: O=C(CI)Nc1ccccc1
Reactant: C#Cc1ccccc1N
Product: C#Cc1ccccc1NC(C)=O

Procedure:
The N-acetyl-2-ethynylaniline was prepared from 2-iodoacetanilide by Sonogashira coupling and using the same method as the synthesis of 2-ethynyl aniline. Afforded light brown solid 45% yield.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[S:20][C:19]([CH3:21])=[N:18][CH:17]=1>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[Br:1][CH2:21][C:19]1[S:20][C:16]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[Cl:9])=[CH:17][N:18]=1
Reactant: Cc1ncc(-c2ccccc2Cl)s1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: Clc1ccccc1-c1cnc(CBr)s1
Temperature: 75 °C
Reaction time: 18 h

Procedure:
N-Bromosuccinimide (344 mg, 1.61 mmol) is added to a solution of 5-(2-chlorophenyl)-2-methylthiazole (337 mg, 1.93 mmol) in carbon tetrachloride (15 mL). The above solution is stirred at 75° C. for 18 h. The solution is diluted with CH2Cl2 (50 mL) and washed with saturated NaHCO3 (50 mL) and brine (30 mL). The organic layer is dried (MgSO4), filtered, concentrated and purified by silica gel chromatography (EtOAc/hexane, gradient) to give 2-(bromomethyl)-5-(2-chlorophenyl)thiazole 7 as a white solid. MS calcd. for C10H8BrClNS (M+H+) 287.9. found 286.9.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[N:8][N+:9]([O-:11])=[O:10])[NH:6][CH2:5][O:4][CH2:3]1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19]Cl)=[CH:15][N:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][N:6]2[CH2:5][O:4][CH2:3][N:2]([CH3:1])[C:7]2=[N:8][N+:9]([O-:11])=[O:10])=[CH:15][N:14]=1
Reactant: CN1COCNC1=N[N+](=O)[O-]
Reactant: ClCc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN1COCN(Cc2ccc(Cl)nc2)C1=N[N+](=O)[O-]

Procedure:
A mixture of 1.44 g of 3-methyl-4-nitroiminoperhydro-1,3,5-oxadiazine, 2.2 g of 2-chloro-5-chloromethylpyridine, 3.7 g of potassium carbonate and 20 ml of N,N-dime-thylformamide is heated for 4 hours at 50° and filtered, the filtrate is evaporated in vacuo on a rotary evaporator, and the residue is purified by chromatography [silica gel; dichloro-methane/methanol (95:5)]. This gives the tide compound which melts at 116 to 118°.
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[C:10]([C:11](=O)[C:12]#[CH:13])=[C:6]2[CH:5]=[CH:4][CH:3]=1.Cl.[C:23]([NH2:31])(=[NH:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[O-]CC.[Na+]>C(O)C.O>[Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[C:10]([C:11]3[CH:12]=[CH:13][N:31]=[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[N:30]=3)=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: C#CC(=O)c1c(-c2ccc(F)cc2)nn2c(Cl)cccc12
Reactant: N=C(N)c1ccccc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Fc1ccc(-c2nn3c(Cl)cccc3c2-c2ccnc(-c3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.7 %

Procedure:
To a suspension of 1-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-2-propyn-1-one (36 mg, 0.12 mmol) and benzamidine hydrochloride (25 mg, 0.16 mmol) in ethanol (500 μL) was added sodium ethoxide (52 μL, 3 M in ethanol, 0.16 mmol). The reaction mixture was stirred at room temperature 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and brine, then dried over magnesium sulfate. Filtration and concentration, followed by flash chromatography (3:1 hexanes-ethyl acetate) provided 7-chloro-2-(4-fluorophenyl)-3-(2-phenylpyrimidin-4-yl)pyrazolo[1,5-α]pyridine (34 mg, 71%). Rf 0.36 (3:1 hexanes-ethyl acetate); 1H NMR (CDCl3) δ 8.60–8.56 (m, 2H), 8.52–8.48 (m, 2H), 7.67 (m, 2H), 7.56–7.52 (m, 3H), 7.39 (m, 1H), 7.22–7.11 (m, 3H), 6.93 (d, 1H); 19F NMR (CDCl3) δ −112.30; MS m/z 401 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C@H:5]([CH2:7][S:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[NH2:6])[CH3:2].[C:17]([O:21][C:22](=[O:26])[CH:23](Br)[CH3:24])([CH3:20])([CH3:19])[CH3:18].C(N(CC)CC)C>CN(P(N(C)C)(N(C)C)=O)C>[C:17]([O:21][C:22](=[O:26])[C@H:23]([CH3:24])[NH:6][C@H:5]([C:4]([O:3][CH2:1][CH3:2])=[O:16])[CH2:7][S:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: CCCCCCCSC[C@H](N)C(=O)OCC
Reactant: CC(Br)C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCCCCCSC[C@H](N[C@@H](C)C(=O)OC(C)(C)C)C(=O)OCC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
In 20 ml of HMPA were dissolved 5.9 g of S-heptyl-L-cysteine ethyl ester and 5.5 g of 2-bromopropionic acid t-butyl ester. A 3.4 ml quantity of triethylamine was added to the solution. The mixture was stirred at room temperature for 24 hours. The reaction mixture was poured into ice water, followed by extraction with ethyl acetate. The extract was sufficiently washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was separated and purified by silica gel column chromatography (a 1:3 mixture of ether and n-hexane as an eluent), producing the α-isomer of the title compound as a colorless oil from the first eluate. Yield 2.8 g.
Reaction SMILES: C([O:3][C:4](=[O:27])[C@@H:5]([O:25][CH3:26])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)=[CH:9][CH:8]=1)C.[CH3:28][N:29]([CH3:38])[CH2:30][CH2:31][CH2:32]OS(C)(=O)=O>>[CH3:28][N:29]([CH3:38])[CH2:30][CH2:31][CH2:32][O:24][C:21]1[CH:20]=[CH:19][C:18]([O:17][CH2:16][CH2:15][CH2:14][O:13][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:25][CH3:26])[C:4]([OH:3])=[O:27])=[CH:12][CH:11]=2)=[CH:23][CH:22]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCOc2ccc(O)cc2)cc1)OC
Reactant: CN(C)CCCOS(C)(=O)=O
Product: CO[C@@H](Cc1ccc(OCCCOc2ccc(OCCCN(C)C)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-{4-[3-(4-hydroxy-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic acid ethyl ester (Example 263, Step B) and methanesulfonic acid 3-dimethylaminopropyl ester (Step A) following the procedure described for Example 264. 1H-NMR (CDCl3, 200.15 MHz): δ 7.14 (d, 2H, J=7.8), 6.83–6.77 (m, 6H), 4.10–4.04 (m, 5H), 3.95–3.89 (m, 4H), 3.37 (s, 3H), 3.16–3.13 (m, 2H), 3.06–2.99 (m, 2H), 2.77 (s, 6H), 2.21–2.15 (m, 4H).
Reaction SMILES: [CH2:1]([C:8]([CH3:34])([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N+:28]=2[O-])=[CH:18][CH:17]=1)[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(O)(=O)C.[Fe]>[CH2:1]([C:8]([CH3:34])([CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)=[CH:20][CH:21]=1)[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(C)(Cc1ccccc1)Cc1ccc(OCCCNc2cccc[n+]2[O-])cc1
Agent: [Fe]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)O
Product: CCOC(=O)CC(C)(Cc1ccccc1)Cc1ccc(OCCCNc2ccccn2)cc1
Temperature: 25 °C
Yield: 69 %

Procedure:
To ethyl 3-benzyl-3-methyl-4-(4-{3-[(1-oxidopyridin-2-yl)amino]propoxy}phenyl)butanoate (322 mg) and PPh3 (220 mg, 0.84 mmol) in glacial acetic acid (5 mL) was added Fe powder (58 mg, 1.0 mmol). The reaction mixture was refluxed for 20 min and cooled to RT. The iron was removed by using a magnet and the mixture concentrated to an oil. The oil was purified by flash column chromatography using 80% EtOAc/hexane as eluent. Obtained was an oily ethyl 3-benzyl-3-methyl-4-{4-[3-(pyridin-2-ylamino) propoxy]phenyl}butan-oate (218 mg, 0.48 mmol, 2 step yield 55%). LC-MS (MH+)=447. H NMR (DMSO-d6) δ0.81 (s, 3H), 1.20 (t, 3H), 1.95 (m, 2H), 2.02 (s, 2H), 2.54-2.78 (m, 4H), 3.37 (q, 2H), 4.02 (t, 2H), 4.09 (q, 2H), 6.43 (m, 2H), 6.55 (t, 1H), 6.85 (d, 2h), 7.06 (d, 2H), 7.15 (d, 2H), 7.21 (dd, 1H), 7.28 (d, 2H), 7.33 (dd, 1H), 7.95 (d, 1H).