Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][C:9]1[S:13][C:12]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=2[F:21])=[N:11][C:10]=1[C:22]([OH:24])=O)=O)(C)(C)C.[NH2:25][C:26]1[CH:27]=[N:28][CH:29]=[CH:30][C:31]=1[N:32]1[CH2:37][CH2:36][CH2:35][C@H:34]([OH:38])[CH2:33]1>>[NH2:8][C:9]1[S:13][C:12]([C:14]2[C:15]([F:21])=[CH:16][CH:17]=[CH:18][C:19]=2[F:20])=[N:11][C:10]=1[C:22]([NH:25][C:26]1[CH:27]=[N:28][CH:29]=[CH:30][C:31]=1[N:32]1[CH2:37][CH2:36][CH2:35][C@H:34]([OH:38])[CH2:33]1)=[O:24]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Reactant: Nc1cnccc1N1CCC[C@H](O)C1
Product: Nc1sc(-c2c(F)cccc2F)nc1C(=O)Nc1cnccc1N1CCC[C@H](O)C1
Yield: 100 %

Procedure:
Followed the procedure as described in EXAMPLE 1, starting with 5-(tert-butoxycarbonylamino)-2-(2,6-bisfluorophenyl)thiazole-4-carboxylic acid and (S)-1-(3-aminopyridin-4-yl)piperidin-3-ol. Obtained the desired product as a white solid (111 mg, 100%). 1H NMR (400 MHz, DMSO) δ 9.37 (s, 1H), 9.30 (s, 1H), 8.21 (d, J=5.3 Hz, 1H), 7.67 (s, 2H), 7.59-7.47 (m, 1H), 7.29 (t, J=8.9 Hz, 2H), 7.14 (d, J=5.3 Hz, 1H), 4.81 (d, J=4.7 Hz, 2H), 3.81-3.63 (m, 3H), 3.19-3.07 (m, 1H), 2.99 (d, J=11.2 Hz, 1H), 2.61-2.33 (m, 2H), 1.90 (d, J=12.1 Hz, 1H), 1.71 (m, 3H), 1.30-1.09 (m, 2H). ESIMS m/z=432.2 (M+1).
Reaction SMILES: C[C:2]1([CH3:9])[O:6][C@H:5]([CH2:7][OH:8])[CH2:4][O:3]1.[OH-].[K+].[CH2:12](Br)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]CC>C1(C)C=CC=CC=1.ClCCl>[CH2:2]([O:3][CH2:4][C@H:5]([CH2:7][OH:8])[OH:6])[CH2:9][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH3:12]
Reactant: CC1(C)OC[C@@H](CO)O1
Reactant: CCCCCCCCCCCCCCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCOC[C@@H](O)CO
Temperature: 25 °C
Yield: 709.4 %

Procedure:
19.4 grams of (R)-(−)-2,2-dimethyl-1,3-dioxolane-4-methanol, 49 grams of powdered KOH and 4.8 grams of hexadecyl bromide were stirred in 500 ml toluene (500 ml) were stirred and refluxed for 6 hours, while removing the water formed by azeotropic distillation. The volume of the solvent was gradually reduced to about 100 ml and the reaction mixture was cooled to room temperature. The cooled reaction mixture was dissolved in 500 ml dichloromethane, washed twice with 200 ml water, and the solvent was removed under reduced pressure. The obtained residue was dissolved in 500 ml of a 90:10:5 (v/v) mixture of methanol:water:concentrated H2SO4, and the resulting solution was refluxed for 30 minutes, cooled to room temperature, and extracted with 500 ml dichloromethane. The extract was washed twice with 100 ml water, 100 ml aqueous 5% sodium carbonate, and again with 100 ml water, until neutral. The solvent was removed under reduced pressure and the crude product was recrystallized from hexane at 4° C., yielding 35.3 grams of pure 1-hexadecyl-sn-glycerol. The yield was 76%.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]1[CH:7]=[C:8]([C:16]([O:18]C)=[O:17])[C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2.CO.[Li+].[OH-]>C1COCC1>[CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]1[CH:7]=[C:8]([C:16]([OH:18])=[O:17])[C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2
Reactant: COCCNc1cc(C(=O)OC)c2ccccc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COCCNc1cc(C(=O)O)c2ccccc2c1

Procedure:
Methyl 3-{[2-(methyloxy)ethyl]amino}-1-naphthalenecarboxylate (1 eq.) from the previous step was taken up in a 2:1 (v/v) mixture of MeOH:THF (0.08 M). To this solution was then added LiOH (1.0 M aq. solution, 3.4 eq.) and the resulting cloudy solution was vigorously stirred at RT for 16 h. The volatiles were then removed in vacuo and the pH of the residue was carefully adjusted to ˜2 with 1 N aq. HCl before it was extracted with EtOAc. The combined organic extracts were washed further with water and brine, dried over Na2SO4 and filtered. Concentration of the filtrate in vacuo afforded the title compound as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13][CH2:12][C:7]=3[N:8]([CH3:11])[C:9]=2[CH:10]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][NH:34][C:33](=[O:37])[CH2:32]1>>[CH3:11][N:8]1[C:9]2[CH:10]=[C:2]([N:34]3[CH2:35][CH2:36][N:31]([CH2:30][CH2:29][C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=4)[CH2:32][C:33]3=[O:37])[CH:3]=[CH:4][C:5]=2[C:6]2[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13][CH2:12][C:7]1=2
Reactant: Cn1c2c(c3ccc(Br)cc31)CN(C(=O)OC(C)(C)C)CC2
Reactant: O=C1CN(CCc2ccccn2)CCN1
Product: Cn1c2c(c3ccc(N4CCN(CCc5ccccn5)CC4=O)cc31)CN(C(=O)OC(C)(C)C)CC2
Yield: 56.4 %

Procedure:
tert-Butyl 7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (280 mg, 0.761 mmol) and 4-(2-(pyridin-2-yl)ethyl)piperazin-2-one (156 mg, 0.760 mmol) were reacted according to Example 2 (step f) to provide the title compound (210 mg, 56%) as a yellow oil: ESI MS m/z 490 [M+H]+.
Reaction SMILES: [Li+].[OH-].[O:3]=[C:4]1[N:16]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C@@H:26]([C:44]([O:46]C)=[O:45])[CH2:27][C:28]3[CH:33]=[C:32]([CH3:34])[C:31]([O:35][CH2:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)=[C:30]([CH3:43])[CH:29]=3)=[O:24])[CH2:19][CH2:18]2)[C:7]2[CH:8]=[N:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:6]=2[NH:5]1>O.C1COCC1>[O:3]=[C:4]1[N:16]([CH:17]2[CH2:18][CH2:19][N:20]([C:23]([O:25][C@@H:26]([C:44]([OH:46])=[O:45])[CH2:27][C:28]3[CH:33]=[C:32]([CH3:34])[C:31]([O:35][CH2:36][C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)=[C:30]([CH3:43])[CH:29]=3)=[O:24])[CH2:21][CH2:22]2)[C:7]2[CH:8]=[N:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:6]=2[NH:5]1
Reactant: COC(=O)[C@@H](Cc1cc(C)c(OCc2ccccc2)c(C)c1)OC(=O)N1CCC(n2c(=O)[nH]c3c4ccccc4ncc32)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(n3c(=O)[nH]c4c5ccccc5ncc43)CC2)C(=O)O)cc(C)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 250 mg (10.42 mmol) LiOH in 10 mL water was added to a solution of 2.50 g (4.11 mmol) (R)-2-(4-benzyloxy-3,5-dimethyl-phenyl)-1-methoxycarbonyl-ethyl 4-(2-oxo-1,2-dihydro-imidazo[4,5-c]quinolin-3-yl)-piperidine-1-carboxylate in 20 mL THF and the reaction mixture was stirred for 2 h at RT. The organic solvent was removed i.vac., the aqueous residue was acidified with 2 M HCL and combined with EtOAc/DCM (2:1). The precipitate formed was filtered off and dried.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)=[O:7])=[C:4]([CH:15]=O)[CH:3]=1.[C:17]([CH:22]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:19][CH2:20][CH3:21])=[O:18]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([N:8]2[CH2:9][CH2:10][CH2:11][CH2:12]2)=[O:7])=[C:4](/[CH:15]=[CH:22]/[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:3]=1
Reactant: O=Cc1cc(Br)ccc1C(=O)N1CCCC1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)/C=C/c1cc(Br)ccc1C(=O)N1CCCC1

Procedure:
A solution of 1.27 g (4.5 mmol) of N-(4-bromo-2-formyl-benzoyl)-pyrrolidine and 1.65 g (4.5 mmol) of carboethoxymethylene triphenylphosphorane in 45 ml of toluene is heated to 80° C. for 4 hours. After removal of the solvent the residue is purified by flash chromatography (silica gel; methylene chloride/ethanol 99:1 to 99:2).
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[C:12]2=[N:13][CH:14]=[N:15][C:16]([NH2:17])=[C:11]2[C:10]([C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]3[N:28]([CH3:36])[C:29]4[C:34]([CH:35]=3)=[CH:33][CH:32]=[CH:31][CH:30]=4)=[O:26])=[C:20]([O:37][CH3:38])[CH:19]=2)=[N:9]1)(=O)=O.C(N(CC)CC)C.[I-].[Na+].[NH:48]1[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1>CN(C=O)C>[NH2:17][C:16]1[N:15]=[CH:14][N:13]=[C:12]2[N:8]([CH2:7][CH2:6][N:48]3[CH2:53][CH2:52][O:51][CH2:50][CH2:49]3)[N:9]=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]4[N:28]([CH3:36])[C:29]5[C:34]([CH:35]=4)=[CH:33][CH:32]=[CH:31][CH:30]=5)=[O:26])=[C:20]([O:37][CH3:38])[CH:19]=3)[C:11]=12
Reactant: C1COCCN1
Reactant: COc1cc(-c2nn(CCOS(C)(=O)=O)c3ncnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(-c2nn(CCN3CCOCC3)c3ncnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 60 °C
Yield: 14.5 %

Procedure:
To a mixture of 2-[4-amino-3-(3-methoxy-4-{[(1-methyl-1H-2-indolyl)carbonyl]amino}phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl methanesulfonate (Intermediate 4) (0.200 g, 0.373 mmol), triethylamine (0.052 mL, 0.37 mmol), and sodium iodide (0.056 g, 0.37 mmol) in DMF (5 mL) was added morpholine (0.039 mL, 0.45 mmol). The reaction mixture was heated at 60° C. for 60 h. Morpholine (0.100 mL, 1.15 mmol) was added and the reaction mixture was heated at 80° C. for 30 h. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. Water (5 mL) was added and the resulting precipitate was collected by filtration, washed with water (5 mL) and ether (10 mL), and dried in vacuo to afford a tan solid which was purified twice by silica gel chromatography (elution with 20% MeOH—CH2Cl2); the appropriate fractions were combined and concentrated to afford a beige solid which was triturated from ether and dried in vacuo to afford N2-{4-[4-amino-1-(2-morpholinoethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-1-methyl-1H-2-indolecarboxamide as a white solid (0.048 g, 0.054 mmol): 1H NMR (d6-DMSO, 400 MHz): δH 9.44 (1H, s), 8.26 (1H, s), 8.11 (1H, d, J=8.0 Hz), 7.70 (1H, d, J=7.6 Hz), 7.58 (1H, d, J=7.6 Hz), 7.29-7.35 (4H, m), 7.15 (1H, t, J=7.6 Hz), 4.48 (2H, t, J=6.4 Hz), 4.04 (3H, s), 3.96 (3H, s), 3.50-3.53 (4H, m), 2.82 (2H, t, J=6.2 Hz), and 2.47-2.51 (4H, m);); RP-HPLC (Hypersil C18, 5 μm, 100 Å, 15 cm; 5%-100% acetonitrile-0.1 M ammonium acetate over 15 min, 1 mL/min). Rt 10.02 min. MS: M+ 527.3.
Reaction SMILES: [CH:1]([C:3]1[N:8]=[N:7][C:6]2[O:9][CH2:10][CH2:11][CH2:12][C:5]=2[CH:4]=1)=C.O.I([O-])(=O)(=O)=[O:15].[Na+]>O1CCOCC1.[Os](=O)(=O)(=O)=O>[N:7]1[C:6]2[O:9][CH2:10][CH2:11][CH2:12][C:5]=2[CH:4]=[C:3]([CH:1]=[O:15])[N:8]=1
Reactant: C=Cc1cc2c(nn1)OCCC2
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=Cc1cc2c(nn1)OCCC2
Temperature: 25 °C
Reaction time: 4.75 h
Yield: 54.3 %

Procedure:
A solution of 3-ethenyl-6,7-dihydro-5H-pyrano[2,3-c]pyridazine (100 mg, 0.617 mmol) in 1,4-dioxane (5.5 ml)/water (1.1 ml) was cooled in ice/water and treated with sodium periodate (306 mg, 1.43 mmol) and a 4% aqueous solution of osmium tetroxide (0.55 ml). The mixture was allowed to warm to room temperature after an hour, and after a total of 4.75 hours stirring, the solvent was evaporated. 1,4-Dioxane was added and evaporated, followed by dichloromethane and the mixture briefly held in an ultrasonic bath. The whole mixture was applied to a silica gel column and eluted with ethyl acetate to give product (55 mg, 54%).
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Cl[CH2:10][CH2:11][S:12](Cl)(=[O:14])=[O:13]>C(Cl)Cl>[CH:3]1([N:2]([CH3:1])[S:12]([CH:11]=[CH2:10])(=[O:14])=[O:13])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: O=S(=O)(Cl)CCCl
Reactant: CNC1CCCCC1
Solvent: ClCCl
Product: C=CS(=O)(=O)N(C)C1CCCCC1
Temperature: 5 °C
Reaction time: 2 h

Procedure:
A mixture of N-methylcyclohexylamine (0.048 mol) and TEA (0.053 mol) in DCM (200 mL) was cooled in an ice bath to 5° C., and then a solution of 2-chloro-ethanesulfonyl chloride (0.048 mol, 97%) in DCM (20 mL) was added dropwise. The reaction mixture was stirred for 2 hours at room temperature and then was washed with H2O. The organic layer was separated, dried (MgSO4), and filtered, and the solvent was evaporated to yield the title compound as a residue.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][C:4]([C:6]([OH:8])=[O:7])=O.[C:9]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)(=[O:11])[CH3:10]>>[O:11]=[C:9]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[CH2:10]/[C:4](=[CH:3]\[CH2:2][CH3:1])/[C:6]([OH:8])=[O:7]
Reactant: CCCC(=O)C(=O)O
Reactant: CC(=O)c1cccnc1
Product: CC/C=C(\CC(=O)c1cccnc1)C(=O)O

Procedure:
In a manner analogous to that described above, by an aldol condensation of 2-oxo-n-valeric acid with 3-acetylpyridine there is obtained γ-oxo-α-[(E)-propylidene]-3-pyridinebutyric acid, MS: 219 (M+H)+. Ring closure with hydrazine yields 4-propyl-6-(3-pyridyl)-3(2H)-pyridazinone, MS: 215 (M)+, which is converted into the corresponding chloride, 3-chloro-4-propyl-6-(3-pyridyl)pyridazine, MS: 233 (M)+. Hydrazinolysis to 3-hydrazino-4-propyl-6-(3-pyridyl)pyridazine, MS: 229 (M)+, and condensation with diethyl (3-pyridyl)malonate yields ethyl rac-8-propyl-α-(3-pyridylmethyl)-6-(3-pyridyl)-s-triazolo[4,3-b]pyridazine-3-acetate, which is converted by basic saponification into the above acid, MS: 388 (M)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=[C:10]([C:18]3[CH:23]=[CH:22][N:21]=[C:20](Cl)[CH:19]=3)[N:9]=2)=[CH:4][C:3]=1[CH3:25].[C:26]([NH:30][S:31]([C:34]1[S:35][C:36](B2OC(C)(C)C(C)(C)O2)=[CH:37][CH:38]=1)(=[O:33])=[O:32])([CH3:29])([CH3:28])[CH3:27]>>[C:26]([NH:30][S:31]([C:34]1[S:35][C:36]([C:20]2[CH:19]=[C:18]([C:10]3[N:9]=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH3:25])[CH:4]=4)[CH:13]=[C:12]([C:14]([F:16])([F:17])[F:15])[N:11]=3)[CH:23]=[CH:22][N:21]=2)=[CH:37][CH:38]=1)(=[O:32])=[O:33])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)s1
Reactant: Cc1cc(-c2cc(C(F)(F)F)nc(-c3ccnc(Cl)c3)n2)ccc1Cl
Product: Cc1cc(-c2cc(C(F)(F)F)nc(-c3ccnc(-c4ccc(S(=O)(=O)NC(C)(C)C)s4)c3)n2)ccc1Cl

Procedure:
5-{4-[4-(4-Chloro-3-methyl-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-pyridin-2-yl}-thiophene-2-sulfonic acid tert-butyl amide was prepared from 4-(4-chloro-3-methylphenyl)-2-(2-chloro-pyridin-4-yl)-6-trifluoromethyl-pyrimidine (example E.43) (0.14 g, 0.36 mmol) and N-tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophene-2-sulfonamide (example F.1) (0.15 g, 0.43 mmol) according to the general procedure VI. Obtained as a light brown solid (0.14 g), which was subsequently deprotected.
Reaction SMILES: C([C:3]1[CH:18]=[CH:17][C:6]([O:7][CH:8]([CH3:16])[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:10])=[CH:5][CH:4]=1)=O.C1(C)C=CC=CC=1.C(OO)(=[O:28])C>O>[OH:28][C:3]1[CH:18]=[CH:17][C:6]([O:7][CH:8]([CH3:16])[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:10])=[CH:5][CH:4]=1
Reactant: CC(=O)OO
Reactant: CCCCOC(=O)C(C)Oc1ccc(C=O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCOC(=O)C(C)Oc1ccc(O)cc1
Temperature: 25 °C
Yield: 81.9 %

Procedure:
While stirring a mixture of 25 g of butyl 2-(4-formylphenoxy)propionate and 75 g of toluene at room temperature, 22.8 g of 40% peracetic acid was dropwise added. After stirring at 20° to 30° C. for 2 hours and at 50° C. for 2 hours, 2.0 g of water was added, and the mixture was stirred for 2 hours. The reaction mixture was cooled to room temperature and subjected to the same after-treatment as in Example 1, whereby 19.5 g of butyl 2-(4-hydroxyphenoxy)propionate was obtained as a colorless transparent liquid by the distillation under reduced pressure. The boiling point was 160° C./1 mmHg.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:38]/[O:39]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)/[C:8]([NH:10][CH:11]2[C:36](=[O:37])[N:13]3[C:14]([C:21]([O:23][CH:24]([O:26][C:27]([O:29][CH:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)=[O:28])[CH3:25])=[O:22])=[C:15](/[CH:18]=[CH:19]\[CH3:20])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.C(O)=O.[OH-].[Na+]>CCOC(C)=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:38]/[OH:39])/[C:8]([NH:10][CH:11]2[C:36](=[O:37])[N:13]3[C:14]([C:21]([O:23][CH:24]([O:26][C:27]([O:29][CH:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)=[O:28])[CH3:25])=[O:22])=[C:15](/[CH:18]=[CH:19]\[CH3:20])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: C/C=C\C1=C(C(=O)OC(C)OC(=O)OC2CCCCC2)N2C(=O)C(NC(=O)/C(=N\OC(c3ccccc3)(c3ccccc3)c3ccccc3)c3csc(N)n3)[C@H]2SC1
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Solvent: CCOC(C)=O
Product: C/C=C\C1=C(C(=O)OC(C)OC(=O)OC2CCCCC2)N2C(=O)C(NC(=O)/C(=N\O)c3csc(N)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.1 %

Procedure:
A mixture of the product of Procedure 13 (62.7 g, 0.076 mol) and 90% aqueous formic acid (110 ml) was stirred at room temperature for 1 hr. The reaction mixture was diluted with EtOAc (600 ml) and ice-water (300 ml) and the lower layer was adjusted to pH 3.3 with 30% aq. NaOH under vigorous stirring. The upper layer was diluted to 2 L, separated, washed with water (500 ml×3) and brine, dried over MgSO4 and concentrated under diminished pressure. The residue was dissolved in toluene (300 ml) which was carefully transferred to the top surface of a silica gel column (Wakogel C-200, 800 g). The column was eluted with CH2Cl2, 0.5%, 1.0%, 1.5%, 2.0% and 3.0% MeOH in CH2Cl2, successively. The fractions which exhibited approximately Rf: 0.12 on TLC (SiO2, 5% MeOH-CH were combined and concentrated in vacuo to give 30.0 g (68%) of the desired product as an amorphous powder. The starting material was recovered (8.4 g, 14%) from the fractions which showed Rf 0.55 on TLC.
Reaction SMILES: C[CH:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]2[CH:14]=[CH:15][CH:16]=[CH:17][C:3]1=2.CCN(CC)CC.[Si]([I:29])(C)(C)C.II>C(Cl)Cl>[I:29][N:7]1[C:8](=[O:9])[CH2:2][C:3]2[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=2[C:5]2[CH:13]=[CH:12][CH:11]=[CH:10][C:6]1=2
Reactant: CC1C(=O)Nc2ccccc2-c2ccccc21
Reactant: C[Si](C)(C)I
Agent: II
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1Cc2ccccc2-c2ccccc2N1I
Temperature: 7.5 °C

Procedure:
A solution of 5,7-dihydro-6H-dibenz[b,d]azepin-6-one (1.0 g, 4.77 mmol) (Example 3-A) and Et3N (2.66 mL, 19.12 mmol) was stirred for 5.0 minutes at −15° C. in CH2Cl2 and treated with TMSI (1.36 mL, 9.54 mmol). After stirring for 15 minutes I2 (1.81 g, 7.16 mmol) was added in a single portion and the reaction allowed to warm to 5-10° C. over 3 h. The reaction was quenched with sat. Na2SO3, diluted with CH2Cl2 and separated. The organics were washed with Na2SO3 and NaHSO3 and dried over MgSO4. After filtration, the organics were concentrated to approximately 20 mL and diluted with an additional 20 mL of hexanes. The title compound was isolated as a tan precipitate by filtration.
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][CH:21]([C:30](=O)[C:31]#[C:32][CH:33]1[CH2:36][CH:35]([CH2:37][CH:38]([CH3:40])[CH3:39])[CH2:34]1)[CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.S([O-])([O-])(=O)=O.[Na+].[Na+].[Cl-].[CH3:52][O:53][NH3+:54]>N1C=CC=CC=1>[Si:1]([O:18][CH2:19][CH2:20][CH:21]([C:30](=[N:54][O:53][CH3:52])[C:31]#[C:32][CH:33]1[CH2:36][CH:35]([CH2:37][CH:38]([CH3:39])[CH3:40])[CH2:34]1)[CH2:22][C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])([C:14]([CH3:17])([CH3:15])[CH3:16])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)CC1CC(C#CC(=O)C(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC(=O)OC(C)(C)C)C1
Reactant: CO[NH3+]
Agent: O=S(=O)([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CO
Product: CON=C(C#CC1CC(CC(C)C)C1)C(CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
tert-Butyl 3-[2-(tert-butyldiphenylsilanyloxy)ethyl]-6-(3-isobutylcyclobutyl)-4-oxo-5-hexynoate (58.1 g) and methanol (300 mL) were mixed. To the mixture were added sodium sulfate (21.55 g), pyridine (30 mL) and O-methylhydroxylammonium chloride (12.67 g) at ice temperature. The mixture was stirred at RT overnight and the resultant precipitate was removed by filtration. After concentration of the filtrate in vacuo, toluene (350 mL) was poured into the residue. The mixture was washed with 1 N hydrochloric acid (300 mL), water (300 mL) and brine (150 mL), then dried over sodium sulfate. The sodium sulfate was filtered off and the filtrate was concentrated in vacuo. After an addition of silica gel (80 g) and ethyl acetate/hexane=1/20 (600 mL) to the residue, the mixture was stirred at RT for 1 hr. The silica gel was filtered off and the filtrate was concentrated in vacuo to give the title compound (55.54 g) as a crude product.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]([O:8]CC)=[CH2:7])CCC.Br[C:20]1[C:21]([O:29][CH3:30])=[N:22][CH:23]=[C:24]([N+:26]([O-:28])=[O:27])[CH:25]=1.C(=O)([O-])O.[Na+]>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.CC(N(C)C)=O>[CH3:30][O:29][C:21]1[C:20]([C:6](=[O:8])[CH3:7])=[CH:25][C:24]([N+:26]([O-:28])=[O:27])=[CH:23][N:22]=1
Reactant: COc1ncc([N+](=O)[O-])cc1Br
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
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: [Na+]
Solvent: CC(=O)N(C)C
Product: COc1ncc([N+](=O)[O-])cc1C(C)=O

Procedure:
Pd(PPh3)4 (60 mg) and tributyl (1-ethoxyvinyl)tin were added to a DMAc (3 ml) solution containing 3-bromo-2-methoxy-5-nitropyridine (69 mg) obtained in the 1st step, followed by microwave irradiation (Initiator™, 180° C., 10 minutes, 2.45 GHz, 0-240 W). Saturated sodium hydrogen carbonate was added to the reaction solution, followed by extraction with ethyl acetate. The organic layers were dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure and the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=9:1 to 3:7). A light yellow solid of 1-(2-methoxy-5-nitropyridin-3-yl)ethanone (72 mg) was thus obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH:8]([CH:9]=O)[C:7]1([CH3:12])[CH3:11])=[O:5])[CH3:2].P(OCC)(OCC)OCC.[Cl:23][C:24](Cl)([Cl:28])C([O-])=O.[Na+].O>COCCOCCOC>[CH2:1]([O:3][C:4]([CH:6]1[CH:8]([CH:9]=[C:24]([Cl:28])[Cl:23])[C:7]1([CH3:12])[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1C(C=O)C1(C)C
Reactant: O=C([O-])C(Cl)(Cl)Cl
Agent: CCOP(OCC)OCC
Agent: [Na+]
Solvent: COCCOCCOC
Solvent: O
Product: CCOC(=O)C1C(C=C(Cl)Cl)C1(C)C
Temperature: 150 °C
Yield: 73 %

Procedure:
A mixture of 17.0 g (0.1 mole) of 3-formyl-2,2-dimethyl-cyclopropane-1-carboxylic acid ethyl ester, 16.6 g (0.1 mole) of triethyl phosphite and 18.5 g (0.1 mole) of sodium trichloroacetate in 100 ml of diglyme was heated to 150° C. under argon for 6 hours. The reaction mixture was then poured into water. Extraction with 2 portions of 100 ml each of methylene chloride followed. The combined methylene chloride extracts were dried over sodium sulphate. 3-(2,2-Dichlorovinyl)-2,2-dimethyl-cyclopropane-1-carboxylic acid ethyl ester was obtained as a crude product in a yield of 73% of theory.
Reaction SMILES: [F:1][C:2]([F:14])([CH3:13])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH:11]=[C:10]([NH2:12])[CH:9]=[N:8]1.[F:15][C:16]([F:29])([F:28])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1/[CH:23]=[CH:24]/[C:25](O)=[O:26]>>[F:14][C:2]([F:1])([CH3:13])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH:11]=[C:10]([NH:12][C:25](=[O:26])/[CH:24]=[CH:23]/[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[C:16]([F:28])([F:29])[F:15])[CH:9]=[N:8]1
Reactant: O=C(O)/C=C/c1ccccc1C(F)(F)F
Reactant: CC(F)(F)CCCCn1cc(N)cn1
Product: CC(F)(F)CCCCn1cc(NC(=O)/C=C/c2ccccc2C(F)(F)F)cn1

Procedure:
Following general procedure B, starting from 1-(5,5-difluoro-hexyl)-1H-pyrazol-4-ylamine and (E)-3-(2-trifluoromethyl-phenyl)-acrylic acid. LC-MS-conditions 05b: tR=1.12 min; [M+H]+=402.11.