Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[N+:13]([O-])=O)[N:6]([CH2:16][C:17]3[CH:21]=[CH:20][N:19]([CH:22]([CH3:24])[CH3:23])[N:18]=3)[N:5]=2)[CH2:3][CH2:2]1.[Cl-].[NH4+]>[Fe].CCO.O>[CH:1]1([C:4]2[C:12]3[C:11]([NH2:13])=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]([CH2:16][C:17]3[CH:21]=[CH:20][N:19]([CH:22]([CH3:24])[CH3:23])[N:18]=3)[N:5]=2)[CH2:2][CH2:3]1
Reactant: CC(C)n1ccc(Cn2nc(C3CC3)c3c([N+](=O)[O-])cccc32)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CC(C)n1ccc(Cn2nc(C3CC3)c3c(N)cccc32)n1
Yield: 83.1 %

Procedure:
To a mixture of 3-cyclopropyl-1-((1-isopropyl-1H-pyrazol-3-yl)methyl)-4-nitro-1H-indazole (1.08 g, 3.32 mmol), ammonium chloride (88.8 mg, 1.66 mmol) in 4:1 EtOH/water (15 mL) was added iron powder (1.85 g, 33.2 mmol) and the mixture was heated at reflux for 3 hours. The solvent was removed under reduced pressure and the residue was mixed with in EtOAc/water and filtered through GF/F paper. The organic phase was separated and concentrated under reduced pressure to provide 3-cyclopropyl-1-((1-isopropyl-1H-pyrazol-3-yl)methyl)-1H-indazol-4-amine (0.815 g, 83% yield) as a yellow solid.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([I:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH:15]1[C:27]2[NH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]=2[CH:18]=[CH:17][CH:16]=1.C1OCCOCCOCCOCCOCCOC1.C(=O)([O-])[O-].[K+].[K+]>[Cu]I.O.CN1CCCN(C)C1=O>[I:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:26]3[C:27]4[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=4[C:20]4[C:25]3=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:3][CH:4]=2)=[CH:9][CH:10]=1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: Ic1ccc(-c2ccc(I)cc2)cc1
Agent: [Cu]I
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN1CCCN(C)C1=O
Product: Ic1ccc(-c2ccc(-n3c4ccccc4c4ccccc43)cc2)cc1
Temperature: 170 °C
Reaction time: 6.5 h
Yield: 89 %

Procedure:
Initially, 49 g (120 mmol) of diiodobiphenyl, 17 g (100 mmol) of carbazole, 1.0 g (5.0 mmol) of copper(I) iodide, 1.3 g (5.0 mmol) of 18-crown-6-ether, 10 g (75 mmol) of potassium carbonate, 40 mL of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (abbreviation: DMPU) were put in a 500 mL three-neck flask, and the atmosphere of the flask was substituted by nitrogen. The mixture was stirred at 170° C. for 6.5 hours. After stirring, water was added to the mixture and the mixture was filtrated to give a precipitate. The precipitate was washed with 1M hydrochloric acid, water, an aqueous solution of sodium hydrogen carbonate, and water in this order, and then was recrystallized from a mixture solution of toluene and hexane. The resulting solid was recrystallized from chloroform to give 40 g of the target substance, white powder of 9-(4′-iodobiphenyl-4-yl)-9H-carbazole in a yield of 89%.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C@@H:4]2[CH2:5][C:6]3[C:10]([C@H:3]12)=[C:9]([CH3:11])[S:8][C:7]=3[C:12](=[O:14])[CH3:13].[CH:16](=O)[C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=1>C(O)C.Cl.C(O)(C)C.C(OCC)C>[O:14]=[C:12]([C:7]1[S:8][C:9]([CH3:11])=[C:10]2[C:6]=1[CH2:5][C@H:4]1[C:2]([CH3:15])([CH3:1])[C@H:3]12)[CH:13]=[CH:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=1
Reactant: CC(=O)c1sc(C)c2c1C[C@@H]1[C@H]2C1(C)C
Reactant: O=Cc1ccc(C=O)cc1
Agent: Cl
Solvent: CC(C)O
Solvent: CCO
Solvent: CCOCC
Product: Cc1sc(C(=O)C=Cc2ccc(C=O)cc2)c2c1[C@H]1[C@@H](C2)C1(C)C
Reaction time: 24 h
Yield: 36.7 %

Procedure:
A solution of (1aS,5aR)-1-(1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-ethanone (600 mg, 2.72 mmol) and terephthalaldehyde (913 mg, 6.81 mmol) in ethanol (10 mL) and approx. 6 N HCl in isopropanol (6 mL) is stirred at rt for 16 h. Further 6 N HCl in isopropanol (5 mL) is added and stirring of the dark solution is continued at rt for 24 h. The reaction mixture is diluted with diethyl ether (150 mL) and washed with sat. aq. NaHCO3 solution followed by water. The organic phase is dried over MgSO4 and evaporated. The crude product is purified by CC on silica gel eluting with heptane:EA 4:1 to give 4-[3-oxo-3-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propenyl]-benzaldehyde (336 mg) as a yellow powder; LC-MS: tR=1.14 min, [M+1]+=337.29; 1H NMR (CDCl3): δ 10.04 (s, 1H), 7.94-7.89 (m, 2H), 7.80-7.71 (m, 3H), 7.30 (d, J=15.8 Hz, 1H), 3.14 (dd, J=5.9, 18.8 Hz, 1H), 2.95 (d, J=18.8 Hz, 1H), 2.44 (s, 3H), 2.00-1.91 (m, 2H), 1.15 (s, 3H), 0.75 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:15]([CH3:25])[CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37](B3OC(C)(C)C(C)(C)O3)=[CH:36][CH:35]=2)[CH2:33][CH2:32]1)=[O:30])[CH3:27]>>[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[NH:14][CH:15]([CH3:25])[CH2:16][CH2:17][C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=4)=[CH:4][CH:3]=3)=[CH:36][CH:35]=2)[CH2:32][CH2:33]1)=[O:30])[CH3:27]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(C)CCc1ccc(Cl)cc1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(C)CCc4ccc(Cl)cc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 108, Step 2, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-[3-(4-chloro-phenyl)-1-methyl-propyl]-amine and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: C1(P([N:15]=[N+:16]=[N-:17])(C2C=CC=CC=2)=O)C=CC=CC=1.[CH3:18][C:19]1[O:23][C:22]([CH:24]([C:26]2([CH3:30])[CH2:29][O:28][CH2:27]2)O)=[CH:21][CH:20]=1.N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1>[N:15]([CH:24]([C:26]1([CH3:30])[CH2:29][O:28][CH2:27]1)[C:22]1[O:23][C:19]([CH3:18])=[CH:20][CH:21]=1)=[N+:16]=[N-:17]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: Cc1ccc(C(O)C2(C)COC2)o1
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: Cc1ccc(C(N=[N+]=[N-])C2(C)COC2)o1
Temperature: 0 °C
Reaction time: 23 h
Yield: 47.7 %

Procedure:
5.30 g (19 mmol, 1.1 eq) of diphenylphosphoryl azide were added dropwise to a solution of 3.02 g (17 mmol, 1 eq) of (5-methylfuran-2-yl)-(3-methyloxetan-3-yl)methanol in 50 ml of toluene. The reaction medium was cooled to 0° C. and then 2.9 ml (19 mmol, 1.1 eq) of 1,8-diazabicyclo[5.4.0]undec-7-ene were added dropwise. The reaction medium was stirred at ambient temperature for 23 hours. The reaction medium was separated by settling out and the organic phase was washed with water and then with 1 N hydrochloric acid, dried over magnesium sulfate, filtered and evaporated. The residue was chromatographed on silica gel (column Analogix SF40-150 g, Spot II) eluted with heptane/ethyl acetate (95/5). 1.68 g of 2-[azido-(3-methyloxetan-3-yl)methyl]-5-methylfuran were obtained in the form of an orange oil. Yield=48%.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:24][C@@H:6]2[C:7](=[O:23])[O:8][C:9]3[C@@H:10]4[CH2:17][CH2:16][C@H:15]([C@H:18]([CH3:21])[CH2:19][OH:20])[C@@:11]4([CH3:22])[CH2:12][CH2:13][C:14]=3[C@@:5]2([CH3:25])[CH2:4][CH2:3]1>C(Br)C=C.[Ag]=O>[CH2:24]([O:20][CH2:19][C@H:18]([C@@H:15]1[C@@:11]2([CH3:22])[CH2:12][CH2:13][C:14]3[C@@:5]4([CH3:25])[CH2:4][CH2:3][C@H:2]([O:1][CH2:7][O:8][CH3:9])[CH2:24][C@@H:6]4[C:7](=[O:23])[O:8][C:9]=3[C@@H:10]2[CH2:17][CH2:16]1)[CH3:21])[CH:2]=[CH2:3]
Reactant: C[C@H](CO)[C@H]1CC[C@H]2C3=C(CC[C@]12C)[C@@]1(C)CC[C@H](O)C[C@@H]1C(=O)O3
Agent: O=[Ag]
Solvent: C=CCBr
Product: C=CCOC[C@@H](C)[C@H]1CC[C@H]2C3=C(CC[C@]12C)[C@@]1(C)CC[C@H](OCOC)C[C@@H]1C(=O)O3
Reaction time: 14 h
Yield: 40.2 %

Procedure:
Compound 95 (16.7 mg, 0.0425 mmol) obtained in Example 67 was dissolved in allylbromide (2 mL), and silver oxide (986 mg, 4.25 mmol) was added thereto, followed by stirring under light shading at room temperature for 14 hours. Silver oxide was separated by filtration, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (33% ethyl acetate/n-hexane) to obtain the title compound (3.7 mg, 21%).
Reaction SMILES: C(OC(=O)[N:7]([C:16]1[CH:21]=[CH:20][C:19]([CH:22]2[O:39][C:38]3[C:33](=[CH:34][CH:35]=[C:36]([F:40])[CH:37]=3)[C:32]3[C:23]2=[C:24]2[C:29](=[CH:30][CH:31]=3)[CH:28]=[C:27]([O:41]C)[CH:26]=[CH:25]2)=[CH:18][CH:17]=1)[CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)(C)(C)C.[ClH:44].B(Br)(Br)Br>ClCCl.CCOCC.C(=O)(O)[O-].[Na+].CO>[ClH:44].[ClH:44].[F:40][C:36]1[CH:37]=[C:38]2[C:33](=[CH:34][CH:35]=1)[C:32]1[C:23](=[C:24]3[C:29](=[CH:30][CH:31]=1)[CH:28]=[C:27]([OH:41])[CH:26]=[CH:25]3)[CH:22]([C:19]1[CH:18]=[CH:17][C:16]([NH:7][CH2:8][CH2:9][N:10]3[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]3)=[CH:21][CH:20]=1)[O:39]2
Reactant: COc1ccc2c3c(ccc2c1)-c1ccc(F)cc1OC3c1ccc(N(CCN2CCCCC2)C(=O)OC(C)(C)C)cc1
Agent: BrB(Br)Br
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CCOCC
Solvent: CO
Product: Oc1ccc2c3c(ccc2c1)-c1ccc(F)cc1OC3c1ccc(NCCN2CCCCC2)cc1
Temperature: 0 °C

Procedure:
Dissolve [4-(8-fluoro-2-methoxy-5H-6-oxa-chrysen-5-yl)-phenyl]-(2-piperidin-1-yl-ethyl)-carbamic acid tert-butyl ester in dichloromethane (25 mL). Add a 1.0 M solution of hydrogen chloride in ether (5 mL). Concentrate in vacuo. Redissolve in dichloromethane (20 mL). Cool to 0° C. Add boron tribromide (0.238 mL, 2.52 mmol). After 3 hrs dilute with saturated aqueous sodium bicarbonate (10 mL) and methanol (10 mL). Separate the organic layer and wash the aqueous layer twice with dichloromethane. Combine the organics and dry over magnesium sulfate. Filter and concentrate in vacuo. Purify the residue by column chromatography using a silica gel column eluting with a linear gradient beginning with dichloromethane and ending with 4:1 dichloromethane:methanol. Combine the product containing fractions and add 1.0 M hydrogen chloride in ether (2 mL). Concentrate in vacuo to isolate the title compound: mass spectrum (ion spray) m/z=469.2 (M+H). Purify the mixture by chiral chromatography (conditions A). The two isomers eluted with retention times of 4.02 and 5.46 minutes.
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH2:23][OH:24])[CH:16]=2)=[C:7]([NH:25][C:26]([NH:28][C:29]2[C:34]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:32]=[CH:31][C:30]=2[CH:38]([CH3:40])[CH3:39])=[O:27])[C:6]1=[O:41])[CH2:2][CH2:3][CH3:4].[C:42]1([CH3:52])[CH:47]=[CH:46][C:45]([S:48](Cl)(=[O:50])=[O:49])=[CH:44][CH:43]=1.C(N(CC)CC)C.O>C1COCC1>[CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH2:23][O:24][S:48]([C:45]3[CH:46]=[CH:47][C:42]([CH3:52])=[CH:43][CH:44]=3)(=[O:50])=[O:49])[CH:16]=2)=[C:7]([NH:25][C:26]([NH:28][C:29]2[C:34]([CH:35]([CH3:36])[CH3:37])=[CH:33][CH:32]=[CH:31][C:30]=2[CH:38]([CH3:40])[CH3:39])=[O:27])[C:6]1=[O:41])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)c(NC(=O)Nc2c(C(C)C)cccc2C(C)C)c(-c2cccc(OCCO)c2)c2cccnc21
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCn1c(=O)c(NC(=O)Nc2c(C(C)C)cccc2C(C)C)c(-c2cccc(OCCOS(=O)(=O)c3ccc(C)cc3)c2)c2cccnc21
Reaction time: 8 h
Yield: 54.3 %

Procedure:
To a solution of N-[1-butyl-4-{3-(2-hydroxyethoxy)phenyl}-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl]-N'-(2,6-diisopropylphenyl)urea (2.02 g, 3.63 mmol) in THF (20 ml) were added p-toluenesulfonyl chloride (0.69 g, 3.63 mmol) and triethylamine (0.40 g, 3.99 mmol), and the mixture was stirred at 40°-50° C. for 8 hours. The mixture was poured into water, and extracted with ethyl acetate. The extract was washed with water, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The resultant was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1) to give the title compound (1.40 g, 1.97 mmol).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][NH:6][C@@H:5]([CH3:8])[CH2:4][N:3]1[C@@H:9]([C:16]1[CH:17]=[C:18]([OH:22])[CH:19]=[CH:20][CH:21]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:23]([Si:27](Cl)([CH3:29])[CH3:28])([CH3:26])([CH3:25])[CH3:24].N1C=CN=C1.O>CN(C)C=O.C(O)C.ClCCl>[Si:27]([O:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([C@H:9]([N:3]2[CH2:4][C@H:5]([CH3:8])[NH:6][CH2:7][C@H:2]2[CH3:1])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:17]=1)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:29])[CH3:28]
Reactant: C[C@@H]1CN[C@@H](C)CN1[C@H](c1ccccc1)c1cccc(O)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Solvent: CCO
Product: C[C@@H]1CN[C@@H](C)CN1[C@H](c1ccccc1)c1cccc(O[Si](C)(C)C(C)(C)C)c1
Yield: 61.1 %

Procedure:
A mixture of (±)-3-((αR*)-α-((2R*,5S*)-2,5-dimethyl-1-piperazinyl)benzyl)phenol (1.98 g, 6.7 mmol), from Example 38, tert-butylchlorodimethylsilane (1.51 g, 10.1 mmol), and imidazole (1.14 g, 16.8 mmol) in 30 mL of N,N-dimethylformamide was stirred at room temperature under nitrogen overnight. The reaction mixture was poured into cold water and extracted with diethyl ether. The ether extracts were dried over sodium sulfate and the solvent removed under vacuum to give a yellow oil. Chromatography on silica gel with dichloromethane:ethanol (1-7%) gave 1.68 g (61%) of (±)-(3-((αR*)-α-((2R*,5S*)-2,5-dimethyl-1-piperazinyl)benzyl)phenyl) (tert-butyldimethylsilyl) ether as a yellow oil. NMR (CDCl3, 200 MHz): δ0.1 (s, 6H); 0.9 (s, 9H); 1.05 (d, J=6 Hz, 3H); 1.2 (d, J=6 Hz, 3H); 1.7 (t, J=10 Hz, 1H); 2.45 (br m, 1H); 2.7 (m, 2H); 3.0 (m, 2H); 3.4 (br s, 1H); 5.25 (s, 1H); 6.7 (d, J=8 Hz, 1H); 6.9 (d, J=8 Hz, 1H); 7.05 (s, 1H); 7.1 (m, 3H); 7.3 (m, 3H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]([C:15](=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18](O)[C:17]=1[Cl:23])([CH3:14])[C:9](OCC)=[O:10].OS([O-])(=O)=O.[Na+]>CCOCC>[Cl:23][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH:15]([OH:24])[C:8]([CH3:7])([CH3:14])[CH2:9][OH:10]
Reactant: CCOC(=O)C(C)(C)C(=O)c1cccc(O)c1Cl
Agent: O=S(=O)([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: CC(C)(CO)C(O)c1ccccc1Cl
Temperature: -20 °C
Reaction time: 3 h
Yield: 77.6 %

Procedure:
Lithium aluminum hydride (0.5 g, 11.7 mmol) was suspended in ether (50 ml) and cooled to −20° C. to −30° C. Thereto was added dropwise a solution of ethyl 2,2-dimethyl-3-hydroxy(2-chlorobenzoyl)acetate (2 g, 7.8 mmol) in ether (10 ml) while maintaining at not higher than −20° C. The mixture was stirred at −20° C. for 1 h and at 0° C. for 3 h, cooled to −20° C. and 10%—NaHSO4 aqueous solution (20 ml) was added dropwise. The mixture was stirred at room temperature for 30 min, and an insoluble material was removed by decantation. This was washed twice with ether (100 ml) and the organic layer was combined. The mixture was washed with water, dried over anhydrous sodium sulfate, and concentrated to dryness to give the title compound (1.3 g, 78%) as a colorless oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[C:10]([Cl:18])[CH:9]=2)[N:5]=[CH:4][N:3]=1.[NH2:19][CH2:20][C@H:21]([NH:29][S@@:30]([C:32]([CH3:35])([CH3:34])[CH3:33])=[O:31])[C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[Cl:18][C:10]1[CH:9]=[C:8]([C:6]2[N:5]=[CH:4][N:3]=[C:2]([NH:19][CH2:20][C@H:21]([NH:29][S@@:30]([C:32]([CH3:35])([CH3:34])[CH3:33])=[O:31])[C:22]3[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=3)[CH:7]=2)[CH:13]=[CH:12][C:11]=1[C:14]([F:17])([F:16])[F:15]
Reactant: FC(F)(F)c1ccc(-c2cc(Cl)ncn2)cc1Cl
Reactant: CC(C)(C)[S@@](=O)N[C@@H](CN)c1ccc(F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[S@@](=O)N[C@@H](CNc1cc(-c2ccc(C(F)(F)F)c(Cl)c2)ncn1)c1ccc(F)cc1
Temperature: 25 °C
Yield: 49.1 %

Procedure:
A solution of 4-chloro-6-(3-chloro-4-trifluoromethyl-phenyl)-pyrimidine (0.200 g, 0.68 mmol), (R,R)-2-methyl-propane-2-sulfinic acid [2-amino-1-(4-fluoro-phenyl)-ethyl]-amide (0.720 g, 2.79 mmol) and DIPEA (0.18 mL, 1.02 mmol) in DMF (5 mL) was heated at 80° C. for 16 h. The reaction mixture was cooled to rt, diluted with EtOAc (20 mL) and washed with NaCl (sat. aq., 2×30 mL). The organic layer was dried (MgSO4) and concentrated under reduced pressure. The crude residue was purified (FCC) to give the title compound (0.172 g, 50%) as a yellow solid. MS (ESI+): calcd for C23H23ClF4N4OS m/z 514.12. found 515.1 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12](=[O:20])[C:13]3[CH:18]=[CH:17][C:16](Cl)=[CH:15][CH:14]=3)=[CH:9][CH:10]=2)[CH2:5][C:4]1=[O:21])[CH3:2].C(N1C2C(=CC(C(=O)C3C=CC(F)=CC=3)=CC=2)CC1=O)C.C(N1C2C(=CC(C(=O)C3C=CC(C)=CC=3)=CC=2)CC1=O)C.C(N1C2C(=CC(C(=O)C3C=CC(C#N)=CC=3)=CC=2)CC1=O)C>>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12](=[O:20])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:9][CH:10]=2)[CH2:5][C:4]1=[O:21])[CH3:2]
Reactant: CCN1C(=O)Cc2cc(C(=O)c3ccc(Cl)cc3)ccc21
Agent: CCN1C(=O)Cc2cc(C(=O)c3ccc(C#N)cc3)ccc21
Agent: CCN1C(=O)Cc2cc(C(=O)c3ccc(C)cc3)ccc21
Agent: CCN1C(=O)Cc2cc(C(=O)c3ccc(F)cc3)ccc21
Product: CCN1C(=O)Cc2cc(C(=O)c3ccccc3)ccc21

Procedure:
In a similar manner were prepared 1-ethyl-5-(4-chlorobenzoyl)oxindole, m.p. 154°-156° C.; 1-ethyl-5-(4-fluorobenzoyl)oxindole, m.p. 110°-120° C.; 1-ethyl-5-(4-methylbenzoyl)oxindole, m.p. 169°-170° C.; 1-ethyl-5-(4-cyanobenzoyl)oxindole, m.p. 163°-168° C.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]=[C:2]2[C:8]1[N:13]=[C:12]([CH2:14][NH:15][C@H:16]([CH:19]([CH3:21])[CH3:20])[CH2:17][OH:18])[C:11]([F:22])=[CH:10][CH:9]=1>[Pd]>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[C:8]1[N:13]=[C:12]([CH2:14][NH:15][C@H:16]([CH:19]([CH3:20])[CH3:21])[CH2:17][OH:18])[C:11]([F:22])=[CH:10][CH:9]=1
Reactant: CC(C)[C@H](CO)NCc1nc(C2=CC3CCC2C3)ccc1F
Agent: [Pd]
Product: CC(C)[C@H](CO)NCc1nc(C2CC3CCC2C3)ccc1F

Procedure:
A microwave vial was charged with SiliaCat DPP-Pd (0.10 equivalent, 127 mg, purchased from Silicycle). A solution of Example 73A (100 mg, 0.30 mmol) in ethanol (1.0 mL) was added, followed by a solution of bicyclo[2.2.1]hept-2-en-2-ylboronic acid (41 mg, 0.30 mmol) in ethanol (1.0 mL) and 1 M aqueous Cs2CO3 (1.03 mL). The resulting mixture was heated in a microwave for 20 minutes at 120° C., filtered, and concentrated to provide (2R)-2-(((6-(bicyclo[2.2.1]hept-2-en-2-yl)-3-fluoropyridin-2-yl)methyl)amino)-3-methylbutan-1-ol. (2R)-2-(((6-(bicyclo[2.2.1]hept-2-en-2-yl)-3-fluoropyridin-2-yl)methyl)amino)-3-methylbutan-1-ol was subjected to hydrogenation (H2 atmosphere, Pd/C catalyst) then purified by reverse phase HPLC to provide the title compound. MS (ESI+) m/z 307 (M+H)+.
Reaction SMILES: Cl[C:2](=[N:9][OH:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:11]([O:15][C:16]([NH:18][CH2:19][C:20]#[CH:21])=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>C1COCC1>[C:11]([O:15][C:16]([NH:18][CH2:19][C:20]1[O:10][N:9]=[C:2]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH:21]=1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: ON=C(Cl)c1ccccc1
Reactant: C#CCNC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCc1cc(-c2ccccc2)no1
Temperature: 25 °C
Reaction time: 48 h
Yield: 53.9 %

Procedure:
A solution of α-chlorobenzaldehyde oxime (Method 22; 1 g, 6.4 mmol) in THF (13 ml) was added dropwise to a solution of N-tert-butoxycarbonyl-propargylamine (0.5 g, 3.2 mmol) and triethylamine (0.9 ml, 6.4 mmol) in THF (25 ml) cooled with an ice bath. The mixture was allowed to warm to ambient temperature and stirred for 2 days. The volatiles were removed by evaporation and the residue dissolved in DCM. The solution was washed with water and brine, dried (MgSO4) and the solvent removed by evaporation. The residue was triturated with isohexane/ether (9:1) and collected by filtration to give the title compound (473 mg, 54%). NMR (CDCl3) 1.45 (s, 9H), 4.45 (d, 2H), 5.10 (bs, 1H), 6.5 (s, 1H), 7.42 (m, 3H), 7.8 (m, 2H).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[C:9]([O:13][CH3:14])=[CH:8][C:7]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[C:21]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:22]([CH3:24])[NH:23][C:16]=23)[CH2:3][CH2:2]1.Cl[CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36]>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[C:9]([O:13][CH3:14])=[CH:8][C:7]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[C:21]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:22]([CH3:24])[N:23]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:16]=23)[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1c(C)[nH]c2c(-c3cc(OC)c(F)cc3OCC3CC3)ccnc12
Reactant: C[Si](C)(C)CCOCCl
Product: CCOC(=O)c1c(C)n(COCC[Si](C)(C)C)c2c(-c3cc(OC)c(F)cc3OCC3CC3)ccnc12

Procedure:
Starting from ethyl 7-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxylate (example D.a7) and commercially available (2-chloromethoxy-ethyl)-trimethyl-silane the title compound is prepared as pale yellow viscous oil.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]3=[N:20][CH:21]=[CH:22][CH:23]=[C:18]3[C:17]([O:24][CH3:25])=[N:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1>[Pd].CO>[CH3:25][O:24][C:17]1[C:18]2[C:19](=[N:20][CH:21]=[CH:22][CH:23]=2)[N:15]([C:12]2[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=2)[N:16]=1
Reactant: COc1nn(-c2ccc(OCc3ccccc3)cc2)c2ncccc12
Agent: [Pd]
Solvent: CO
Product: COc1nn(-c2ccc(O)cc2)c2ncccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.4 %

Procedure:
A suspension of 1-[4-(benzyloxy)phenyl]-3-methoxy-1H-pyrazolo[3,4-b]pyridine (1.1 g) and 10% palladium on carbon (containing water (50%), 0.10 g) in methanol (50 ml) was stirred for 3 hr under a hydrogen atmosphere at room temperature. The reaction mixture was filtered through celite, and the filtrate was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (0.50 g).
Reaction SMILES: [C:1]([C:3]([C:23](=O)[CH3:24])=[CH:4][C:5]1[O:13][C:12]2[CH:11]=[CH:10][N:9]=[C:8]([NH:14][C:15](=[O:22])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:7]=2[CH:6]=1)#[N:2].[NH2:26][C:27]([CH:31]([F:33])[F:32])=[CH:28][C:29]#[N:30]>CC(O)C>[C:29]([C:28]1[CH:4]([C:5]2[O:13][C:12]3[CH:11]=[CH:10][N:9]=[C:8]([NH:14][C:15](=[O:22])[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:7]=3[CH:6]=2)[C:3]([C:1]#[N:2])=[C:23]([CH3:24])[NH:26][C:27]=1[CH:31]([F:33])[F:32])#[N:30]
Reactant: N#CC=C(N)C(F)F
Reactant: CC(=O)C(C#N)=Cc1cc2c(NC(=O)c3ccccc3)nccc2o1
Solvent: CC(C)O
Product: CC1=C(C#N)C(c2cc3c(NC(=O)c4ccccc4)nccc3o2)C(C#N)=C(C(F)F)N1

Procedure:
A mixture of 200 mg (0.604 mmol) N-{2-(2-cyano-3-oxobut-1-en-1-yl)furo[3,2-c]pyridin-4-yl}benzamide (Example 4A) and 285 mg (2.41 mmol) 3-amino-4,4-difluorobut-2-enenitrile [obtainable by Thorpe reaction of acetonitrile with 2,2-difluoroacetonitrile, cf. Org. React. 15, 1 (1967), ibid. 31, 1 (1984)] in 2-propanol (1 ml) was stirred at reflux for 12 h. Upon cooling, the mixture was concentrated under reduced pressure, and the residue was directly purified by preparative RP-HPLC (acetonitrile/water+0.1% TFA gradient, final mixture 90:10 v/v) to yield 176 mg (67% of th.) of the racemic title compound.
Reaction SMILES: [O:1]([CH2:8][C:9]1[CH:20]=[CH:19][C:12]([O:13][CH:14]([CH3:18])[C:15](N)=[O:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)[OH:22].[OH-].[K+]>C(O)C>[O:1]([CH2:8][C:9]1[CH:20]=[CH:19][C:12]([O:13][CH:14]([CH3:18])[C:15]([OH:22])=[O:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(O)O
Reactant: CC(Oc1ccc(COc2ccccc2)cc1)C(N)=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(Oc1ccc(COc2ccccc2)cc1)C(=O)O

Procedure:
One gram of 2-(4-phenoxymethylphenoxy)-propionamide (obtainable from the nitrile with sulfuric acid at 25°) and 2 g. of KOH are refluxed in 40 ml. of ethanol for 3 hours; after evaporation, the mixture is worked up as usual, yielding 2-(4-phenoxymethylphenoxy)-propionic acid.