Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]([C:11]1([C:16]([CH3:20])([CH3:19])[CH2:17][CH3:18])[CH:15]=[CH:14][CH:13]=[CH:12]1)([CH3:10])[CH2:8][CH3:9].S(C1C=CC(C)=CC=1)(O[CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])(=O)=O.O>CCCCCC.O1CCCC1.O1CCCC1.CCCCCC>[CH3:28][N:27]([CH2:26][CH2:25][C:15]1[C:11]([C:16]([CH3:19])([CH3:20])[CH2:17][CH3:18])([C:7]([CH3:6])([CH3:10])[CH2:8][CH3:9])[CH:12]=[CH:13][CH:14]=1)[CH3:29]
Reactant: Cc1ccc(S(=O)(=O)OCCN(C)C)cc1
Reactant: CCC(C)(C)C1(C(C)(C)CC)C=CC=C1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: CCC(C)(C)C1(C(C)(C)CC)C=CC=C1CCN(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Twenty-five mL of a 1.6 molar solution of n-butyllithium in hexane was added dropwise to a cooled (0° C. ) solution of di-(1,1-dimethyl-propyl)cyclopentadiene (8.25 g; 40.0 mmol) in dry tetrahydrofuran (125 ml) under a nitrogen atmosphere in a 250 mL three-necked round-bottomed flask provided with a magnetic stirrer and a dropping funnel. After 24 hours of stirring at room temperature, a solution of 2-dimethylaminoethyl tosylate (40.0 mmol) prepared in situ in tetrahydrofuran/hexane was added. After 18 hours of stirring, the conversion was found to be 91%, and water (100 mL) was carefully added dropwise to the reaction mixture and the tetrahydrofuran was then distilled off. The crude product was extracted with ether, and the combined organic phase was then dried with sodium sulphate, and boiled down. The residue was purified on a silica gel column, which resulted in 9.1 grams (82%) of (dimethyl-aminoethyl)di(1,1-dimethyl-propyl)cyclopentadiene.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:5][C@H:4]1[CH2:6][C:7]([OH:9])=[O:8].[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[OH:1][CH2:2][C@@H:3]1[CH2:5][C@H:4]1[CH2:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8]
Reactant: BrCc1ccccc1
Reactant: O=C(O)C[C@@H]1C[C@H]1CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(C[C@@H]1C[C@H]1CO)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.6 %

Procedure:
A mixture of trans-2-(2-(hydroxymethyl)cyclopropyl)acetic acid (50 mg, 0.38 mmol), benzyl bromide (0.050 mL, 0.42 mmol), potassium carbonate (58.4 mg, 0.42 mmol) and DMF (2 mL) was stirred overnight at room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 5→80% ethyl acetate/hexane) to give benzyl trans-2-(2-(hydroxymethyl)cyclopropyl)acetate (44.0 mg, 0.200 mmol, 52%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[S:14][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:16][CH:17]=3)=[CH:11][C:10]([C:22]#[N:23])=[N:9]2)=[CH:4][CH:3]=1.[CH:24](O)=[O:25]>>[CH:24]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[S:14][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:16][CH:17]=3)=[CH:11][C:10]([C:22]#[N:23])=[N:9]2)=[CH:4][CH:3]=1)=[O:25]
Reactant: CS(=O)(=O)c1ccc(-c2cc(C#N)nn2-c2ccc(N)cc2)s1
Reactant: O=CO
Product: CS(=O)(=O)c1ccc(-c2cc(C#N)nn2-c2ccc(NC=O)cc2)s1

Procedure:
A mixture of 1-(4-aminophenyl)-5-[5-(methylsulfonyl)-2-thienyl]pyrazole-3-carbonitrile (1.1 g) and formic acid (5 ml) was refluxed for 30 minutes. The mixture was concentrated and the residue was triturated in water to give crystals of 1-[4-(formylamino)phenyl]-5-[5-(methylsulfonyl)-2-thienyl]pyrazole-3-carbonitrile (1.1 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[NH:4][CH:5]([C:9]([N:11]1[CH:15]([C:16]2[NH:17][CH:18]=[C:19]([C:21]3[CH:26]=[CH:25][C:24](Br)=[CH:23][CH:22]=3)[N:20]=2)[CH2:14][N:13]([C:28](=[O:35])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:12]1)=[O:10])[CH:6]([CH3:8])[CH3:7].[CH3:37][O:38][C:39](=[O:72])[NH:40][CH:41]([C:45]([N:47]1[CH2:51][CH2:50][CH2:49][CH:48]1[C:52]1[NH:53][CH:54]=[C:55]([C:57]2[CH:62]=[CH:61][C:60](B3OC(C)(C)C(C)(C)O3)=[CH:59][CH:58]=2)[N:56]=1)=[O:46])[CH:42]([CH3:44])[CH3:43].C(=O)([O-])[O-].[K+].[K+].COCCOC>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.O>[CH3:1][O:2][C:3](=[O:36])[NH:4][CH:5]([C:9]([N:11]1[CH:15]([C:16]2[NH:20][C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:60]4[CH:61]=[CH:62][C:57]([C:55]5[NH:56][C:52]([CH:48]6[CH2:49][CH2:50][CH2:51][N:47]6[C:45](=[O:46])[CH:41]([NH:40][C:39]([O:38][CH3:37])=[O:72])[CH:42]([CH3:44])[CH3:43])=[N:53][CH:54]=5)=[CH:58][CH:59]=4)=[CH:23][CH:22]=3)=[CH:18][N:17]=2)[CH2:14][N:13]([C:28](=[O:35])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:12]1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)NC(C(=O)N1CN(C(=O)c2ccccc2)CC1c1nc(-c2ccc(Br)cc2)c[nH]1)C(C)C
Reactant: COC(=O)NC(C(=O)N1CCCC1c1nc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c[nH]1)C(C)C
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: [K+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(C5CN(C(=O)c6ccccc6)CN5C(=O)C(NC(=O)OC)C(C)C)[nH]4)cc3)cc2)[nH]1)C(C)C
Temperature: 120 °C

Procedure:
{1-[1′-Benzoyl-4-(4-bromo-phenyl)-1′,2′,4′,5′-tetrahydro-1H-[2,4′]biimidazolyl-3′-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (crude, <0.101 mmol) was combined with [2-Methyl-1-(2-{4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamic acid methyl ester (45.1 mg, 0.091 mmol) under an argon atmosphere. Potassium carbonate (27.8 mg, 0.202 mmol) and Pd(PPh3)4 (10 mg, 0.009 mmol) were added, followed by DME (2.0 mL) and water (0.4 mL). The mixture was heated under microwave conditions for 20 minutes at 120° C. All volatiles were removed in vacuo and the crude material was dissolved in DMF and purified via RP-HPLC (eluent: water/MeCN w 0.1% TFA) to yield the product {1-[1′-Benzoyl-5-(4′-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1′,2′,4′,5′-tetrahydro-1H-[2,4′]biimidazolyl-3′-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (20.7 mg): LCMS-ESI+: calc'd for C46H53N9O7: 843.9 (M+). Found: 844.3 (M+H+); 1H-NMR: 300 MHz, (MeOH-d4) δ: 7.90-7.84 (m, 10H), 7.66-7.52 (m, 5H), 5.68 (m, 1H), 5.59 (m, 1H), 5.49 (m, 1H), 5.26 (m, 1H), 4.24 (d, J=7.5 Hz, 1H), 4.11 (m, 2H), 3.86 (m, 2H), 3.66 (s, 3H), 3.65 (s, 3H), 3.46 (d, J=5.7 Hz, 1H), 2.57 (m, 1H), 2.29-2.09 (m, 5H), 1.01-0.85 (m, 12H).
Reaction SMILES: [I:1][C:2]1[N:3]=[N:4][C:5](I)=[CH:6][CH:7]=1.[CH3:9][O-:10].[Na+].O>CO>[CH3:9][O:10][C:5]1[N:4]=[N:3][C:2]([I:1])=[CH:7][CH:6]=1
Reactant: C[O-]
Reactant: Ic1ccc(I)nn1
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc(I)nn1
Temperature: 25 °C
Reaction time: 13 h
Yield: 86 %

Procedure:
To 2.73 g (8.23 mmol) of 3,6-diiodopyridazine were added 80 ml of methanol and 3.17 g (16.46 mmol) of 28 wt % of sodium methylate in methanol, and the mixture was stirred at room temperature for 13 hours. Water was added to the reaction mixture, and the solution was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The obtained crude product was purified by silica-gel column chromatography (200 ml of silica gel, hexane:ethyl acetate=8:1) to give 1.661 g (7.04 mmol) of 3-methoxy-6-iodopyridazine (yield: 86%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH2:10](Cl)[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:10]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: ClCC=Cc1ccccc1
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCC=Cc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 5 h
Yield: 76.7 %

Procedure:
24.4 g of 4-hydroxybenzaldehyde is mixed with 50 ml of dimethylformamide, 30.4 g of cinnamyl chloride and 30.4 g of potassium carbonate. The resulting mixture is stirred in a stream of nitrogen at 100°-110° C. for 5 hours and then cooled. The cooled mixture is added to 2 l of ice water to deposit solid. The solid is separated therefrom by filtration and then washed with water until the solid becomes neutral. The washed solid is dried and then recrystallized from 200 ml of ethanol to obtain 36.4 g of 4-cinnamyloxybenzaldehyde. Thus obtained 4-cinnamyloxybenzaldehyde has a melting point of 89.5°-90.5° C.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17](=[O:22])[CH2:18][C:19](=[O:21])[CH3:20])=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>[Pd].ClCCl>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][C:17](=[O:22])[CH2:18][C:19](=[O:21])[CH3:20])=[CH:13][CH:14]=1
Reactant: [H][H]
Reactant: CC(=O)CC(=O)CCc1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: ClCCl
Product: CC(=O)CC(=O)CCc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 11 h
Yield: 77.3 %

Procedure:
That is, 1.5 g of Pd-activated carbon (10%) was weighed in a nitrogen atmosphere and 20 ml of dichloromethane and 1.31 g (4.4 mmol) of 6-(4-benzyloxyphenyl)-2,4-hexanedione were added thereto. The atmosphere in the reaction system was exchanged with hydrogen at 1 atm and stirred at room temperature for 11 hours. The obtained reaction mixture was filtered to remove insoluble matter and the solvent was distilled off under reduced pressure. The residue was charged in a silica gel column and developed first with dichloromethane to remove byproducts. Subsequently, a solution containing a compound eluted from the column with a mixed solvent of 1:1 (by volume ratio) acetone/hexane was concentrated to dryness under reduced pressure to obtain 0.70 g (3.4 mmol) of the objective 6-(4-hydroxyphenyl)-2,4-hexanedione as pale yellow solid. Yield: 77%. Identification was performed by elementary analysis of C and H, and 1H-NMR.
Reaction SMILES: [N:1]1([C:7]2[CH:28]=[CH:27][C:10]([NH:11][C:12]3[N:17]=[C:16]([C:18]4[N:22]([CH:23]([CH3:25])[CH3:24])[C:21]([CH3:26])=[N:20][CH:19]=4)[CH:15]=[CH:14][N:13]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[Cl:38][CH2:39][C:40](Cl)=[O:41]>C(Cl)Cl>[Cl:38][CH2:39][C:40]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:28]=[CH:27][C:10]([NH:11][C:12]3[N:17]=[C:16]([C:18]4[N:22]([CH:23]([CH3:25])[CH3:24])[C:21]([CH3:26])=[N:20][CH:19]=4)[CH:15]=[CH:14][N:13]=3)=[CH:9][CH:8]=2)[CH2:2][CH2:3]1)=[O:41]
Reactant: Cc1ncc(-c2ccnc(Nc3ccc(N4CCNCC4)cc3)n2)n1C(C)C
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ncc(-c2ccnc(Nc3ccc(N4CCN(C(=O)CCl)CC4)cc3)n2)n1C(C)C
Reaction time: 2 h
Yield: 86.3 %

Procedure:
2-[4-(Piperazin-1-yl)anilino]-4-(1-isopropyl-2-methyl-1H-imidazol-5-yl)pyrimidine (Example 20; 1.89 g, 5 mmol), di-isopropylethylamine (0.956 ml, 5.5 mmol) in DCM (25 ml) was treated at 0° C. with chloroacetyl chloride (0.438 ml, 5.5 mmol). The mixture was stirred at ambient for 2 hours, diluted with DCM (25 ml), washed with aqueous saturated sodium bicarbonate solution (20 ml) and aqueous saturated sodium chloride solution (20 ml). The solution was dried and evaporated at reduced pressure to give the title compound, (1.96 g, 87%). NMR (CDCl3) 8.30 (d, 1H), 7.44 (d, 2H), 7.35 (s, 1H), 6.96 (s, 1H), 6.92 (d, 1H), 6.85 (d, 1H), 5.68-5.56 (m, 1H), 4.12 (s, 2H), 3.83-3.76 (m, 2H), 3.72-3.67 (m, 2H), 3.22-3.11 (m, 4H), 2.59 (s, 3H), 1.48 (d, 6H); m/z 454.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:16](Br)=[CH:15][CH:14]=[CH:13][C:10]=1[C:11]#[N:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]([O:22][C:23]([N:25]1[CH:30]2[CH2:31][CH2:32][CH:26]1[CH:27]=[C:28](B1OC(C)(C)C(C)(C)O1)[CH2:29]2)=[O:24])([CH3:21])([CH3:20])[CH3:19].C1COCC1.C(=O)([O-])[O-].[Na+].[Na+]>O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:18]([O:22][C:23]([N:25]1[CH:30]2[CH2:31][CH2:32][CH:26]1[CH:27]=[C:28]([C:16]1[CH:15]=[CH:14][CH:13]=[C:10]([C:11]#[N:12])[C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:29]2)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: N#Cc1cccc(Br)c1OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1C2C=C(B3OC(C)(C)C(C)(C)O3)CC1CC2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C2C=C(c3cccc(C#N)c3OCc3ccccc3)CC1CC2
Temperature: 25 °C
Yield: 64.5 %

Procedure:
To a flask was added 2-benzyloxy-3-bromobenzonitrile (1.29 g, 4.47 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylic acid tert-butyl ester (1.50 g, 4.47 mmol), and THF (30 mL), 2.0 M sodium carbonate in water (8.95 mL), and bis(triphenylphosphine)palladium(II) chloride (78 mg, 0.11 mmol). The reaction mixture was purged with nitrogen, heated to reflux overnight, cooled to room temperature, and concentrated. The resulting solution was diluted with DCM (25 mL) and washed with water (25 mL) The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by flash column chromatography eluting with ethyl acetate in hexanes (0-50%) to give partially purified product (1.2 g). (m/z): [M+H]+ calcd for C26H28N2O3 416.21; (-tert-butyl 361.2); found 361; (-Boc 317.2); found 317.
Reaction SMILES: [CH2:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[CH2:4][CH2:3][N:2]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].Br[C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[N:21]1[CH:22]=[CH:23][CH:24]=[C:19]([N:8]2[CH2:7][CH2:6][C:5]3([CH2:1][N:2]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:3][CH2:4]3)[CH2:10][CH2:9]2)[CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNCC2)C1
Reactant: Brc1cccnc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC2(CCN(c3cccnc3)CC2)C1
Temperature: 120 °C
Yield: 69 %

Procedure:
Sodium t-butylate (5.4 mmol, 3.0 eq.) was added to a stirred solution of tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate (1.8 mmol, 1.0 eq.) and 3-bromopyridine (1.8 mmol, 1.0 eq.) in toluene (30 ml) and the reaction mixture was degassed with N2. BINAP (0.108 mmol, 0.06 eq.) and Pd(OAc)2 (0.036 mmol, 0.02 eq.) were added and the reaction mixture obtained was heated at 120° C. for 12 h. The reaction mixture was filtered over Celite and the filtrate was concentrated in vacuo. The crude product was purified by column chromatography (silica gel, 30% ethyl acetate in hexane) in order to obtain the desired product. Yield: 69%
Reaction SMILES: [C:1](=[O:8])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[NH2:2].[OH-].[Na+].Cl[O:12]C(C)(C)C.CC[C@@H]1[C@@H]2C[C@H]([C@@H](OC3C4C(=CC=CC=4)C(O[C@@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C(OC)C=C4)N(CC2)C1.[Br:75][C:76]1[CH:77]=[C:78](/[CH:83]=[CH:84]/[C:85]2[CH:90]=[C:89]([F:91])[CH:88]=[CH:87][C:86]=2[F:92])[C:79]([F:82])=[N:80][CH:81]=1>C(O)CC.O>[Br:75][C:76]1[CH:77]=[C:78]([C@@H:83]([NH:2][C:1](=[O:8])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[C@@H:84]([C:85]2[CH:90]=[C:89]([F:91])[CH:88]=[CH:87][C:86]=2[F:92])[OH:12])[C:79]([F:82])=[N:80][CH:81]=1
Reactant: Fc1ccc(F)c(/C=C/c2cc(Br)cnc2F)c1
Reactant: CC(C)(C)OC(N)=O
Reactant: CC(C)(C)OCl
Agent: CC[C@H]1CN2CC[C@H]1C[C@@H]2[C@@H](Oc1nnc(O[C@@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCCO
Product: CC(C)(C)OC(=O)N[C@H](c1cc(Br)cnc1F)[C@H](O)c1cc(F)ccc1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To tert-butyl carbamate (0.462 g, 3.95 mmol) in propanol (6 mL) was added sodium hydroxide (0.155 g, 3.88 mmol) in water (12 mL) followed by tert-butyl hypochlorite (0.438 mL, 3.88 mmol). The solution was cooled to 0° C., and (DHQD)2PHAL (0.060 g, 0.076 mmol) was added in propanol (6 mL), followed by (E)-5-bromo-3-(2,5-difluorostyryl)-2-fluoropyridine (0.4 g, 1.273 mmol) as a solid. The remaining residue was dissolved in propanol (12 mL) and added to the reaction mixture to give a suspension. To this was added potassium osmate dihydrate (0.019 g, 0.051 mmol) as a solid in one portion. The reaction was allowed to gradually warm in the dewar overnight. The reaction was recooled to 0° C., and the reaction quenched by addition of sodium thiosulfate (0.5 g) in water (3 mL). The ice bath was removed, and the reaction stirred at room temperature for 30 min. The reaction was diluted with diethyl ether, washed with water (2×), then brine, dried over magnesium sulfate, and concentrated. Column chromatography (25% EtOAc/Hex) gave 0.445 g (78%) as a white foam solid. Mass spec.: 447.1 (MH)+.
Reaction SMILES: [CH2:1]([C:3]1([CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:8]2[NH:9][C:10]3[C:15]([C:7]=2[CH2:6][CH2:5][O:4]1)=[CH:14][CH:13]=[CH:12][C:11]=3[C:16]#[C:17][CH3:18])[CH3:2].[H][H]>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].CO>[CH2:1]([C:3]1([CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:8]2[NH:9][C:10]3[C:15]([C:7]=2[CH2:6][CH2:5][O:4]1)=[CH:14][CH:13]=[CH:12][C:11]=3/[CH:16]=[CH:17]\[CH3:18])[CH3:2]
Reactant: CC#Cc1cccc2c3c([nH]c12)C(CC)(CC(=O)OC)OCC3
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CO
Product: C/C=C\c1cccc2c3c([nH]c12)C(CC)(CC(=O)OC)OCC3
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.7 %

Procedure:
A mixture of 1-ethyl-8-(1-propynyl)-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid, methyl ester (155 mg, 0.5 mmol), Lindlar catalyst (15 mg), and methanol (10 mL) was charged with 1 atmosphere of hydrogen and allowed to stir at room temperature overnight. The catalyst was then removed by filtration through a celite plug, and the filtrate concentrated to give 170 mg of the crude product. This material was purified by flash chromatography (10% ethyl acetate/hexane, silica gel) to give the pure title compound as yellow oil (70 mg).
Reaction SMILES: B(F)(F)F.CCOCC.[N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][C:11]=1[CH2:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1.[C:30]([O:34][CH3:35])(=[O:33])[CH2:31][SH:32].[Cl:36][C:37]1[CH:44]=[CH:43][C:40]([CH2:41][SH:42])=[CH:39][CH:38]=1>C(Cl)Cl>[Cl:36][C:37]1[CH:44]=[CH:43][C:40]([CH2:41][S:42][CH:26]([S:32][CH2:31][C:30]([O:34][CH3:35])=[O:33])[C:25]2[CH:28]=[CH:29][C:22]([O:21][CH2:20][C:11]3[CH:12]=[CH:13][C:14]4[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=4)[N:10]=3)=[CH:23][CH:24]=2)=[CH:39][CH:38]=1
Reactant: O=Cc1ccc(OCc2ccc3ccccc3n2)cc1
Reactant: COC(=O)CS
Reactant: SCc1ccc(Cl)cc1
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)CSC(SCc1ccc(Cl)cc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
At 0° C., BF3 /Et2O (380 μL, 2.3 equiv.) was added to a solution of 4-(2-quinolinylmethoxy)benzaldehyde (Example 1, Step 1, 352 mg, 1.34 mmoles), methyl thioglycolate (130 μL, 1.1 equiv.) and 4-chlorobenzyl mercaptan (195 μL, 1.1 equiv.) in CH2Cl2 (7 mL) and the mixture was stirred at 0° C. an hour and at room temperature 15 minutes. 25% Aqueous NH4OAc was then added at 0° C. and the products were extracted with EtOAc, dried over Na2SO4 and separated by flash chromatography on silica using EtOAc:toluene 2.5:97.5 and 5:95 to yield the title compound.
Reaction SMILES: [C:1]([NH:5][C:6](=[O:8])[OH:7])([CH3:4])([CH3:3])[CH3:2].C[O:10][CH2:11][C:12]1([S:15]([NH2:18])(=[O:17])=[O:16])[CH2:14][CH2:13]1.[CH2:19]([N:22]=C=O)[CH2:20][CH3:21]>>[C:1]([NH:5][C:6](=[O:7])[OH:8])([CH3:4])([CH3:3])[CH3:2].[CH2:19]([NH:22][C:11]([C:12]1([S:15]([NH2:18])(=[O:17])=[O:16])[CH2:14][CH2:13]1)=[O:10])[CH2:20][CH3:21]
Reactant: CCCN=C=O
Reactant: COCC1(S(N)(=O)=O)CC1
Agent: CC(C)(C)NC(=O)O
Product: CCCNC(=O)C1(S(N)(=O)=O)CC1
Yield: 100 %

Procedure:
This compound was obtained in a crude 100% yield according to the procedure described for the synthesis of 1-methoxymethylcyclopropylsulfonylamine tert-butyl-carbamate except that 1.10 equivalents of n-propyl isocyanate was used as the electrophile. The compound was taken directly into the next reaction without purification: 1H NMR (CDCl3) δ 0.10 (m, 2H), 0.51 (m, 2H), 0.67 (m, 1H), 1.10 (m, 2H), 1.49 (s, 9H), 1.62 (m, 2H), 1.87 (d, J=7.0 Hz, 2H).
Reaction SMILES: [C:1]1([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.[Cl:18]CCCN1CCCCC1.Cl.ClCCC[N:33]1[CH2:38][CH2:37][CH2:36][CH:35]([C:39]2C=CC(OC)=[CH:41][CH:40]=2)[CH2:34]1>>[ClH:18].[C:1]1([CH:11]2[CH2:16][CH2:15][N:14]([CH2:41][CH2:40][CH2:39][CH:35]3[CH2:36][CH2:37][CH2:38][NH:33][CH2:34]3)[CH2:13][CH2:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: ClCCCN1CCCCC1
Reactant: COc1ccc(C2CCCN(CCCCl)C2)cc1
Reactant: c1ccc2c(C3CCNCC3)cccc2c1
Agent: Cl
Product: c1ccc2c(C3CCN(CCCC4CCCNC4)CC3)cccc2c1

Procedure:
Using 4-(1-naphthyl)piperidine (149 mg, 0.60 mmol) and 1-(3-chloropropyl)piperidine hydrochloride (166 mg, 0.84 mmol) instead of 4-(3-indolyl)piperidine and 1-(3-chloropropyl)-3-(4-methoxyphenyl)piperidine hydrochloride respectively, reaction, extraction, and concentration were carried out in the same procedure as Example 2. The resulting crude product was purified by column chromatography on a silica gel (silica gel NH-DM 1020 produced by Fuji Silysia Chemical Ltd., eluent; hexane:ethyl acetate=2:1) to afford a free form (202 mg) of the title compound as a yellow viscous oil. After adding hydrochloric acid/methanol to a solution of the free form in methanol, the mixture was concentrated and was then recrystallized from methanol/ether to afford the title compound (85 mg, yield: 35%) as white crystals.
Reaction SMILES: [F:1][C:2]1[CH:29]=[C:28]2[C:5]([CH2:6][CH2:7][C:8]3[C:9]2=[N:10][O:11][C:12]=3[C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:14]=2[C:24]([F:27])([F:26])[F:25])=[CH:4][C:3]=1[C:30]([O:32]C)=[O:31].O.[OH-].[Li+]>C1COCC1.O>[F:1][C:2]1[CH:29]=[C:28]2[C:5]([CH2:6][CH2:7][C:8]3[C:9]2=[N:10][O:11][C:12]=3[C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:14]=2[C:24]([F:25])([F:27])[F:26])=[CH:4][C:3]=1[C:30]([OH:32])=[O:31]
Reactant: COC(=O)c1cc2c(cc1F)-c1noc(-c3onc(-c4ccccc4)c3C(F)(F)F)c1CC2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc2c(cc1F)-c1noc(-c3onc(-c4ccccc4)c3C(F)(F)F)c1CC2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of methyl 8-fluoro-3-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-4,5-dihydronaphtho[1,2-c]isoxazole-7-carboxylate (Preparation 67C, 0.050 g, 0.109 mmol) and lithium hydroxide monohydrate (0.005 g, 0.119 mmol) in THF (4.0 mL) and water (4 mL) was stirred at room temperature for 4 h. An additional amount of lithium hydroxide monohydrate (0.005 g, 0.119 mmol) was added and the contents stirred at room temperature for 2 h. The reaction mixture was concentrated under vacuum and the residue was partitioned between ethyl acetate (3×10 mL) and water (5.0 mL). The ethyl acetate extracts were combined, dried, and concentrated to give 8-fluoro-3-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-4,5-dihydronaphtho[1,2-c]isoxazole-7-carboxylic acid as a white solid. [40 mg, 0.090 mmol, 83%]. The product had an HPLC ret. time=4.15 min. (condition B). LC/MS M+1=445.0.