Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[CH2:12][NH:11][C:10]2[N:15]=[CH:16][C:17]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=3)[C:22]([OH:24])=O)=[CH:18][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28]([NH2:30])[CH3:29]>>[CH2:1]([N:8]1[C:13](=[O:14])[CH2:12][NH:11][C:10]2[N:15]=[CH:16][C:17]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=3)[C:22]([NH:30][CH2:28][CH3:29])=[O:24])=[CH:18][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2ccccc2)C(=O)CN3)c1
Product: CCNC(=O)c1cccc(-c2cnc3c(c2)N(Cc2ccccc2)C(=O)CN3)c1
Yield: 3 %

Procedure:
3-(1-Benzyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)benzoic acid (35 mg) was coupled with ethylamine as in General Procedure 8 to give the title compound as a yellow solid (3% yield). LCMS: m/z=387.26 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 1.27 (3H, t, J=7.2 Hz), 3.47 (2H, quartet, J=7.2 Hz), 4.50 (2H, s), 5.28 (2H, s), 7.36 (8H, m), 7.48 (1H, t, J=7.6 Hz), 7.79 (2H, m), 7.84 (1H, s).
Reaction SMILES: [CH:1]1[C:13]2[C:12](=[O:14])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:15][Mg+].[Br-]>C1COCC1>[CH3:15][C:12]1([OH:14])[C:13]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[C:6]2[C:11]1=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: C[Mg+]
Reactant: O=C1c2ccccc2-c2ccccc21
Agent: [Br-]
Solvent: C1CCOC1
Product: CC1(O)c2ccccc2-c2ccccc21
Temperature: 0 °C

Procedure:
In a glovebox, in a 50 mL round bottom flask, 9H-fluorene-9-one (5.458 g, 30.3 mmol) was dissolved in 20 mL of THF and cooled to 0° C. for 30 minutes. MeMgBr (1.2 eq.) was then slowly added via syringe while stirring. A slurry formed once all of the Grignard was added. The reaction was allowed to stir for 48 hours. The flask was then removed from the glovebox and 4 mL of 2M NaOH were added. The mixture was washed with brine and the organic portion collected and dried over MgSO4, filtered and the volatiles removed under a N2 stream. NMR of the resultant yellow solid showed pure 9-methyl-9H-fluoren-9-ol. Yield is 5.67 g (95 wt %).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1.[CH:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1(C)C=CC=CC=1>C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[C:10]1([C@@H:9]2[N:7]3[C:6](=[O:8])[CH2:5][CH2:4][CH:3]3[CH2:2][O:1]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C1CCC(CO)N1
Reactant: O=Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1CCC2CO[C@H](c3ccccc3)N12
Reaction time: 9 h
Yield: 86 %

Procedure:
A mixture of 5-hydroxymethyl-2-pyrrolidone (85.0 g), benzaldehyde (98.0 g), p-toluenesulfonic acid (1.6 g) and toluene (500 ml) was heated to reflux using a Dean-Stark water separator and an oil bath, with vigorous stirring. After nine hours, the collection of water stopped and the cooled reaction mixture was washed with 5% sodium bicarbonate solution (2×50 ml), saturated sodium bisulfite solution (4×50 ml), water (2×50 ml) and brine (1×50 ml). The toluene solution was dried over anhydrous magnesium sulfate and the solvent removed on a rotary evaporator. The residue obtained was distilled, 145°-150° C./0.1 mm Hg to give the title compound as an oil (129.0 g). [α]D =+269.6° (chloroform; c=1). TLC single spot at Rf =0.5 (silica gel, ethyl acetate-hexane; 4:1 UV and iodine).
Reaction SMILES: C([O:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[CH:14][NH:15]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[H-].[Na+].[CH:20]([Si:23](Cl)([CH:27]([CH3:29])[CH3:28])[CH:24]([CH3:26])[CH3:25])([CH3:22])[CH3:21]>O1CCCC1>[CH:20]([Si:23]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[N:15]1[C:16]2[C:12](=[CH:11][CH:10]=[C:9]([OH:8])[CH:17]=2)[CH:13]=[CH:14]1)([CH3:22])[CH3:21]
Reactant: c1ccc(COc2ccc3cc[nH]c3c2)cc1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2ccc(O)cc21

Procedure:
6-Benzyloxy-indole (1.0 g) was treated with NaH (135 mg) and triisopropylsilyl chloride (1.0 g) in tetrahydrofuran for 1 hour, purified by flash chromatography (98/2 ethyl acetate/hexanes), then debenzylated in ethanol (35 mL) using Pearlman's catalyst (0.19 g) and a hydrogen balloon.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[CH:11][C:10]2[C:5](=[N:6][C:7](=[O:16])[C:8](=[O:15])[N:9]=2)[CH:4]=1.[N+]([O-])(O)=O.[C:21]([OH:24])(=[O:23])[CH3:22]>>[C:21]([O:24][C:4]1[C:5]2[C:10]([CH:11]=[C:12]([O:13][CH3:14])[C:3]=1[O:2][CH3:1])=[N:9][C:8](=[O:15])[C:7](=[O:16])[N:6]=2)(=[O:23])[CH3:22]
Reactant: COc1cc2c(cc1OC)=NC(=O)C(=O)N=2
Reactant: CC(=O)O
Solvent: O=[N+]([O-])O
Product: COc1cc2c(c(OC(C)=O)c1OC)=NC(=O)C(=O)N=2
Temperature: 25 °C
Reaction time: 24 h
Yield: 54 %

Procedure:
6,7-Dimethoxy-2,3-quinoxalinedione (45) (222 mg, 1.0 mmol) was dissolved in glacial acetic acid (10 mL) at 100° C. (oil bath). The oil bath was removed and fuming nitric acid (53 μL, 1.2 mmol; Baker) was added dropwise to the solution. The reaction mixture was then stirred at room temperature for 24 h. The mixture was filtered and washed with water to give a white solid, giving 150 mg (54%) of the title compound; mp 321°-322° C.; 1H NMR (DMSO-d6, 300 MHz) δ2.300 (s, 3H), 3.619 (s, 3H), 3.746 (s, 3H), 6.661 (s, 1H), 11.700 (s, 1H), 11.832 (s, 1H). EIMS m/e 280 (M+, 30), 238 (100). Anal. Calcd for C12H12N2O6 : C, 51.43; H, 4.32; N, 10.00. Found: C, 51.29; H, 4.04; N, 9.90. (HPLC purity>99%).
Reaction SMILES: [OH:1][C:2]([CH3:26])([CH3:25])[C:3]#[C:4][C:5]1[CH:6]=[C:7]2[C:18]3([CH2:22][O:21][C:20]([NH2:23])=[N:19]3)[C:17]3[C:12](=[N:13][CH:14]=[C:15]([Br:24])[CH:16]=3)[O:11][C:8]2=[CH:9][CH:10]=1.CO.[CH3:29]S(O)(=O)=O.C(OCC)(=O)C>C(=O)(O)[O-].[Na+]>[CH3:29][O:1][C:2]([CH3:26])([CH3:25])[C:3]#[C:4][C:5]1[CH:6]=[C:7]2[C:18]3([CH2:22][O:21][C:20]([NH2:23])=[N:19]3)[C:17]3[C:12](=[N:13][CH:14]=[C:15]([Br:24])[CH:16]=3)[O:11][C:8]2=[CH:9][CH:10]=1
Reactant: CS(=O)(=O)O
Reactant: CC(C)(O)C#Cc1ccc2c(c1)C1(COC(N)=N1)c1cc(Br)cnc1O2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(C)(C)C#Cc1ccc2c(c1)C1(COC(N)=N1)c1cc(Br)cnc1O2
Temperature: 60 °C
Yield: 87 %

Procedure:
To a flask charged with 7-(3-hydroxy-3-methyl-1-butyn-1-yl)-3-bromo-spiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazol]-2′-amine (340 mg, 0.821 mmol) was added methanol (9962 μL, 246 mmol) and methane sulfonic acid (533 μL, 8.21 mmol). The flask was sealed and heated at 60° C. for 3 hours. The reaction was diluted with saturated sodium bicarbonate (100 mL) and poured into a separatory funnel containing ethyl acetate (50 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to provide a tan solid that was purified by silica gel chromatography (Redi-Sep pre-packed silica gel column (40 g), 0-10% methanol in methylenechloride with 0.1% ammonium hydroxide) to provide 7-(3-methoxy-3-methyl-1-butyn-1-yl)-3-bromo-spiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazol]-2′-amine (306 mg, 0.714 mmol, 87% yield) as a tan solid. MS m/z=428.0 [M+H]+. Calc'd for C20H19BrN3O3: 428.1.
Reaction SMILES: [OH:1][CH:2]([CH3:10])/[CH:3]=[CH:4]/[C:5]([O:7][CH2:8][CH3:9])=[O:6].N1C=CC=CC=1.[Cl:17][CH2:18][C:19](Cl)=[O:20]>CN(C1C=CN=CC=1)C.C1COCC1>[Cl:17][CH2:18][C:19]([O:1][CH:2]([CH3:10])/[CH:3]=[CH:4]/[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:20]
Reactant: O=C(Cl)CCl
Reactant: CCOC(=O)/C=C/C(C)O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/C(C)OC(=O)CCl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 74 %

Procedure:
21 (rac-Ethyl (2E)-4-hydroxypent-2-enoate) (crude, HPLC: ˜94 area %, 9.20 g, 60 mmol), pyridine (9.7 ml, 0.12 mol) and DMAP (1.47 g, 12 mmol) are dissolved in THF (300 ml) and cooled to 0° C. Chloroacetylchloride (9.6 ml, 0.12 mol) in THF (60 ml) is added dropwise under stirring at ≦2° C. over 10 min. The reaction mixture is stirred 40 min at 0° C. The resulting suspension is then poured onto H2O (250 ml) and extracted with tBuOMe (1 l). The organic phase is washed with saturated NaHCO3 (100 ml), 1 M HCl (100 ml), H2O (3×100 ml) and brine (100 ml) successively. The organic phase is dried with Na2SO4 and evaporated under reduced pressure at 40° C. The residue is purified by HPLC (tBuOMe:hexane fraction 5:95) and yields 30 (rac-Ethyl (2E)-4-(chloroacetoxy)pent-2-enoate) (9.81 g, 74%) as a yellowish oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15].O.O.O.C([O-])(=O)C.[Na+]>C(O)C>[CH3:17][O:16][C:14]([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:15]
Reactant: COC(=O)CCCCCBr
Reactant: Nc1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COC(=O)CCCCCNc1ccccc1
Temperature: 0 °C

Procedure:
Aniline (2.79 g, 2.73 ml), 6.27 g of methyl 6-bromohexanoate and 12.24 g (0.09 mole) of sodium acetate trihydrate are heated at 80°-100° overnight in 15 ml of absolute ethanol. After cooling, the mixture is poured into 75 ml of ice-water and extracted with ether. The organic extract is washed with water, dried over magnesium sulfate and evaporated in vacuo to give N-(5-methoxycarbonylpentyl)aniline.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[NH2:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.O>CS(C)=O>[N:14]1([CH2:13][CH2:12][NH:11][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=2)[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: O=[N+]([O-])c1cccc(F)c1
Reactant: NCCN1CCOCC1
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])c1cccc(NCCN2CCOCC2)c1
Temperature: 100 °C
Reaction time: 60 h

Procedure:
28.2 g 3-fluoronitrobenzene and 143 g 4-(2-aminoethyl)morpholine were dissolved in 300 ml dimethyl sulfoxide, and the batch was stirred for 60 h at 100° C. After cooling, the batch was poured into 1 l water. The mixture was extracted several times with methyl tert-butyl ether, and the combined organic phases were reduced to dryness in a rotary evaporator, yielding a dark liquid.
Reaction SMILES: C(O[C:4](=[O:33])[C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[C:8]([O:21][CH2:22][CH2:23][OH:24])=[C:7]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[CH:6]=1)C.[C:34]1([CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][NH2:48])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[C:34]1([CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][NH:48][C:4](=[O:33])[C:5]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:18])([F:19])[F:20])[CH:12]=3)[C:8]([O:21][CH2:22][CH2:23][OH:24])=[C:7]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[CH:6]=2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: NCCCCCCCCc1ccccc1
Reactant: CCOC(=O)c1cc(-c2ccc(OC)cc2)c(OCCO)c(-c2cccc(C(F)(F)F)c2)c1
Product: COc1ccc(-c2cc(C(=O)NCCCCCCCCc3ccccc3)cc(-c3cccc(C(F)(F)F)c3)c2OCCO)cc1

Procedure:
The product was prepared as a viscous yellow oil (0.165 g, 61%) from 3-(4-methoxyphenyl)-5-(3-trifluoromethylphenyl)-4-(2-hydroxyethoxy)benzoic acid ethyl ester and 8-phenyloctylamine using a procedure similar to step 2 of example 1; 1H NMR (300 MHz, DMSO-d6) δ 1.21-1.34 (m, 8H), 1.45-1.58 (m, 4H), 2.50 (t, J=7.5 Hz, 2H), 3.10 (q, J=6 Hz, 2H), 3.20-3.30 (m, 4H), 3.80 (s, 3H), 4.38 (t, J=6 Hz, 1H), 7.01-7.05 (m, 2H), 7.10-7.25 (m, 5H),7.60 (d, J=9 Hz, 2H), 7.68-7.78 (m, 2H), 7.84-7.88 (m, 2H), 7.90-7.95 (m, 2H), 8.54 (t, J=5 Hz, 1H); mass spectrum [(+)ESI], m/z 620 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH:18]3[CH2:23][CH2:22][N:21]([CH:24]([CH3:28])[CH2:25][CH2:26][NH2:27])[CH2:20][CH2:19]3)[O:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[O:10]2)=[CH:5][CH:4]=1.[CH3:29][C:30]1[C:35]([C:36](O)=[O:37])=[C:34]([CH3:39])[N:33]=[CH:32][N:31]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH:18]3[CH2:23][CH2:22][N:21]([CH:24]([CH3:28])[CH2:25][CH2:26][NH:27][C:36]([C:35]4[C:30]([CH3:29])=[N:31][CH:32]=[N:33][C:34]=4[CH3:39])=[O:37])[CH2:20][CH2:19]3)[O:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[O:10]2)=[CH:5][CH:4]=1
Reactant: Cc1ncnc(C)c1C(=O)O
Reactant: COc1ccc(C2(C3CCN(C(C)CCN)CC3)Oc3ccccc3O2)cc1
Product: COc1ccc(C2(C3CCN(C(C)CCNC(=O)c4c(C)ncnc4C)CC3)Oc3ccccc3O2)cc1
Yield: 62.5 %

Procedure:
Using general procedure E, 3-{4-[2-(4-methoxy-phenyl)-benzo[1,3]dioxol-2-yl]-piperidin-1-yl}-butylamine (see EXAMPLE 284) (50 mg, 0.13 mmol) and 4,6-dimethyl-pyrimidine-5-carboxylic acid (24 mg, 0.16 mmol) afforded COMPOUND 285 as a white solid (42 mg, 63%). 1H NMR (CDCl3) δ 0.70-0.84 (m, 1H), 0.94 (d, 3H, J=6.6 Hz), 0.95-1.08 (m, 1H), 1.45-1.63 (m, 3H), 1.66-1.80 (m, 1H), 1.86-1.98 (m, 2H), 2.38 (t, 1H, J=11.4 Hz), 2.52 (s, 6H), 2.66-2.84 (m, 3H), 3.22-3.31 (m, 1H), 3.79 (s, 3H), 3.87-3.97 (m, 1H), 6.74-6.79 (m, 2H), 6.83-6.88 (m, 3H), 6.91-6.94 (m, 1H), 7.29 (d, 2H, J=9.0 Hz), 8.86-8.88 (m, 1H), 9.08 (s, 1H). 13C NMR (CDCl3) δ 13.37, 22.07, 25.89, 26.55, 30.77, 40.43, 43.83, 45.63, 52.47, 55.45, 60.96, 108.65, 108.73, 113.61, 118.42, 121.44, 126.99, 131.00, 131.96, 147.38, 147.50, 157.84, 159.96, 163.05, 166.71. ES-MS m/z 517 (M+H). Anal. Calcd. for C30H36N4O4.0.1CH2Cl2: C, 68.85; H, 6.95; N, 10.67. Found: C, 69.00; H, 7.03; N, 10.76.
Reaction SMILES: CO[C:3](=[O:20])[C:4]([C:9](=[O:19])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([F:18])[CH:11]=1)=[CH:5]OCC.[CH3:21][C:22]1[N:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=1.C1(OC2C=CC=CC=2)C=CC=CC=1>>[F:18][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][C:13]=1[O:16][CH3:17])[C:9]([C:4]1[C:3](=[O:20])[C:26]2[C:25](=[CH:24][CH:23]=[C:22]([CH3:21])[N:27]=2)[NH:28][CH:5]=1)=[O:19]
Reactant: CCOC=C(C(=O)OC)C(=O)c1ccc(OC)c(F)c1
Reactant: Cc1ccc(N)cn1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COc1ccc(C(=O)c2c[nH]c3ccc(C)nc3c2=O)cc1F
Yield: 40.1 %

Procedure:
Experimental conditions analogous to those described for Step 1 of Example 1 were used with 0.50 g (1.86 mmol) of 3-Ethoxy-2-(3-fluoro-4-methoxy-benzoyl) acrylic acid methyl ester, 0.20 g (1.86 mmol) of 6-Methyl-pyridin-3-ylamine, and 15 mL of diphenyl ether to yield 0.233 g of 3-(3-Fluoro-4-methoxy-benzoyl)-6-methyl-1H-[1,5]naphthyridin-4-one.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[C:5]2[N:6]([N:17]=[CH:18][N:19]=2)[C:7]([NH2:16])=[N:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:20]12([C:30](Cl)=[O:31])[CH2:29][CH:24]3[CH2:25][CH:26]([CH2:28][CH:22]([CH2:23]3)[CH2:21]1)[CH2:27]2>>[C:20]12([C:30]([O:1][CH2:2][CH2:3][C:4]3[C:5]4[N:6]([N:17]=[CH:18][N:19]=4)[C:7]([NH2:16])=[N:8][C:9]=3[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:31])[CH2:27][CH:26]3[CH2:25][CH:24]([CH2:23][CH:22]([CH2:28]3)[CH2:21]1)[CH2:29]2
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: Nc1nc(-c2ccccc2)c(CCO)c2ncnn12
Product: Nc1nc(-c2ccccc2)c(CCOC(=O)C23CC4CC(CC(C4)C2)C3)c2ncnn12

Procedure:
The title compound was prepared by the method of Example 2 using 2.5 g (0.01 mole) of the product compound of Example 1 and 2.0 g (0.01 mole) of 1-adamantanecarbonyl chloride, except that the solution was not divided before purification.
Reaction SMILES: [C:1]1([CH:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:8][C:9]([CH:11]2[CH:15]([C:16]([OH:18])=[O:17])[CH2:14][C:13](=[O:19])[O:12]2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:26](O)([CH3:29])([CH3:28])[CH3:27].Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[O:19]=[C:13]1[O:12][CH:11]([C:9]([O:8][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:10])[CH:15]([C:16]([O:18][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:17])[CH2:14]1
Reactant: O=C1CC(C(=O)O)C(C(=O)OC(c2ccccc2)c2ccccc2)O1
Reactant: CC(C)(C)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C1CC(=O)OC1C(=O)OC(c1ccccc1)c1ccccc1
Yield: 77.9 %

Procedure:
163 mg of (2RS,3SR)-2-diphenylmethoxycarbonyl-5-oxotetrahydrofuran-3-carboxylic acid, 59 mg of 4-dimethylaminopyridine and 36 mg of tert-butanol in 4 ml of methylene chloride were stirred with 110 mg of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride at room temperature for 13 hours. The reaction solution was diluted with methylene chloride, washed successively with 10% aqueous citric acid, saturated aqueous sodium hydrogencarbonate and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The desiccant was filtered off, the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography [hexane/ethyl acetate=10/1] to give 148 mg of the title compound as a colorless oily substance.
Reaction SMILES: C[O-].[Na+].[N+](C(C)C)([O-])=[O:5].[Br:10][C:11]1[C:12]([CH2:19]Br)=[N:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17]>CO>[Br:10][C:11]1[C:12]([CH:19]=[O:5])=[N:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17]
Reactant: Cc1cc(C)c(Br)c(CBr)n1
Reactant: CC(C)[N+](=O)[O-]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(C)c(Br)c(C=O)n1
Reaction time: 0.33 h

Procedure:
Sodium methoxide (581 mg) was added to a solution of 2-nitropropane (0.982 mL) in methanol (20 mL) at room temperature, and the mixture was stirred at the same temperature for 20 minutes. 3-bromo-2-(bromomethyl)-4,6-dimethylpyridine obtained in Preparation Example 33(1) (1.00 g) was added to the reaction mixture, and the mixture was stirred at 50° C. for five hours. The reaction mixture was concentrated under reduced pressure, and water was added to the residue, followed by extraction with ethyl acetate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/n-heptane, 0% to 50%) to give the title compound (467 mg).
Reaction SMILES: C[O:2][C:3](=O)[C:4]([C:11]#[N:12])=[CH:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.FC(F)(F)C(O)=O.[NH2:21][C:22]1[CH2:27][C:26]([CH3:29])([CH3:28])[CH2:25][C:24](=[O:30])[CH:23]=1>C(#N)C>[CH:6]1([CH:5]2[C:23]3[C:24](=[O:30])[CH2:25][C:26]([CH3:29])([CH3:28])[CH2:27][C:22]=3[NH:21][C:3](=[O:2])[CH:4]2[C:11]#[N:12])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(C#N)=CC1CCCC1
Reactant: CC1(C)CC(=O)C=C(N)C1
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CC1(C)CC(=O)C2=C(C1)NC(=O)C(C#N)C2C1CCCC1
Temperature: 0 °C

Procedure:
13.3 g 2-Cyano-3-cyclopentyl-acrylic acid methyl ester and 5.8 ml trifluoroacetic acid are dissolved in 70 ml acetonitrile and heated for 7 days to reflux. During the first 5 days 3-amino-5,5-dimethyl-cyclohex-2-enone is added in daily portions (12 g in total). Afterwards the reaction mixture is cooled to 0° C., the precipitate is isolated by filtration, washed 2 times with cold acetonitrile and dried in vacuo. The product is obtained as a mixture of diastereomers.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH:11]([Mg]Br)([CH3:13])[CH3:12]>O1CCCC1>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH:4]([OH:5])[CH:11]([CH3:13])[CH3:12]
Reactant: CC(C)[Mg]Br
Reactant: O=C(Cl)c1ccccc1Br
Solvent: C1CCOC1
Product: CC(C)C(O)c1ccccc1Br
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 33 %

Procedure:
To a solution of 2-bromobenzoyl chloride (1.3 mL, 9.9 mmol) in dry tetrahydrofuran (38 mL) at 0° C. under nitrogen was added dropwise a 2.0 M solution of isopropylmagnesium bromide in tetrahydrofuran (12.4 mL, 24.8 mmol) over ca. 5 minutes. The reaction mixture was stirred at 0° C. for 30 minutes then at room temperature for 27 hours. The reaction was quenched by the addition of 1 M aqueous hydrochloric acid (30 mL) and concentrated in vacuo to remove tetrahydrofuran. The aqueous phase was diluted to ca. 50 mL with water and extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with water (50 mL) and brine (50 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give the crude product as an orange oil (2.1 g). Purification by flash chromatography using a solvent gradient of 1 to 4% ethyl acetate in hexane gave the title compound (0.77 g, 33%) as a clear, pale yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]2[N:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:7]=2[O:6][C:5]=1[C:22]([NH2:24])=O)[CH3:2]>O>[CH2:1]([O:3][C:4]1[C:8]2[N:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:7]=2[O:6][C:5]=1[C:22]#[N:24])[CH3:2]
Reactant: CCOc1c(C(N)=O)oc2c3ccccc3n(-c3ccccc3)c12
Solvent: O
Product: CCOc1c(C#N)oc2c3ccccc3n(-c3ccccc3)c12
Yield: 91 %

Procedure:
Prepared by the procedure described in Example 21 from 6.5 g (0.020 mole) of 3-ethoxy-4-phenyl-4H-furo[3,2-b]indole-2-carboxamide. The crude product (5.5 g, 90% yield), after being washed with water and dried, was converted to the corresponding tetrazole without additional purification. A portion of the crude nitrile recrystallized from methanol yielded an analytically pure sample, mp 121°-122° C.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[S:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][C:20]1[O:21][C:22]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([O:34][C:35]([F:38])([F:37])[F:36])[CH:29]=2)=[C:23]([C:25](O)=[O:26])[N:24]=1>>[C:2]([C:7]1[S:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:25]([C:23]3[N:24]=[C:20]([CH3:19])[O:21][C:22]=3[C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([O:34][C:35]([F:37])([F:36])[F:38])[CH:29]=3)=[O:26])=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ccc(N)n3)s2)OCCO1
Reactant: Cc1nc(C(=O)O)c(-c2cccc(OC(F)(F)F)c2)o1
Product: CC(=O)c1ccc(Cn2ccc(NC(=O)c3nc(C)oc3-c3cccc(OC(F)(F)F)c3)n2)s1

Procedure:
Following general procedure X followed by C, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-thiophen-2-ylmethyl]-1H-pyrazol-3-ylamine and 2-methyl-5-(3-trifluoromethoxy-phenyl)-oxazole-4-carboxylic acid. LC-MS-conditions 05c: tR=0.83 min; [M+H]+=492.2.
Reaction SMILES: [O:1]=[C:2]1[CH:11]([NH:12]C(=O)OC(C)(C)C)[CH2:10][C:9]2[C:4](=[C:5]([N:20]3[CH2:24][CH2:23][CH2:22][C:21]3=[O:25])[CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:26][C:27]1[CH:31]=[CH:30][S:29][CH:28]=1.Cl.C(=O)(O)[O-].[K+]>C(OCC)(=O)C.O>[NH2:12][CH:11]1[CH2:10][C:9]2[C:4](=[C:5]([N:20]3[CH2:24][CH2:23][CH2:22][C:21]3=[O:25])[CH:6]=[CH:7][CH:8]=2)[N:3]([CH2:26][C:27]2[CH:31]=[CH:30][S:29][CH:28]=2)[C:2]1=[O:1]
Reactant: CC(C)(C)OC(=O)NC1Cc2cccc(N3CCCC3=O)c2N(Cc2ccsc2)C1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: NC1Cc2cccc(N3CCCC3=O)c2N(Cc2ccsc2)C1=O
Temperature: 37.5 °C
Reaction time: 1 h

Procedure:
tert-Butyl 2-oxo-8-(2-oxopyrrolidin-1-yl)-1-(thiophen-3-ylmethyl)-1,2,3,4-tetrahydroquinolin-3-ylcarbamate (5.0 g) was suspended in ethyl acetate (30 mL), and 4N hydrochloric acid in ethyl acetate (28.3 mL) was added thereto, followed by stirring at 35-40° C. for one hour. The reaction mixture was added to a solution of potassium bicarbonate (11.3 g) in water (20 mL), and the mixture was partitioned at 45° C. The aqueous layer was extracted with ethyl acetate twice, and the organic layers were combined. The combined organic layer was concentrated under reduced pressure until precipitates were formed. The concentrated residue was stirred at room temperature for 30 minutes, and the formed precipitates were recovered through filtration. The thus-obtained solid was washed with ethyl acetate, and then dried under reduced pressure, whereby the title compound (2.93 g) was yielded as crystals.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[C:8]([O:13][CH2:14][CH:15]([OH:18])[CH2:16][OH:17])=[N:9][CH:10]=[CH:11][CH:12]=1>N1C=CC=CC=1>[Cl:6][C:7]1[C:8]([O:13][CH2:14][CH:15]([OH:18])[CH2:16][O:17][S:2]([CH3:1])(=[O:4])=[O:3])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: OCC(O)COc1ncccc1Cl
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)OCC(O)COc1ncccc1Cl
Temperature: 0 °C

Procedure:
25.2 g of methanesulphonic acid chloride are added dropwise over the course of 1 hour to a solution of 40.6 g of 3-chloro-2-(2',3'-dihydroxy-propoxy)-pyridine in 100 ml of pyridine whilst stirring and cooling at 0°-5° C. The reaction mixture is then stirred further for 5 hours at room temperature and is subsequently poured onto 200 ml of ice water. The oil which separates out is isolated as in Example (1b). Crude 3-chloro-2-(3'-methanesulphonyloxy-2'-hydroxy-propoxy)-pyridine is thus obtained and is converted further in the crude state.