Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[C@@H](N(C)C)[C@@H](O)C1C=CC=CC=1.C(N(CC)CC)C.C[Si]([C:25]#[CH:26])(C)C.[Br:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[O:38][N:37]=[C:36]([CH3:39])[C:35]=2[CH:40]=[O:41])=[CH:30][CH:29]=1>C1(C)C=CC=CC=1.[O-]S(C(F)(F)F)(=O)=O.[Zn+2].[O-]S(C(F)(F)F)(=O)=O>[Br:27][C:28]1[CH:29]=[CH:30][C:31]([C:34]2[O:38][N:37]=[C:36]([CH3:39])[C:35]=2[C@@H:40]([OH:41])[C:25]#[CH:26])=[CH:32][CH:33]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C=O
Reactant: C#C[Si](C)(C)C
Agent: C[C@H]([C@@H](O)c1ccccc1)N(C)C
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Zn+2]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C#C[C@H](O)c1c(C)noc1-c1ccc(Br)cc1
Reaction time: 0.25 h

Procedure:
Zinc triflate (0.75 g, 2.1 mmol), (1S,2R)-(+)-N-methylephedrine (0.41 g, 2.3 mmol) and triethylamine (0.23 g, 2.3 mmol) were stirred in toluene (10 mL) at room temperature for 2 hours. (Trimethylsilyl)acetylene (0.32 g, 2.3 mmol) was added and the reaction stirred for 15 minute then 5-(4-bromo-phenyl)-3-methyl-isoxazole-4-carbaldehyde (0.5 g, 1.9 mmol) was added and the reaction stirred at room temperature for 2 weeks. The reaction mixture was purified on by silica gel chromatography (0-20% EtOAc in hexanes) to afford the title product with 97.5% ee as measured by analytical chiral HPLC.
Reaction SMILES: [OH:1][CH:2]([CH2:12][CH2:13][CH2:14][CH3:15])[C:3]([CH3:11])([CH3:10])[C:4]#[C:5][Si](C)(C)C.[F-].[K+].CN(C)C=O>CCOCC.O>[CH3:11][C:3]([CH3:10])([CH:2]([OH:1])[CH2:12][CH2:13][CH2:14][CH3:15])[C:4]#[CH:5]
Reactant: CCCCC(O)C(C)(C)C#C[Si](C)(C)C
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: C#CC(C)(C)C(O)CCCC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 1 part of (4(RS)-hydroxy-3,3-dimethyl-1-octynyl)trimethylsilane, 1 part of potassium fluoride and 5 parts by volume of dimethylformamide is stirred vigorously at room temperature for about 16 hours, then is diluted with ether and water. The ether layer is separated, washed with water, dried over anhydrous sodium sulfate and stripped of solvent under reduced pressure to afford 3,3-dimethyl-1-octyn-4(RS)-ol, which exhibits an infrared absorption maximum at about 3320 reciprocal centimeters.
Reaction SMILES: [C:1]1([CH3:15])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:14][CH2:13][CH:12]=[CH:11]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:24])C=1.ClC1C=C(C=CC=1)C(O)=O>ClCCl>[C:1]1([CH3:15])[CH:2]=[CH:3][C:4]([S:7]([N:10]2[CH2:14][CH:13]3[CH:12]([O:24]3)[CH2:11]2)(=[O:9])=[O:8])=[CH:5][CH:6]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(S(=O)(=O)N2C=CCC2)cc1
Agent: O=C(O)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N2CC3OC3C2)cc1
Temperature: 5 °C

Procedure:
334.5 g (1.5 mol) of 1-(toluene-4-sulphonyl)-pyrroline are dissolved in 1.5 l of dichloromethane at room temperature and treated in the course of 15 minutes with a suspension of 408 g (about 1.65-1.77 mol) of 70-75% strength m-chloroperbenzoic acid in 900 ml of dichloromethane (cools during preparation). The mixture is heated under reflux for 16 hours (test for peroxide with KI/starch paper still indicates peroxide content), the suspension is cooled to 5° C., and the precipitated m-chlorobenzoic acid is, filtered off with suction and washed with 300 ml of dichloromethane (peroxide test with precipitate: negative; precipitate discarded). The filtrate is washed twice with 300 ml of 10% strength sodium sulphite solution in each case to destroy excess peroxide (test for peroxide is now negative), extracted with 300 ml of saturated sodium bicarbonate solution, washed with water, dried using sodium sulphate and concentrated to about a quarter of the volume. Test for peroxide again: negative. The mixture is concentrated and the solid residue is stirred with 400 ml of isopropanol with ice-cooling, and the precipitate is filtered off with suction and dried in vacuo at 70° C.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH:11]([OH:13])[CH:10]2[N:14]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:15][CH2:16][CH:9]12)=O)(C)(C)C.[ClH:27].O1CCOCC1>C(Cl)Cl.C1(C)C=CC=CC=1>[ClH:27].[CH2:20]([O:19][C:17]([N:14]1[CH2:15][CH2:16][CH:9]2[NH:8][CH2:12][CH:11]([OH:13])[CH:10]12)=[O:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CC(O)C2C1CCN2C(=O)OCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCC2NCC(O)C21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of bicyclic alcohol 43 (6.5 g, 17.9 mmol) in DCM (20 mL) at 0° C. was added 4N HCl/1,4-dioxane (20 mL, 80 mmol) and the reaction mixture was slowly warming to ambient temperature. After 90 min, an additional portion of 4N HCl/1,4-dioxane (20 mL) was added. After 3 h, the reaction mixture was diluted with toluene and concentrated in vacuo. The crude 52 (HCl salt) was used in the next step without further purification. Mass spectrum, m/z [262.5] (M+H)+.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH3:10])[CH:3]=1.O1CCCCC1[N:17]1[C:21](B2OC(C)(C)C(C)(C)O2)=[CH:20][CH:19]=[N:18]1>>[CH3:10][C:4]1[CH:3]=[C:2]([C:21]2[CH:20]=[CH:19][NH:18][N:17]=2)[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
Reactant: Cc1cc(Br)ccc1C#N
Product: Cc1cc(-c2cc[nH]n2)ccc1C#N

Procedure:
The title compound was synthesized using the method of Example 34(b), but starting from 4-bromo-2-methylbenzonitrile and 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. 1H-NMR (400 MHz; CDCl3): δ 2.60 (s, 3H), 6.69 (d, 1H), 7.64 (m, 2H), 7.70 (d, 1H), 7.78 (s, 1H), 10.47 (br s, 1H).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:4]=[C:5]([C:9]2[CH:20]=[C:19]([CH:21]([NH:23][CH3:24])[CH3:22])[CH:18]=[CH:17][C:10]=2[O:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:6]=[CH:7][CH:8]=1.CCN(C(C)C)C(C)C.[F:36][C:37]1[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[CH:39][CH:38]=1>C1COCC1>[F:1][C:2]([F:25])([F:26])[C:3]1[CH:4]=[C:5]([C:9]2[CH:20]=[C:19]([CH:21]([N:23]([CH3:24])[S:43]([C:40]3[CH:41]=[CH:42][C:37]([F:36])=[CH:38][CH:39]=3)(=[O:45])=[O:44])[CH3:22])[CH:18]=[CH:17][C:10]=2[O:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:6]=[CH:7][CH:8]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: CNC(C)c1ccc(OCC(=O)OC)c(-c2cccc(C(F)(F)F)c2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)COc1ccc(C(C)N(C)S(=O)(=O)c2ccc(F)cc2)cc1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of crude methyl 2-(2-(3-trifluoromethylphenyl)-4-(1-(methylamino)ethyl)phenoxy)acetate (18) (100 mg) in 2 mL of THF, was added DIEA (105 mg), and 4-fluorobenzene-1-sulfonyl chloride (87 mg). The reaction mixture was stirred at room temperature for 1 hr and then purified via silica gel chromatography (25% EtOAc/hexane) to give methyl 2-(2-(3-trifluoromethylphenyl)-4-(1-(4-fluoro-N-methylphenylsulfonamido)ethyl)phenoxy)acetate (19) which was carried directly to the next step.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][CH:7]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=1[C:23]1[CH:24]=[CH:25][C:26]([CH2:34]O)=[N:27][C:28]=1[CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.C1(C)C=CC=CC=1>[F:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=1[C:23]1[CH:24]=[CH:25][C:26]([CH2:34][O:1][C:2]2[CH:3]=[C:4]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][CH:7]=2)=[N:27][C:28]=1[CH2:29][C:30]([CH3:32])([CH3:31])[CH3:33]
Reactant: COc1ccc(F)c(-c2ccc(CO)nc2CC(C)(C)C)c1
Reactant: COC(=O)CCc1cccc(O)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)CCc1cccc(OCc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)c1
Reaction time: 0.5 h
Yield: 81.1 %

Procedure:
Under an argon atmosphere, to a solution of methyl 3-(3-hydroxyphenyl)propanoate (131 mg), (5-(2-fluoro-5-methoxyphenyl)-6-neopentylpyridin-2-yl)methanol (200 mg) and triphenylphosphine (259 mg) in THF (3.0 mL) was added a about 2.2 M solution of diethyl azodicarboxylate in toluene (450 μL), and the mixture was stirred for 30 min. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (249 mg) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[O:27])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)=[CH:15][CH:14]=1.[C:29]([O:33][C:34]([NH:36][C:37]1[CH:38]=[C:39]([CH:42]=[CH:43][CH:44]=1)[CH2:40]O)=[O:35])([CH3:32])([CH3:31])[CH3:30].N(C(N(C)C)=O)=NC(N(C)C)=O.C(P(CCCC)CCCC)CCC>C(Cl)Cl.C1COCC1>[CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[O:27])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]2[CH:21]=[CH:22][C:23]([O:26][CH2:40][C:39]3[CH:42]=[CH:43][CH:44]=[C:37]([NH:36][C:34]([O:33][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:35])[CH:38]=3)=[CH:24][CH:25]=2)=[CH:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(CO)c1
Reactant: COC(=O)c1ccccc1NC(=O)Cc1ccc(Oc2ccc(O)cc2)cc1
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)c1ccccc1NC(=O)Cc1ccc(Oc2ccc(OCc3cccc(NC(=O)OC(C)(C)C)c3)cc2)cc1
Yield: 83 %

Procedure:
2-(2-(4-(4-Hydroxyphenoxy)phenyl)acetylamino)benzoic acid methyl ester obtained by the Reference Example 24 (315 mg, 0.83 mmol) was dissolved in 20 ml of methylene chloride-THF mixture (1:1 v/v), added with 3-(tert-butoxycarbonylamino)benzyl alcohol (465 mg, 2.1 mmol), 1,1′-azobis(N,N′-dimethylformamide) (359 mg, 2.08 mmol) and tri-n-butyl phosphine (520 ml, 2.1 mmol) and the reaction mixture was stirred over a night. After completing the reaction, the solvent was removed under reduced pressure and the obtained crude residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate 75:25 v/v) to obtain the subject compound (404 mg, 0.693 mmol) in the form of a colorless gummy substance. The result of 1H-NMR was consistent with the above structure.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([OH:5])=O.[NH2:32][CH2:33][C:34]1[NH:38][N:37]=[N:36][N:35]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH:35]1[C:34]([CH2:33][NH:32][C:3](=[O:5])[CH:2]([OH:1])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:16]=[C:15]([C:17]4[O:21][N:20]=[C:19]([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=5)[C:18]=4[C:28]([F:29])([F:30])[F:31])[O:14][N:13]=3)=[CH:8][CH:7]=2)=[N:38][N:37]=[N:36]1
Reactant: NCc1nnn[nH]1
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(NCc1nnn[nH]1)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 50 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 20 mg, 0.046 mmol), 5-(aminomethyl)tetrazole (6.89 mg, 0.070 mmol), 4-methylmorpholine (18.76 mg, 0.185 mmol), and HATU (22.92 mg, 0.060 mmol) were added to DMF (1 mL). This was stirred for 1 h and was then purified by prep HPLC (PHENOMENEX® Luna 5u 21×250 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 30 min, 25 mL/min, 220 nM, product retention=29.2 min) to provide (R/S)-N-((1H-tetrazol-5-yl)methyl)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (12 mg, 0.023 mmol, 49.8% yield): LCMS=513.2 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.11-8.24 (2 H, m), 7.53-7.75 (7 H, m), 5.22 (1 H, s), 4.67-4.81 (2 H, m); HPLC peak RT=8.8 min (Method A).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[CH2:7][C:8]1[C:17]([CH3:18])=[C:16]([O:19]C(=O)C)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:23])[CH:14]=2)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C[O-].[Na+].Cl>CO>[C:1]([O:5][C:6](=[O:24])[CH2:7][C:8]1[C:17]([CH3:18])=[C:16]([OH:19])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:23])[CH:14]=2)[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)Oc1c(C)c(CC(=O)OC(C)(C)C)cc2ccc(F)cc12
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Cc1c(CC(=O)OC(C)(C)C)cc2ccc(F)cc2c1O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 95.5 %

Procedure:
To a mixture of the above prepared (4-acetoxy-6-fluoro-3-methyl-naphthalen-2-yl)-acetic acid tert-butyl ester (28.4 g, 85.44 mmol) in 140 mL of methanol was added sodium methoxide (25% solution in methanol, 23.44 mL, 102.5 mmol) rapidly dropwise. The resulting reaction mixture was stirred at room temperature for 20 minutes, when HPLC analysis indicated a completed reaction. The mixture was cooled to 0° C., and then acidified to pH 2 with 1N hydrochloric acid solution (111.1 mL, 111.1 mmol). The mixture was then stirred at 0-5° C. for an additional 30 minutes. The resulting solid was filtered, and washed with water (2×40 mL), then dried under vacuum overnight (40° C.), to produce 23.7 g of (6-fluoro-4-hydroxy-3-methyl-naphthalen-2-yl)-acetic acid tert-butyl ester as a light yellow solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 9.09 (s, 1 H), 7.76-7.86 (m, 2 H), 7.26-7.35 (m, 2 H), 3.71 (s, 2 H), 2.23 (s, 3 H), 1.41 (s, 9 H).
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[C:18]([Cl:23])=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:12]=2)[CH:10]=1)=[O:5].Br[C:26]1[C:31]([CH3:32])=[CH:30][CH:29]=[CH:28][N:27]=1>>[Cl:23][C:18]1[C:17]([C:13]2[CH:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:26]4[C:31]([CH3:32])=[CH:30][CH:29]=[CH:28][N:27]=4)=[O:5])[N:7]=[CH:8]3)[CH:16]=[CH:15][CH:14]=2)=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: Cc1cccnc1Br
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3cccnc3Cl)c2)cn1
Product: Cc1cccnc1C(=O)c1cn(-c2cccc(-c3cccnc3Cl)c2)cn1

Procedure:
This compound is prepared by method C using compound 12l and 2-bromo-3-methylpyridine
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH:13]([Mg]Cl)([CH3:15])[CH3:14].C(Br)C=C.C([Cu])#N>C1COCC1>[CH2:8]([O:7][C:5](=[O:6])[C:4]1[CH:10]=[CH:11][CH:12]=[C:2]([CH2:15][CH:13]=[CH2:14])[CH:3]=1)[CH3:9]
Reactant: CC(C)[Mg]Cl
Reactant: CCOC(=O)c1cccc(I)c1
Agent: N#C[Cu]
Solvent: C1CCOC1
Solvent: C=CCBr
Product: C=CCc1cccc(C(=O)OCC)c1
Reaction time: 1 h
Yield: 68.4 %

Procedure:
A −45° C. solution of ethyl 3-iodobenzoate (2.434 g, 8.8 mmol) in 40 mL THF was treated with i-PrMgCl (4.8 mL, 9.6 mmol, 2 M/ether). After 1 h, allyl bromide (1.6 mL, 18.9 mmol) was added followed by CuCN (79 mg, 0.88 mmol). The reaction was stirred for 1 h and then was quenched by addition of 50 mL saturated NH4Cl solution. Water (30 mL) was added and the resulting mixture was extracted with ethyl acetate (3×50 mL). The combined ethyl acetate solution was dried (MgSO4), filtered and evaporated. Purification by flash chromatography on silica gel (5% ethyl acetate/hexanes→10%) gave compound 7 (1.145 g, 68%).
Reaction SMILES: P(Cl)(Cl)[Cl:2].O[CH2:6][C:7]1[CH:8]=[CH:9][C:10]2[C:19]([N:20]=1)=[C:18]1[N:21]=[CH:22][CH:23]=[CH:24][C:17]1=[C:16]1[C:11]=2[N:12]=[C:13]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:14]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[N:15]1>C(Cl)(Cl)Cl>[Cl:2][CH2:6][C:7]1[CH:8]=[CH:9][C:10]2[C:19]([N:20]=1)=[C:18]1[N:21]=[CH:22][CH:23]=[CH:24][C:17]1=[C:16]1[C:11]=2[N:12]=[C:13]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:14]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[N:15]1
Reactant: ClP(Cl)Cl
Reactant: CCOC(=O)c1nc2c3cccnc3c3nc(CO)ccc3c2nc1C(=O)OCC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1nc2c3cccnc3c3nc(CCl)ccc3c2nc1C(=O)OCC
Temperature: 25 °C
Yield: 25.6 %

Procedure:
Phosphorus trichloride (473 mg, 3.44 mmol) was added to a solution diethyl 7-(hydroxymethyl)dipyrido[3,2-f:2′,3′-h]quinoxaline-2,3-dicarboxylate (350 mg, 0.86 mmol) in CHCl3 (150 ml). The reaction mixture was heated under reflux for 6 h and allowed to cool down to room temperature afterwards. The reaction was quenched by addition of concentrated Na2CO3 solution (150 ml). The layers were separated and the water was extracted by CH2Cl2 (3×150 ml) and CHCl3 (1×50 ml). The organic layer was dried over K2CO3. The solvent was removed under reduced pressure to give the crude product. Purification was achieved by chromatography on alumina (gradient elution: CH2Cl2 to 2% CH3OH—CH2Cl2) The product was obtained as a yellow glass (95 mg, 0.22 mmol, 26%). 1H NMR (300 MHz, CDCl3): δ 1.45 (6H, t, J=7.2, OCH2CH3), 4.53 (4H, q, J=7.2, OCH2), 5.07 (2H, s, CH2Cl), 7.78 (1H, dd, J=8.1, 4.5, H11), 8.05 (1H, d, J=8.4, H6), 9.31 (1H, dd, J=4.5, 1.8, H10), 9.50 (1H, dd, J=8.1, 1.8, H12), 9.53 (1H, d, J=8.7, H5). 13C NMR (75 MHz, CDCl3): δ14.4 (CH3), 47.3 (CH2Cl), 63.2 (OCH2), 123.8 (C11), 124.6 (C6), 125.6 (q Ar), 126.6 (q Ar), 134.5 (C12), 135.7 (C5), 140.1 (q Ar), 140.4 (q Ar), 144.3 (q Ar), 144.4 (q Ar), 147.6 (q Ar), 148.1 (q Ar), 153.8 (C10), 161.0 (C7), 165.0 (CO), 165.1 (CO). m/z (ES+) 447 (MNa+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([N:11]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15][N:14]3[C:22]([C:25](O)=[O:26])=[CH:23][CH:24]=[C:13]3[CH2:12]2)=[O:10])[CH:6]=[CH:5][C:4]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]([F:37])([F:36])[F:35].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[CH3:61][NH:62][CH2:63][C:64]1[CH:65]=[N:66][CH:67]=[CH:68][CH:69]=1>CN(C)C=O.O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([N:11]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15][N:14]3[C:22]([C:25]([N:62]([CH3:61])[CH2:63][C:64]4[CH:65]=[N:66][CH:67]=[CH:68][CH:69]=4)=[O:26])=[CH:23][CH:24]=[C:13]3[CH2:12]2)=[O:10])[CH:6]=[CH:5][C:4]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]([F:37])([F:36])[F:35]
Reactant: CNCc1cccnc1
Reactant: COc1cc(C(=O)N2Cc3ccc(C(=O)O)n3Cc3ccccc32)ccc1-c1ccccc1C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C(=O)N2Cc3ccc(C(=O)N(C)Cc4cccnc4)n3Cc3ccccc32)ccc1-c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.4 %

Procedure:
To a stirred solution of the 10-{[2-methoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid of Step E (0.17 g, 0.37 mmol) in N,N-dimethylformamide (15 mL), was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.092 g, 0.48 mmol) and 1-hydroxybenzotriazole monohydrate (0.065 g, 0.48 mmol). After the solution became homogeneous 3-(methylaminomethyl) pyridine (0.045 g, 0.37 mmol) was added, and the solution was stirred at room temperature overnight. The solution was then poured into water and extracted with ethyl acetate. The combined ethyl acetate layers were washed with water, dried and concentrated to dryness. The residue was subjected to silica chromatography eluting with 10% methanol in chloroform. The pure fractions were concentrated and the residue azeotroped and triturated several times with hexane to provide the title product (0.150 g) as an amorphous white solid, 150–153° C. (dec.)
Reaction SMILES: [NH2:1][C:2](=[S:13])[C:3]1[CH:4]=[C:5]([C:9]([O:11][CH3:12])=[S:10])[S:6][C:7]=1[CH3:8].[O:14]1[C:19]2[CH:20]=[CH:21][C:22]([C:24](=O)[CH2:25]Br)=[CH:23][C:18]=2[O:17][CH2:16][CH2:15]1>CC(C)=O>[CH2:16]1[CH2:15][O:14][C:19]2[CH:20]=[CH:21][C:22]([C:24]3[N:1]=[C:2]([C:3]4[CH:4]=[C:5]([C:9]([O:11][CH3:12])=[S:10])[S:6][C:7]=4[CH3:8])[S:13][CH:25]=3)=[CH:23][C:18]=2[O:17]1
Reactant: COC(=S)c1cc(C(N)=S)c(C)s1
Reactant: O=C(CBr)c1ccc2c(c1)OCCO2
Solvent: CC(C)=O
Product: COC(=S)c1cc(-c2nc(-c3ccc4c(c3)OCCO4)cs2)c(C)s1
Reaction time: 48 h
Yield: 95.1 %

Procedure:
Methyl 4-(4-(2H,3H-benzo[3,4-e]4-dioxin-6-yl)(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxylate: 40 mg (0.162 mmol) of methyl 4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate (Maybridge Chemical Co. LTD., Cornwall, U.K.) was dissolved in 2 mL of reagent grade acetone. 1-(2H,3H-benzo[e]1,4-dioxin-6-yl)-2-bromoethan-1-one (0.162 mmol; 42 mg; Maybridge Chemical Co. LTD., Cornwall, U.K.) was added and the solution was allowed to reflux for 3 h. The solution was allowed to cool and allowed to stir for 2 days after which the reaction solution was concentrated in vacuo. The crude product was dissolved in 50 mL of CH2Cl2 and partitioned between 50 mL of 1 N NaOH (aq.). The organic layer was obtained and dried over sodium sulfate and concentrated to afford 60 mg (90% yield) of methyl 4-[4-(3,4-ethylenedioxyphenyl)thiazol-2-yl]-5-methylthiothiophene-2-carboxylate.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][S:4][CH:3]=1.[Li+].CC([N-]C(C)C)C.C([O:17][CH2:18]C)C.C1C[O:23]CC1>>[Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:18]([OH:17])=[O:23]
Reactant: CCOCC
Reactant: C1CCOC1
Reactant: Brc1ccsc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: O=C(O)c1sccc1Br
Reaction time: 0.67 h

Procedure:
To a solution of 3-bromothiophene (600.0 g, 3.68 mol) in THF (3 L) cooled to −72° C. was added LDA (1.93 L, 3.86 mol, 2 N) slowly over 2 hours. The rate of LDA addition is such that the reaction temperature never exceeded 68° C. After complete addition, the solution is stirred for an additional 40 minutes. Diethyl ether (3 L) is then added via an addition funnel such that the temperature is maintained below −65° C. The addition funnel is then replaced with a dispersion tube and CO2 gas is bubbled through the solution for 3 hours. Dry ice (500 g) is then added and the mixture is stirred overnight. The reaction flask is then placed in an ice bath and 6 N HCl is added slowly to prevent excessive bubbling until the pH of the solution is adjusted to 1–2. The resulting mixture is then extracted with EtOAc. The extract is washed with brine then dried over MgSO4, filtered and evaporated. The product is dried under vacuum at room temperature yielding 585.15 g (77%) as an off-white solid.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH:16]=[CH:17][NH:18]3)[CH2:10][CH2:9]1)(OC(C)(C)C)=O.[F:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[S:31]([Cl:34])(=[O:33])=[O:32]>>[ClH:34].[F:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[S:31]([N:18]1[C:19]2[C:15](=[C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[CH:22]=[CH:21][CH:20]=2)[CH:16]=[CH:17]1)(=[O:33])=[O:32]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc3[nH]ccc23)CC1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1F
Product: Cl
Product: O=S(=O)(c1ccc(F)cc1F)n1ccc2c(N3CCNCC3)cccc21

Procedure:
The title compound was prepared from 4-(4-boc-piperazinyl)-indole and 2,4-di-fluorophenylsulfonylchloride according to Method 3: 1H NMR (270 MHz, DMSO-d6) δ 9.41 (br, 1H), 8.24 (m, 1H), 7.75 (m, 1H), 7.58 (m, 1H), 7.47-7.33 (m, 2H), 7.23 (t, J=8 Hz, 1H), 6.99 (d, J=5 Hz, 1H), 6.70 (d, J=8 Hz, 1H), 3.25 (m, 8H). MS (ESI+) for m/z 378 (M+H)+.
Reaction SMILES: C(O)(=O)C.O.[CH2:6]([N:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[N:24](C2CCCCO2)[N:23]=[CH:22]3)[CH2:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>O1CCCC1>[CH2:6]([N:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[NH:24][N:23]=[CH:22]3)[CH2:15][CH2:14]1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: c1ccc(CN2CCN(c3ccc4c(cnn4C4CCCCO4)c3)CC2)cc1
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: c1ccc(CN2CCN(c3ccc4[nH]ncc4c3)CC2)cc1
Temperature: 80 °C
Reaction time: 7 h
Yield: 47.6 %

Procedure:
Acetic acid (2.6 ml) and water (0.7 ml) were added to a solution of 5-(4-benzyl-1-piperazinyl)-1-tetrahydro-2H-pyran-2-yl-1H-indazole (100 mg, 0.266 mmol) in tetrahydrofuran (1.3 ml) at room temperature and stirred 80° C. for 7 hours. Then, the reaction solution was concentrated and the resulting residue was diluted with ethyl acetate and washed with a saturated aqueous sodium hydrogencarbonate solution and then a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent, and the resulting residue was purified by a thin-layer chromatography (eluent: chloroform/methanol=95/5) to obtain 5-(4-benzyl-1-piperazinyl)-1H-indazole (37 mg, 47%).