Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:22])[C:5]([C:8]2([F:21])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[Cl-].[Li+].[CH:25]([Mg]Cl)([CH3:27])[CH3:26].C(Br)C=C>C1COCC1.[Cu]I>[CH2:27]([C:2]1[CH:3]=[C:4]([F:22])[C:5]([C:8]2([F:21])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1)[CH:25]=[CH2:26]
Reactant: CC(C)(C)OC(=O)N1CCC(F)(c2ncc(Br)cc2F)CC1
Reactant: CC(C)[Mg]Cl
Agent: [Cu]I
Agent: [Cl-]
Agent: [Li+]
Solvent: C=CCBr
Solvent: C1CCOC1
Product: C=CCc1cnc(C2(F)CCN(C(=O)OC(C)(C)C)CC2)c(F)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 83.9 %

Procedure:
In a dry 3-necked flask flushed with argon containing a solution of 23 (3.77 g, 10.0 mmol) in THF (50 mL) at 0° C. was added isopropyl magnesium chloride lithium chloride complex (1.3 M in THF, 10 mL, 13 mmol) over 10 min. After additional 10 min of stirring at 0° C., CuI (0.2 eq, 0.38 g) was added, the mixture was stirred for 10 minutes at 0° C. and then a solution of allyl bromide (1.73 mL, 20 mmol) in THF (4.0 mL) was added at 0° C. over 10 min. After further stirring for 1 h at 0° C., the reaction was quenched with 10% citric acid and extracted with ethyl acetate (100 mL×2). The organic layers were combined which was washed with brine, dried over Na2SO4, and concentrated. The obtained residue was chromatographed on silica gel eluted with EtOAc/hexane (0-10%) to afford 2.84 g (84%) of 24 as a colorless oil. NMR (CDCl3) δ 1.48 (9 H, s), 2.21 (4 H, m), 3.28 (2 H, m), 3.41 (2 H, d, J=6.16 Hz), 4.05 (2 H, m), 5.92 (1 H, m), 7.26 (1 H, dd, J=1.56, 12.08 Hz); LC/MS (M+1) 339.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C:3](=[O:6])[NH:2]1.[F:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11](O)=[O:12].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>ClCCl>[F:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([N:1]1[CH2:5][CH2:4][C:3](=[O:6])[NH:2]1)=[O:12]
Reactant: O=C(O)c1cccc(F)c1
Reactant: O=C1CCNN1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CCN(C(=O)c2cccc(F)c2)N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32422.5 %

Procedure:
To a solution of pyrazolidin-3-one (6.9 gm, 0.080 mmol, 1 equiv.) in dry dichloromethane (70 ml), 3-fluorobenzoic acid (12.3 gm, 0.088 mmol, 1.1 equiv.), triethylamine (24.3 gm, 0.240 mmol, 3 equiv.) and 1-propane phosphonic acid cyclic anhydride (60% by weight in ethyl acetate) (51 gm, 0.16 mmol, 2 equiv.) were added in cooling condition and stirred for overnight at room temperature. The reaction mixture was concentrated and the residue was poured in water (500 ml), extracted with dichloromethane (100 ml×2) and concentrated. The crude product was purified by silica gel column using (60-120) mesh to get the pure product as yellow oil (5.4 gm, 32% yield).
Reaction SMILES: [CH:1]([O:4][C:5]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]4[S:21][C:22](S(C)(=O)=O)=[N:23][N:24]=4)[CH:18]=3)[N:13]([S:29]([C:32]3[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=3)(=[O:31])=[O:30])[CH:12]=2)[CH:8]=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[C:39]([O:43][C:44]([NH:46][C@H:47]1[CH2:51][CH2:50][NH:49][CH2:48]1)=[O:45])([CH3:42])([CH3:41])[CH3:40]>O1CCOCC1>[CH:1]([O:4][C:5]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]4[S:21][C:22]([N:49]5[CH2:50][CH2:51][C@H:47]([NH:46][C:44](=[O:45])[O:43][C:39]([CH3:41])([CH3:40])[CH3:42])[CH2:48]5)=[N:23][N:24]=4)[CH:18]=3)[N:13]([S:29]([C:32]3[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=3)(=[O:30])=[O:31])[CH:12]=2)[CH:8]=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cccc(OC(C)C)n3)c3cc(-c4nnc(S(C)(=O)=O)s4)ccc32)cc1
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cccc(OC(C)C)n3)c3cc(-c4nnc(N5CC[C@H](NC(=O)OC(C)(C)C)C5)s4)ccc32)cc1
Yield: 90.2 %

Procedure:
A yellow solution of 2-(3-(6-isopropoxypyridin-2-yl)-1-tosyl-1H-indol-5-yl)-5-(methylsulfonyl)-1,3,4-thiadiazole (168.4 mg, 0.296 mmol) and (35)-(−)-3-(tert-butoxycarbonylamino)pyrrolidine (TCI America, Portland, Oreg.; 165 mg, 0.888 mmol) in dioxane (1.0 mL) was heated in an open microwave vial at 90° C. for 2 days. Chromatographic purification of the resulting dry residue (silica gel, 0-100% EtOAc/Hex) furnished (S)-tert-butyl 1-(5-(3-(6-isopropoxypyridin-2-yl)-1-tosyl-1H-indol-5-yl)-1,3,4-thiadiazol-2-yl)pyrrolidin-3-ylcarbamate (180 mg, 0.267 mmol, 90%) as a light-yellow solid: MS (ESI, pos. ion) m/z: 675.1 (M+1). 1H NMR (400 MHz, CDCl3) δ ppm 8.80 (s, 1H), 8.07 (s, 2H), 7.94-7.99 (m, 1H), 7.82 (d, J=8.2 Hz, 2H), 7.62 (t, J=7.8 Hz, 1H), 7.28 (d, J=7.4 Hz, 1H), 7.22-7.25 (m, 2H), 6.63 (d, J=8.2 Hz, 1H), 5.57 (spt, J=6.2 Hz, 1H), 4.72 (br. s., 1H), 4.40 (br. s., 1H), 3.84 (dd, J=10.4, 5.9 Hz, 1H), 3.68-3.75 (m, 1H), 3.60-3.68 (m, 1H), 3.41-3.55 (m, 1H), 3.45 (m, J=10.4, 3.5 Hz, 1H), 2.35 (s, 3H), 1.46 (s, 9H), 1.45 (br. s., 6H).
Reaction SMILES: Br[C:2]1[C:10]([CH2:11][OH:12])=[CH:9][C:5]2OCO[C:4]=2[CH:3]=1.[C:13]([C:15]1C=CC2OCOC=2[CH:16]=1)#N.O>CCOCC.C([Li])CCC.C(OCC)(=O)C>[O:12]1[CH:11]2[C:10]3[C:2]([CH:13]1[CH2:15][CH2:16]2)=[CH:3][CH:4]=[CH:5][CH:9]=3
Reactant: N#Cc1ccc2c(c1)OCO2
Reactant: OCc1cc2c(cc1Br)OCO2
Agent: [Li]CCCC
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: c1ccc2c(c1)C1CCC2O1
Temperature: 0 °C
Reaction time: 1 h
Yield: 104.3 %

Procedure:
To a solution of 5-bromo-6-hydroxymethyl-1,3-benzodioxol (5.0 g) in ether (100 ml), butyl lithium (1.6M solution in hexane, 30 ml) was added dropwise at −78° C. After stirring at 0° C. for 1 hour, the solution was again cooled to −78° C.; a solution of 5-cyano-1,3-benzodioxol (3.52 g) in ether (50 ml) was added dropwise. After stirring at room temperature for 3 hours, water was added, followed by extraction with ethyl acetate. After being washed with brine, the organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in toluene (100 ml); dimethyl fumarate (3.13 g) and trichloroacetic acid (0.83 g) were added. The mixture was refluxed for 1 hour and concentrated under reduced pressure. The residue obtained was dissolved in ethyl acetate and washed with a saturated aqueous solution of sodium hydrogen carbonate and brine. After being dried with magnesium sulfate, the mixture was concentrated under reduced pressure; the residue was purified by column chromatography (silica gel: 50 g, eluent: ethyl acetate−hexane=1:2) to yield a tetrahydro-1,4-epoxynaphthalene derivative (3.30 g) as a diastereomer mixture. This was dissolved in THF (15 ml) and methanol (15 ml); an aqueous solution (5 ml) of sodium hydroxide (1.24 g) was added, followed by overnight stirring. The reaction mixture was concentrated under reduced pressure and diluted with water, after which it was washed with ethyl acetate After concentrated hydrochloric acid was added to the water layer until the pH reached about 2, the product was extracted with ethyl acetate. The extract was washed with brine, after which it was dried over magnesium sulfate and concentrated under reduced pressure. The residue obtained was dissolved in ether (10 ml); concentrated hydrochloric acid (0.5 ml) was added; followed by stirring at room temperature for 3 hours. After the reaction mixture was concentrated under reduced pressure, water was added; the resulting precipitate was washed with methanol and ether to yield the title compound (0.38 g).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]2[C:10]([CH2:14][CH2:15]Br)=[C:11]([CH3:13])[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2].Cl.[F:18][C:19]1[CH:20]=[CH:21][C:22]2[O:26][N:25]=[C:24]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[C:23]=2[CH:33]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O.C1(C)C=CC=CC=1>[C:1]([N:4]1[CH2:9][CH2:8][C:7]2[C:10]([CH2:14][CH2:15][N:30]3[CH2:29][CH2:28][CH:27]([C:24]4[C:23]5[CH:33]=[C:19]([F:18])[CH:20]=[CH:21][C:22]=5[O:26][N:25]=4)[CH2:32][CH2:31]3)=[C:11]([CH3:13])[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: Fc1ccc2onc(C3CCNCC3)c2c1
Reactant: CC(=O)N1CCc2c(sc(C)c2CCBr)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC(=O)N1CCc2c(sc(C)c2CCN2CCC(c3noc4ccc(F)cc34)CC2)C1
Temperature: 90 °C
Reaction time: 25 h
Yield: 20.5 %

Procedure:
A mixture of 334 mg of 6-acetyl-3-(2-bromoethyl)-4,5,6,7-tetrahydro-2-methylthieno[2,3-c]pyridine, 308 mg of 4-(5-fluoro-1,2-benzisoxazol-3-yl)piperidine hydrochloride, 500 mg of potassium carbonate and 220 mg of potassium iodide in 10 ml of dimethylformamide and 10 ml of toluene was stirred at 90° C. for 25 hours and concentrated in vacuo. To the residue were added ethyl acetate and water and separated. The ethyl acetate layer was washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on a silica gel to give 100 mg of 6-acetyl-3-(2-(4-(5-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydro-2-methylthieno[2,3-c]pyridine as an oil, m.p. 167°-172° C. as oxalate thereof.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH2:5].Br[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11]>>[CH2:13]([O:12][C:10](=[O:11])[CH2:9][NH:5][CH2:4][CH:3]([O:6][CH3:7])[O:2][CH3:1])[CH3:14]
Reactant: CCOC(=O)CBr
Reactant: COC(CN)OC
Product: CCOC(=O)CNCC(OC)OC

Procedure:
The title compound was synthesized by the method of Example 4 starting with 2,2-dimethoxyethylamine and ethyl bromoacetate.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[C:6]([CH2:9][CH3:10])[N:5]=[CH:4][N:3]=1.[NH2:11][CH:12]1[CH2:17][O:16][CH:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:14][CH2:13]1.C1(C2CCC(O)CO2)C=CC=CC=1.C(N(CC)CC)C>O>[Cl:8][C:7]1[C:2]([NH:11][CH:12]2[CH2:17][O:16][CH:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:14][CH2:13]2)=[N:3][CH:4]=[N:5][C:6]=1[CH2:9][CH3:10]
Reactant: NC1CCC(c2ccccc2)OC1
Reactant: CCc1ncnc(Cl)c1Cl
Agent: OC1CCC(c2ccccc2)OC1
Solvent: O
Solvent: CCN(CC)CC
Product: CCc1ncnc(NC2CCC(c3ccccc3)OC2)c1Cl
Temperature: 85 °C

Procedure:
2.4 g (13.5 mmol) of 4,5-dichloro-6-ethylpyrimidine, 2.4 g (13.5 mmol) of 5-amino-2-phenyltetrahydropyran (prepared from 2-phenyltetrahydropyran-5-ol (cf. U.S. Pat. No. 4,388,104) analogously to the routes described in Example A) and 3 ml (21 mmol) of triethylamine were heated for 12 hours at 85° C. After cooling, the mixture was diluted with water and extracted with ether, and the organic phase was washed with saturated NaCl solution. After drying and concentrating, the residue was purified by column chromatography using petroleum ether/ethyl acetate (9:1, 8:2). This gave 0.65 g (15% of theory) of the trans isomer as a colorless oil and 2.17 g (51% of theory) of the cis isomer as a colorless oil.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:8]([NH:10][C@H:11]([C:16]([NH:18][C@H:19]([C:22]([NH:24][C@H:25]([C:27]([O:29][CH3:30])=[O:28])[CH3:26])=[O:23])[CH2:20][OH:21])=[O:17])[CH2:12][CH:13]([CH3:15])[CH3:14])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6].C(O)(C(F)(F)F)=O>ClCCl>[NH2:1][C@H:2]([C:8]([NH:10][C@H:11]([C:16]([NH:18][C@H:19]([C:22]([NH:24][C@H:25]([C:27]([O:29][CH3:30])=[O:28])[CH3:26])=[O:23])[CH2:20][OH:21])=[O:17])[CH2:12][CH:13]([CH3:15])[CH3:14])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6]
Reactant: COC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC(N)=O)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCC(N)=O

Procedure:
10.3 g (18.8 mM) of Boc-Gln-Leu-Ser-Ala-OCH3 are stirred for 35 mins. in 100 ml of dichloromethane containing 100 ml of TFA. The reaction medium is concentrated in vacuo to about 50 ml and poured over 300 ml of ether. The precipitate is drained, washed with ether and dried in vacuo.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].Cl[C:11]1[N:16]=[C:15]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:14]=[C:13]([N:23]2[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[N:25]=[C:24]2[CH:32]([F:34])[F:33])[N:12]=1.COCCOCCN(CCOCCOC)CCOCCOC>O.O1CCOCC1>[F:34][CH:32]([F:33])[C:24]1[N:23]([C:13]2[N:14]=[C:15]([N:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)[N:16]=[C:11]([O:1][C:2]3[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=3)[N:12]=2)[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[N:25]=1
Reactant: FC(F)c1nc2ccccc2n1-c1nc(Cl)nc(N2CCOCC2)n1
Reactant: Oc1cccnc1
Agent: COCCOCCN(CCOCCOC)CCOCCOC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: FC(F)c1nc2ccccc2n1-c1nc(Oc2cccnc2)nc(N2CCOCC2)n1
Yield: 11.9 %

Procedure:
A mixture of 0.301 g (3.16 mmol) of 3-hydroxypyridine and 0.132 g (3.30 mmol) of NaOH was stirred in water until a clear solution was obtained. The water was removed and the residue was combined with a mixture of 0.301 g (3.16 mmol) of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-1H-benzimidazole and 0.02 g (0.06 mmol) of tris[2-(2-methoxyethoxy)ethyl]amine (TDA-1) in dioxane (12 mL). The resulting mixture was heated under reflux for 2 hr before being cooled, and diluted with water. The resulting precipitate was collected by filtration, and recrystallized from methanol to give 0.160 g (50% yield) of 2-(difluoromethyl)-1-[4-(4-morpholinyl)-6-(3-pyridinyloxy)-1,3,5-triazin-2-yl]-1H-benzimidazole: mp 229-231° C.; 1H NMR (CDCl3) δ8.63-8.60 (m, 2H), 8.12 (dd, J=7.1, 1.4 Hz, 1H), 7.87 (dd, J=7.1, 1.4 Hz, 1H), 7.59 (ddd, J=8.3, 2.7, 1.4 Hz, 1H), 7.45 (ddd, J=8.2, 4.6, 0.3 Hz, 1H), 7.41-7.34 (m, 2H), 7.25 (t, JHF=53.6 Hz, 1H), 3.99-3.96 (m, 2H), 3.89-3.83 (m, 4H), 3.79-3.77 (m, 2H); Anal. Calcd. for C20H17F2N7O2 0.7H2O: C, 54.8; H, 4.2; N, 22.4. Found: C, 54.5; H, 4.0; N, 22.0%.
Reaction SMILES: Cl.FC1C=C(C=CC=1)CN1C=C(C2C3C(=NC=C(C4C=CC(C5CCNCC5)=CC=4)C=3)N(S(C3C=CC(C)=CC=3)(=O)=O)C=2)C=N1.[CH3:46][O:47][C:48]1[CH:49]=[C:50]([CH:95]=[CH:96][CH:97]=1)[CH2:51][N:52]1[CH:56]=[C:55]([C:57]2[C:65]3[C:60](=[N:61][CH:62]=[C:63]([C:66]4[CH:71]=[CH:70][C:69]([CH:72]5[CH2:77][CH2:76][N:75]([C:78]([O:80][C:81]([CH3:84])([CH3:83])[CH3:82])=[O:79])[CH2:74][CH2:73]5)=[CH:68][CH:67]=4)[CH:64]=3)[N:59](S(C3C=CC(C)=CC=3)(=O)=O)[CH:58]=2)[CH:54]=[N:53]1.[OH-].[Li+]>C1COCC1.CO.O>[CH3:46][O:47][C:48]1[CH:49]=[C:50]([CH:95]=[CH:96][CH:97]=1)[CH2:51][N:52]1[CH:56]=[C:55]([C:57]2[C:65]3[C:60](=[N:61][CH:62]=[C:63]([C:66]4[CH:67]=[CH:68][C:69]([CH:72]5[CH2:77][CH2:76][N:75]([C:78]([O:80][C:81]([CH3:84])([CH3:82])[CH3:83])=[O:79])[CH2:74][CH2:73]5)=[CH:70][CH:71]=4)[CH:64]=3)[NH:59][CH:58]=2)[CH:54]=[N:53]1
Reactant: COc1cccc(Cn2cc(-c3cn(S(=O)(=O)c4ccc(C)cc4)c4ncc(-c5ccc(C6CCN(C(=O)OC(C)(C)C)CC6)cc5)cc34)cn2)c1
Agent: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCNCC5)cc4)cnc32)cc1
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1cccc(Cn2cc(-c3c[nH]c4ncc(-c5ccc(C6CCN(C(=O)OC(C)(C)C)CC6)cc5)cc34)cn2)c1
Yield: 91.4 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, tert-butyl 4-(4-(3-(1-(3-methoxybenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperidine-1-carboxylate (120 mg, 0.167 mmol) was hydrolyzed by lithium hydroxide (70 mg, 1.67 mmol) in THF/methanol/water (12/6/3 ml) to yield crude 86 mg (91% yield) of the titled compound. MS: m/z=564.3 (M+1).
Reaction SMILES: C(OC(N1CCC(C([O:20][C:21]2[CH:43]=[CH:42][C:24]3[C:25]4[N:29]([CH2:30][CH2:31][O:32][C:23]=3[CH:22]=2)[CH:28]=[C:27]([C:33]2[N:34]([CH:39]([CH3:41])[CH3:40])[N:35]=[C:36]([CH3:38])[N:37]=2)[N:26]=4)CC)CC1)=O)C1C=CC=CC=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:50]([O:52][C:53](=[O:64])[CH:54](Br)[CH2:55][CH:56]([CH3:62])[C:57]([O:59][CH2:60][CH3:61])=[O:58])[CH3:51]>CC#N>[CH2:50]([O:52][C:53](=[O:64])[CH:54]([O:20][C:21]1[CH:43]=[CH:42][C:24]2[C:25]3[N:29]([CH2:30][CH2:31][O:32][C:23]=2[CH:22]=1)[CH:28]=[C:27]([C:33]1[N:34]([CH:39]([CH3:41])[CH3:40])[N:35]=[C:36]([CH3:38])[N:37]=1)[N:26]=3)[CH2:55][CH:56]([CH3:62])[C:57]([O:59][CH2:60][CH3:61])=[O:58])[CH3:51]
Reactant: CCOC(=O)C(C)CC(Br)C(=O)OCC
Reactant: CCC(Oc1ccc2c(c1)OCCn1cc(-c3nc(C)nn3C(C)C)nc1-2)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)C(C)CC(Oc1ccc2c(c1)OCCn1cc(-c3nc(C)nn3C(C)C)nc1-2)C(=O)OCC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 73.4 %

Procedure:
To a suspension of 2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-ol from Example 4 (330 mg, 1.013 mmol) in CH3CN (18 mL) was added Cs2CO3 (825 mg, 2.53 mmol) followed by a solution of 2-bromo-4-methylpentanedioic acid diethyl ester (640 mg, 2.276 mmol) in CH3CN (2 mL) and stirring at reflux temperature was continued for 1.5 h. After cooling to RT, the reaction mixture was partitioned between water and EtOAc. The aqueous phase was extracted with EtOAc and the combined organic layers were washed with water, followed by brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 2-8% MeOH in DCM) affording 2-[2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-yloxy]-4-methylpentanedioic acid diethyl ester as a pale yellow gum (391 mg, 73%). LCMS: RT 3.59 min [M+H]+ 526.5
Reaction SMILES: [F:1][CH:2]([F:47])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:14]([F:17])([F:16])[F:15])=[N:11][NH:12][CH:13]=2)=[CH:5][C:4]=1[CH:18]([S:23][CH:24]([C:29]1[CH:34]=[C:33]([C:35]2[C:36]([C:40]([F:43])([F:42])[F:41])=[N:37][NH:38][CH:39]=2)[CH:32]=[CH:31][C:30]=1[CH:44]([F:46])[F:45])[C:25]([F:28])([F:27])[F:26])[C:19]([F:22])([F:21])[F:20].ClC1C=CC=C(C(OO)=[O:56])C=1.S([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[F:45][CH:44]([F:46])[C:30]1[CH:31]=[CH:32][C:33]([C:35]2[C:36]([C:40]([F:43])([F:42])[F:41])=[N:37][NH:38][CH:39]=2)=[CH:34][C:29]=1[CH:24]([S:23]([CH:18]([C:4]1[CH:5]=[C:6]([C:9]2[C:10]([C:14]([F:17])([F:16])[F:15])=[N:11][NH:12][CH:13]=2)[CH:7]=[CH:8][C:3]=1[CH:2]([F:1])[F:47])[C:19]([F:20])([F:21])[F:22])=[O:56])[C:25]([F:26])([F:27])[F:28]
Reactant: FC(F)c1ccc(-c2c[nH]nc2C(F)(F)F)cc1C(SC(c1cc(-c2c[nH]nc2C(F)(F)F)ccc1C(F)F)C(F)(F)F)C(F)(F)F
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: O=S(C(c1cc(-c2c[nH]nc2C(F)(F)F)ccc1C(F)F)C(F)(F)F)C(c1cc(-c2c[nH]nc2C(F)(F)F)ccc1C(F)F)C(F)(F)F
Yield: 51.7 %

Procedure:
To 0.37 g (1.0 mmol) of [2-difluoromethyl-5-(3-trifluoromethylpyrazolyl)phenyl]2,2,2-trifluoroethyl sulfide (Compound No. V-295 of the Present Invention) in 5 ml of chloroform, 0.25 g (1.5 mmol) of m-chloroperbenzoic acid was added at 0° C. with stirring, and the reaction solution was stirred for 1 hour. The reaction solution was mixed with 10 ml of 10% aqueous sodium sulfite and stirred at room temperature for 10 minutes, and then 20 ml of chloroform was added. The chloroform layer was washed with 20 ml of saturated aqueous sodium hydrogen carbonate three times and dried over anhydrous magnesium sulfate, and the chloroform was distilled off under reduced pressure to obtain 0.38 g of [2-difluoromethyl-5-(3-trifluoromethylpyrazolyl)phenyl]2,2,2-trifluoroethyl sulfoxide (yield 97.4%) as a yellow dough (nD20 1.4909).
Reaction SMILES: [CH3:1][C@@:2]12[C@H:10](O)[CH2:9][C@@H:5]([C:6]1([CH3:8])[CH3:7])[CH2:4][CH2:3]2.[CH2:12]([CH:15]1[CH2:20][CH2:19][CH:18]([C:21]([OH:23])=[O:22])[CH2:17][CH2:16]1)[CH2:13][CH3:14].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[CH2:12]([CH:15]1[CH2:20][CH2:19][CH:18]([C:21]([O:23][C@@H:9]2[CH2:10][C@@:2]3([CH3:1])[C:6]([CH3:8])([CH3:7])[C@@H:5]2[CH2:4][CH2:3]3)=[O:22])[CH2:17][CH2:16]1)[CH2:13][CH3:14]
Reactant: CCCC1CCC(C(=O)O)CC1
Reactant: CC1(C)[C@H]2CC[C@]1(C)[C@H](O)C2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCC1CCC(C(=O)O[C@@H]2C[C@]3(C)CC[C@H]2C3(C)C)CC1
Yield: 21.36 %

Procedure:
Example 6 was performed as Example 1 except for substitution of 1.0 g of L-borneol, 1.28 g of 4-n-Propyl-cyclohexanecarboxylic acid, 1.61 g of N,N′-Dicyclohexyl carbodimide (DCC), 0.95 g of N,N-(dimethyl amino)-pyridine (DMAP) and 80 ml of dichloromethane into a round-bottom flask. After filtering and condensing, the residue was subjected to recrystallization from a mixed solvent (CH2Cl2:methanol=1:3), giving (1S,2R,4S)-4,7,7-trimethylbicyclo [2.2.1]hept-2-yl 4-propyl-1-cyclohexanecarboxylate, as a white solid in a 21.36% yield. The optical properties of the resulting compound were tested as in Example 1. The compound exhibited a specific rotation [α] of −22.82 and a helical pitch P of 11.8 μm, with helical twisting power of 8.45 μm−1.
Reaction SMILES: [N+]([C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)([O-])=O.C(=O)([O-])[O-].[Cs+].[Cs+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[NH:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:12]=[CH:4]1
Reactant: O=[N+]([O-])c1cc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc2[nH]ccc2c1

Procedure:
Nitroindole AA1 was alkylated with an appropriately substituted alkyl or arylalkyl halide in the presence of a base such as cesium carbonate, potassium carbonate and the like also in the presence of a solvent such as DMF to provide a 1-substututed indole intermediate. The resulting intermediate was reacted with an amine such as pyrrolidine, piperidine and the like while dissolved in an organic acid such as glacial acetic acid in the presence of formaldehyde also in glacial acetic acid to provide a 3-substututed indole intermediate. The nitro group of the resulting intermediate was then reduced to an amino group by reaction with 1,1-dimethylhydrazine in the presence of an alcohol solvent such as MeOH and charcoal and ferric chloride hexahydrate which provided intermediate AA2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9](/[CH:13]=[C:14]2\[N:15]=[C:16](C3C=CC=CC=3)[O:17][C:18]\2=[O:19])[C:4]=1[C:5](OC)=[O:6].[OH-].[K+]>CO>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5](=[O:6])[NH:15][C:14]([C:18]([O:17][CH3:16])=[O:19])=[CH:13]2
Reactant: COC(=O)c1c(/C=C2\N=C(c3ccccc3)OC2=O)cccc1OC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)c1cc2cccc(OC)c2c(=O)[nH]1
Yield: 34.4 %

Procedure:
To a solution of (Z)-methyl 2-methoxy-6-((5-oxo-2-phenyloxazol-4(5H)-ylidene)methyl)benzoate (4.2 g, 12.45 mmol) in MeOH (50 mL) was added KOH (2.1 g, 37.35 mmol). The reaction mixture was heated to reflux for 1 hour. The solvent was subsequently removed and the residue was partitioned between water (30 mL) and EtOAc (20 mL). The aqueous layer was extracted with EtOAc (3×20 mL). The organic layers were combined, concentrated in vacuo, adjusted to pH=3 with a 4M solution of HCl in MeOH, and concentrated. The resulting brown solid which was purified by column chromatography eluting with petroleum ether and ethyl acetate (PE/EtOAc=5:1-1:1 gradient) to give the title compound (1 g, 26.3% over 2 steps). 1H NMR (400 MHz, CDCl3) δ ppm 8.55 (s, 1H), 7.58 (t, 1H, J=8.0 Hz), 7.12 (d, 1H, J=8.0 Hz), 6.97 (d, 1H, J=8.0 Hz), 6.67 (s, 1H), 4.01 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[N:9][CH:10]=[CH:11][C:6]=2[N:5]2[N:12]=[C:13]([CH3:15])[CH:14]=[C:4]2[N:3]=1.[Na].[CH2:17]([OH:19])[CH3:18]>O>[CH2:17]([O:19][C:2]1[C:7]2[CH:8]=[N:9][CH:10]=[CH:11][C:6]=2[N:5]2[N:12]=[C:13]([CH3:15])[CH:14]=[C:4]2[N:3]=1)[CH3:18]
Reactant: CCO
Reactant: Cc1cc2nc(Cl)c3cnccc3n2n1
Agent: [Na]
Solvent: O
Product: CCOc1nc2cc(C)nn2c2ccncc12
Reaction time: 12 h

Procedure:
2.2 g. of 5-chloro-2-methylpyrazolo[1,5-a]pyrido[3,4-e]pyrimidine are added to a solution of 0.5 g. of sodium in 30 ml. of ethanol. The solution is refluxed with stirring for 12 hours. 10 ml. of water are added and the crystalline 5-ethoxy-2-methylpyrazolo[1,5-a]pyrido[3,4-e]pyrimidine is filtered off, yield: 1.4 g. (61%); m.p. 156.2° (methanol).