Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[NH:15]1[CH2:20][CH2:19][C:18]2([CH2:25][C:24]3[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=3[CH2:22][O:21]2)[CH2:17][CH2:16]1.[C:30]([OH:35])(=[O:34])[C:31]([OH:33])=[O:32].CO>C(OCC)(=O)C>[C:30]([OH:35])(=[O:34])[C:31]([OH:33])=[O:32].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:15]3[CH2:20][CH2:19][C:18]4([CH2:25][C:24]5[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=5[CH2:22][O:21]4)[CH2:17][CH2:16]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: c1ccc2c(c1)COC1(CCNCC1)C2
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC2(CC1)Cc1ccccc1CO2

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 1,4-dihydrospiro[3H-2-benzopyran-3,4'-piperidine]. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 78% overall yield. FDMS m/e=392 (M+ of free base). α[D]589 =-12.34 (c=0.57, methanol).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]=[N:10][C:11]2[CH:27]=[CH:26][C:14]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23]CC)=[O:22])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1)#[N:2].[OH-].[Na+].Cl>CN(C)C=O.O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([N:9]=[N:10][C:11]2[CH:27]=[CH:26][C:14]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:13][CH:12]=2)=[CH:7][CH:8]=1)#[N:2]
Reactant: CCOC(=O)CCCCCOc1ccc(N=Nc2ccc(C#N)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(N=Nc2ccc(OCCCCCC(=O)O)cc2)cc1
Temperature: 90 °C
Reaction time: 4 h
Yield: 72.9 %

Procedure:
6.92 g (0.019 mol) of ethyl 6-[4-(4-cyanophenylazo)phenoxy]-hexanoate was dissolved in 250 mL of dimethylformamide in a 500 mL one-neck round flask fitted with a magnetic stirring bar and a reflux condenser by heating to 90° C. while stirring on an oil bath. 7.48 g (0.187 mol) of NaOH in 80 mL of water was added through the condenser: Stirring and heating were continued for 4 h. After cooling on an ice-water bath 40 mL of 8N HCl was added. The precipitated crude product was recovered by filtration. The precipitate was washed with 200 mL of hot ethanol. After vacuum drying at 50° C. for 20 h. 4.67 g (yield 72%) of 6-[4-(4-cyanophenylazo)phenoxy]-hexanoic acid was obtained.
Reaction SMILES: [C:1]([C:5]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:6]=1[O:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:24])[CH2:15][S:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[OH:23])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:38])C=1.S(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[C:1]([C:5]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:6]=1[O:7][CH:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:24])[CH2:15][S:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[OH:23])=[O:38])[CH2:12][CH2:13]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)c1cc(F)ccc1OC1CCN(C(=O)CSc2ccccc2O)CC1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(F)ccc1OC1CCN(C(=O)CS(=O)c2ccccc2O)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.7 %

Procedure:
A solution of 2-({2-[4-(2-tert-butyl-4-fluorophenoxy)piperidin-1-yl]-2-oxoethyl}sulfanyl)phenol (292 mg, 0.70 mmol) obtained in Example 239 and m-chloroperbenzoic acid (275 mg, 1.12 mmol) in ethyl acetate (14 mL) was stirred at 0° C. for 3 hr. Saturated aqueous sodium bisulfite solution (5 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 30 min. The reaction mixture was partitioned between ethyl acetate and water. The ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate 90:10-20:80) to give 2-({2-[4-(2-tert-butyl-4-fluorophenoxy)piperidin-1-yl]-2-oxoethyl}sulfinyl)phenol (163 mg, 54%) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[N:8]([CH2:9]COC(=O)C)[C:7]([C:15]2[N:19]3[N:20]=[C:21](Cl)[CH:22]=[CH:23][C:18]3=[N:17][N:16]=2)=[N:6][CH:5]=1)([O-:3])=[O:2].CN.[N+](C1N(CCOC(=O)C)C(C2N3N=[C:47]([NH:50][CH3:51])[CH:48]=[CH:49][C:44]3=NN=2)=NC=1)([O-])=O>O1CCOCC1>[N+:1]([C:4]1[N:8]([CH3:9])[C:7]([C:15]2[N:19]3[N:20]=[C:21]([N:50]4[CH2:47][CH2:48][CH2:49][CH2:44][CH2:51]4)[CH:22]=[CH:23][C:18]3=[N:17][N:16]=2)=[N:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CNc1ccc2nnc(-c3ncc([N+](=O)[O-])n3CCOC(C)=O)n2n1
Reactant: CC(=O)OCCn1c([N+](=O)[O-])cnc1-c1nnc2ccc(Cl)nn12
Agent: CN
Solvent: C1COCCO1
Product: Cn1c([N+](=O)[O-])cnc1-c1nnc2ccc(N3CCCCC3)nn12
Reaction time: 1 h

Procedure:
0.42 g. crude 3-(5-nitro-1-β-acetoxyethyl-2-imidazolyl)-6-chloro-s-triazolo[4,3-b]pyridazine (see Example 14 for the preparation thereof) was dissolved in 3 ml. dioxan, mixed with 0.36 ml. 33 percent aqueous methylamine solution, maintained at 60° C. for half an hour, then evaporated in a vacuum at a bath temperature of 50° C. The residue was dissolved in 2 ml. isopropanol, left to stand for about one hour at ambient temperature and the precipitated crystals then filtered off with suction, washed with isopropanol and ether and recrystallized (0.1 g.) from about 5 ml. isopropanol, with the addition of charcoal, to give 0.054 g. of the desired 3-(5-nitro-1-β-acetoxyethyl-2-imidazolyl)-6-methylamino-s-triazolo-[4,3-b]pyridazine, which has a melting point of 221° - 233° C.
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([S:16][CH2:17][C:18]2[S:22][C:21]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)=[N:20][C:19]=2[CH3:33])=[C:12]2[C:7]=1[CH2:8][CH2:9][CH2:10][O:11]2.O.[OH-].[Li+].Cl>C1COCC1.O>[CH3:33][C:19]1[N:20]=[C:21]([C:23]2[CH:24]=[CH:25][C:26]([C:29]([F:32])([F:30])[F:31])=[CH:27][CH:28]=2)[S:22][C:18]=1[CH2:17][S:16][C:13]1[CH:14]=[CH:15][C:6]([O:5][CH2:4][C:3]([OH:34])=[O:2])=[C:7]2[C:12]=1[O:11][CH2:10][CH2:9][CH2:8]2
Reactant: COC(=O)COc1ccc(SCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)c2c1CCCO2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CSc1ccc(OCC(=O)O)c2c1OCCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
{8-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-chroman-5-yloxy}-acetic acid methyl ester dissolved in 5 ml THF and 1 ml water, was treated with lithium hydroxide monohydrate (327 mg, 7.8 mmol); stirring at room temperature for 1 hour. The reaction mixture was then acidified to about pH 3 with 2 N HCl. The reaction was then extracted into ethyl acetate (2×20 ml). The organic extracts were washed with brine, dried over anhydrous sodium sulfate, decanted, and concentrated in vacuo. Recrystalization from chloroform/hexanes afforded the title compound (750 mg, 96%) as a pale yellow solid. IR (thin film) cm−1: 1745; 400 MHz 1H NMR (DMSO-d6) δ 7.98 (d, 2H, J=8.0 Hz), 7.75 (d, 2H, J=8.0 Hz), 6.97 (d, 1H, J=8.5 Hz), 6.27 (d, 1H, J=8.5 Hz), 4.60 (s, 2H), 4.18 (s, 2H), 4.11 (t, 2H, J=4.6 Hz), 2.56 (t, 2H, J=6.6 Hz), 2.15 (s, 3H), 1.83 (m, 2H).; MS m/z 496 (M+1). Anal. Calc'd for C23H20F3N1O4S2 0.3 CHCl3 C, 52.67; H, 3.85; N, 2.64; found: C, 52.49; H, 3.77; N, 2.54.
Reaction SMILES: [NH2:1][C:2]([CH3:49])([CH3:48])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH3:16])[N:11]=[C:10]2[C:17]1[N:22]=[C:21]2[C:23]([C:45](O)=[O:46])=[CH:24][N:25]([C:26]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:20]2=[N:19][CH:18]=1.[C:50]([NH2:54])([CH3:53])([CH3:52])[CH3:51].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[NH2:1][C:2]([CH3:49])([CH3:48])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH3:16])[N:11]=[C:10]2[C:17]1[N:22]=[C:21]2[C:23]([C:45]([NH:54][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:46])=[CH:24][N:25]([C:26]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:20]2=[N:19][CH:18]=1
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(OCCCC(C)(C)N)ccc21
Reactant: CC(C)(C)N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: Cn1nc(-c2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(OCCCC(C)(C)N)ccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.1 %

Procedure:
A mixture of 2-(5-(4-Amino-4-methylpentyloxy)-1-methyl-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxylic acid (100 mg, 0.15 mmol), tert-butylamine (0.05 mL, 0.45 mmol) and HATU (68.4 mg, 0.18 mmol) in 10 mL of dry THF was stirred for 4 hours at room temperature. The reaction mixture was evaporated to dryness, the residue was suspended in 50 mL of 0.5 N HCl, and product extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated to afford 2-(5-(4-amino-4-methylpentyloxy)-1-methyl-1H-indazol-3-yl)-N-tert-butyl-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (88 mg, 62%) as dark oil, material used in the next step without further purification. LCMS: (M+H)+=706.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:8][N:9]([CH2:14][C:15]2[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:10][CH2:11][CH2:12][NH2:13])=[N:4][CH:5]=[CH:6][CH:7]=1.[OH:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][N:24]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][C:2]1[C:3]([CH2:8][N:9]([CH2:14][C:15]2[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:10][CH2:11][CH2:12][NH:13][C:27](=[O:28])[C:26]2[CH:30]=[CH:31][C:23]([OH:22])=[N:24][CH:25]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccnc1CN(CCCN)Cc1ncccc1C
Reactant: O=C(O)c1ccc(O)nc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccnc1CN(CCCNC(=O)c1ccc(O)nc1)Cc1ncccc1C
Yield: 13.8 %

Procedure:
Using General Procedure G: To a solution of N1,N1-bis-(3-methyl-pyridin-2-ylmethyl)-propane-1,3-diamine (0.24 g, 0.84 mmol) in dry DMF (4 mL) was added 6-hydroxy-nicotinic acid (0.121 g, 0.87 mmol) followed by EDCI (0.182 g, 0.95 mmol), HOBT (0.128 g, 0.95 mmol), and DIPEA (0.25 mL, 1.44 mmol). Purification of the crude material by column chromatography on silica gel (10:1:1 CH2Cl2-MeOH—NH4OH) provided 47 mg (14%) of the free base of the title compound as a colorless oil. Conversion to the HBr salt gave COMPOUND 232 (65 mg, 78%) as a white solid. 1H NMR (D2O) δ 1.74-1.84 (m, 2H), 2.47 (s, 6H), 2.64-2.69 (m, 2H), 3.24 (dd, 2H, 6.3 Hz), 4.31 (s, 4H), 6.62 (d, 1H, J=9.6 Hz), 7.80-7.84 (m, 3H), 7.95 (d, 1H, J=2.1 Hz), 8.32 (d, 2H, J=8.1 Hz), 8.58 (d, 2H, J=6.0 Hz); 13C NMR (D2O) δ 17.24, 25.16, 37.61, 51.91, 53.99, 115.32, 119.34, 126.02, 137.52, 137.87, 138.75, 140.81, 148.48, 150.88, 166.80; ES-MS m/z 406 (M+H). Anal. Calcd. for C23H27N5O2.3.2HBr.3.0H2O: C, 38.45; H, 5.08; N, 9.75; Br, 35.59. Found: C, 38.32; H, 4.94; N, 9.48; Br, 35.96.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]3[CH:12]=[CH:13][C:14]([NH:17][CH3:18])=[N:15][CH:16]=3)=[CH:8][C:7]=2[CH:19]=1.C(Cl)Cl.B(Br)(Br)Br.C([O-])(O)=O.[Na+]>O>[CH3:18][NH:17][C:14]1[N:15]=[CH:16][C:11]([C:9]2[O:10][C:6]3[CH:5]=[CH:4][C:3]([OH:2])=[CH:19][C:7]=3[CH:8]=2)=[CH:12][CH:13]=1
Reactant: CNc1ccc(-c2cc3cc(OC)ccc3o2)cn1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CNc1ccc(-c2cc3cc(O)ccc3o2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.4 %

Procedure:
[5-(5-Methoxy-benzofuran-2-yl)-pyridin-2-yl]-methylamine (0.24 mmol) was mixed with CH2Cl2 (3 mL) at 0° C. under argon atmosphere. BBr3 (1M in CH2Cl2) (1.0 mL, 1.0 mmol) was added dropwise and the mixture was stirred for 2 h at rt. The mixture was hydrolysed with H2O followed by NaHCO3 (sat. aq.) solution. The resulting mixture was extracted with EtOAc and the organic extracts were dried over Na2SO4. After filtration and evaporation of the solvent, the crude material was purified by preparative HPLC to afford the title compound as a white solid (21 mg). 1H NMR δ ppm 9.10 (s, 1 H) 8.50 (d, 1 H) 7.81 (dd, 1 H) 7.32 (d, 1 H) 6.96 (s, 1 H) 6.81-6.94 (m, 2 H) 6.66 (dd, 1 H) 6.54 (d, 1 H) 2.82 (d, 3 H); MS m/z 241 (M+H).
Reaction SMILES: [F:1][CH:2]([F:24])[O:3][C:4]1[CH:5]=[C:6]([N:10]2[CH:15]=[CH:14][C:13](=[O:16])[C:12]([C:17](=O)/[CH:18]=[CH:19]/[N:20](C)C)=[N:11]2)[CH:7]=[CH:8][CH:9]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[NH:33]N>>[F:1][CH:2]([F:24])[O:3][C:4]1[CH:5]=[C:6]([N:10]2[CH:15]=[CH:14][C:13](=[O:16])[C:12]([C:17]3[N:33]([C:27]4[CH:28]=[C:29]([F:32])[CH:30]=[CH:31][C:26]=4[F:25])[N:20]=[CH:19][CH:18]=3)=[N:11]2)[CH:7]=[CH:8][CH:9]=1
Reactant: NNc1cc(F)ccc1F
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(OC(F)F)c2)ccc1=O
Product: O=c1ccn(-c2cccc(OC(F)F)c2)nc1-c1ccnn1-c1cc(F)ccc1F

Procedure:
The product was obtained starting from 1-(3-Difluoromethoxy-phenyl)-3-((E)-3-dimethylamino-acryloyl)-1H-pyridazin-4-one (A-10) and 2,5-difluoro-phenylhydrazine according to the method described for example 91. MS: M=417.2 (M+H)+
Reaction SMILES: [CH3:1][C@@H:2](OS(C)(=O)=O)[C:3]#[CH:4].[Cl:10][CH2:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[F:21])=[O:13].C([Zn]CC)C.Cl>C1(C)C=CC=CC=1.[Pd](Cl)Cl.CC(CC#N)=N.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:10][CH2:11][C@@:12]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[F:21])([OH:13])[C@@H:3]([CH3:4])[C:2]#[CH:1]
Reactant: O=C(CCl)c1ccc(F)cc1F
Reactant: C#C[C@@H](C)OS(C)(=O)=O
Agent: Cl[Pd]Cl
Agent: CC(=N)CC#N
Agent: CC[Zn]CC
Solvent: Cc1ccccc1
Product: C#C[C@H](C)[C@](O)(CCl)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 130.6 %

Procedure:
163.3 mg (0.630 mmol) of palladium(II)-dichloride-diacetonitrile were dissolved in 60.00 ml of tetrahydrafuran, and 412.9 mg (1.570 mmol) of triphenylphoshine were added. The reaction mixture turned yellow and was stirred for 10 min. at room temperature. 4.198 g (28.33 mmol) of (R)-methanesulfonic acid 1-methyl-prop-2-ynylester and 3.00 g (15.74 mmol) of 2-chloro-1-(2,4-difluorophenyl)-ethanone were added as well as 42.93 ml (47.22 mmol) of diethylzinc solution in toluene (1.1 M) within 5 min. at 25–35° C. dropwise; the mixture was intermittently cooled and subsequently stirred for 40 min. at room temperature. After pouring onto 50 ml of ice-cold water and 50 ml of aqueous 25% hydrochloric acid the mixture was extracted twice with each 50 ml of ethyl acetate. The organic phases were washed once with 50 ml of water, combined, dried over sodium sulfate and evaporated to dryness. 5.029 g of (2R,3S)-1-chloro-2-(2,4-difluoro-phenyl)-3-methyl-pent-4-yne-2-ol were obtained as a dark yellow oil (73% pure) containing 76% of the stated diastereomer, corresponding to a yield of 95.3%.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[O:11][CH2:12][O:13][CH3:14].C(=O)(O)[O-].[Na+].[C:20]([C:22]1[CH:23]=[CH:24][C:25]([O:32][CH3:33])=[C:26]([S:28](Cl)(=[O:30])=[O:29])[CH:27]=1)#[N:21]>O1CCCC1.O>[C:20]([C:22]1[CH:23]=[CH:24][C:25]([O:32][CH3:33])=[C:26]([S:28]([NH:1][CH2:2][CH2:3][C:4]2[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=2[O:11][CH2:12][O:13][CH3:14])(=[O:30])=[O:29])[CH:27]=1)#[N:21]
Reactant: COCOc1cc(O)ccc1CCN
Reactant: COc1ccc(C#N)cc1S(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCOc1cc(O)ccc1CCNS(=O)(=O)c1cc(C#N)ccc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.4 %

Procedure:
4-(2-Aminoethyl)-3-methoxymethoxyphenol (12.3 g) and 7.9 g of sodium bicarbonate were suspended in a mixture of 133 mL of tetrahydrofuran and 14.4 mL of water, to the suspension was added 18 mL portions of a solution of 14.50 g of 5-cyano-2-methoxybenzensulfonyl chloride in 180 mL of tetrahydrofuran every 10 minutes while the internal temperature was kept at 10–20° C. After being stirred at room temperature for 8 hours, the reaction mixture was purified by column chromatography on aminopropylated silica gel (eluent: ethyl acetate), and recrystallized from ethyl acetate-diisopropyl ether to give 21.87 g of 5-cyano-N-[2-(4-hydroxy-2-methoxymethoxyphenyl)ethyl]-2-methoxybenzenesulfonamide as a colorless crystal.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]2[CH2:9][C@H:10]3[N:22]([CH2:23][CH:24]4[CH2:26][CH2:25]4)[CH2:21][CH2:20][C@:16]45[C:17]=2[C:18]=1[O:19][C@H:15]4[C@H:14]([N:27]1[C:31](=[O:32])[CH:30]=[CH:29][C:28]1=[O:33])[CH2:13][CH2:12][C@@:11]35[OH:34])(=[O:3])[CH3:2].[N+]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([O-])=O.C1CCN2C(=NCCC2)CC1.C(=O)([O-])O.[Na+]>C1COCC1>[C:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]2[CH2:9][C@H:10]3[N:22]([CH2:23][CH:24]4[CH2:25][CH2:26]4)[CH2:21][CH2:20][C@:16]45[C:17]=2[C:18]=1[O:19][C@H:15]4[C@H:14]([N:27]1[C:31](=[O:32])[CH2:30][C:29](=[CH:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:28]1=[O:33])[CH2:13][CH2:12][C@@:11]35[OH:34])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc2c3c1O[C@H]1[C@H](N4C(=O)C=CC4=O)CC[C@@]4(O)[C@@H](C2)N(CC2CC2)CC[C@]314
Reactant: O=[N+]([O-])Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CC(=O)Oc1ccc2c3c1O[C@H]1[C@H](N4C(=O)CC(=Cc5ccccc5)C4=O)CC[C@@]4(O)[C@@H](C2)N(CC2CC2)CC[C@]314
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.2 %

Procedure:
In 5 mL of THF, 200 mg (0.43 mmol) of N-(3-acetoxy-17-cyclopropylmethyl-4,5α-epoxy-14-hydroxy-morphinan-6β-yl)-maleimide obtained in Example 21-1 was dissolved, and 85 mg (0.62 mmol) of nitromethylbenzene and 66 mg (0.43 mmol) of DBU were added, followed by stirring the mixture at room temperature for 1 hour. To the reaction mixture, aqueous saturated sodium hydrogen carbonate solution was added, and the resulting mixture was extracted with chloroform. Organic layers were combined, washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated to obtain a crude product. The obtained crude product was purified by silica gel column chromatography to obtain 196 mg (yield: 82%) of the captioned compound.
Reaction SMILES: [CH3:1]N(C)C=O.[H-].[Na+].[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:19]=1[O:20][CH3:21])[N:16]=[CH:15][N:14]=[C:13]2[O:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:38])[O:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)=[CH:25][CH:24]=1.CI>O>[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:19]=1[O:20][CH3:21])[N:16]=[CH:15][N:14]=[C:13]2[O:22][C:23]1[CH:24]=[CH:25][C:26]([N:29]([CH3:1])[C:30](=[O:38])[O:31][CH:32]2[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]2)=[CH:27][CH:28]=1
Reactant: CN(C)C=O
Reactant: COc1cc2ncnc(Oc3ccc(NC(=O)OC4CCCCC4)cc3)c2cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: COc1cc2ncnc(Oc3ccc(N(C)C(=O)OC4CCCCC4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 83 %

Procedure:
Dimethylformamide (5 ml) was added to sodium hydride (7 mg), and cyclohexyl N-{4-[(6,7-dimethoxy-4-quinazolinyl)oxy]phenyl}carbamate (35 mg) was added to the mixture. Subsequently, a dimethylformamide solution (2 ml) of methyl iodide (47 mg) was added thereto, and the mixture was stirred at room temperature for 10 min. Water was added to stop the reaction, and the reaction solution was then extracted with ethyl acetate, followed by washing with water and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (30 mg, yield 83%).
Reaction SMILES: C([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27]Br)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])C.[C:29]1([C:35]([OH:39])([CH3:38])[CH2:36][OH:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[OH:39][C:35]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([CH3:38])[CH2:36][O:37][CH2:27][C:22]1[C:23]([CH3:26])=[N:24][O:25][C:21]=1[C:18]1[CH:19]=[CH:20][C:15]([C:12]2[CH:11]=[CH:10][C:9]([C:6]3([C:4]([OH:3])=[O:5])[CH2:8][CH2:7]3)=[CH:14][CH:13]=2)=[CH:16][CH:17]=1
Reactant: CC(O)(CO)c1ccccc1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CBr)cc3)cc2)CC1
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1COCC(C)(O)c1ccccc1

Procedure:
Prepared according to the procedure described in Example 48, Step 2, using 1-[4′-(4-bromomethyl-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 2-phenyl-propane-1,2-diol.
Reaction SMILES: S(=O)(=O)(O)O.N[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]2=[O:23])=[CH:9][C:8]=1[S:24]([F:29])([F:28])([F:27])([F:26])[F:25].N([O-])=O.[Na+].[Cu][C:35]#[N:36].[C-]#N.[K+]>C(O)(=O)C.O>[O:22]=[C:21]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](=[O:23])[N:13]1[C:10]1[CH:11]=[CH:12][C:7]([C:35]#[N:36])=[C:8]([S:24]([F:27])([F:29])([F:26])([F:25])[F:28])[CH:9]=1
Reactant: N#C[Cu]
Reactant: Nc1ccc(N2C(=O)c3ccccc3C2=O)cc1S(F)(F)(F)(F)F
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [C-]#N
Solvent: CC(=O)O
Solvent: O
Product: N#Cc1ccc(N2C(=O)c3ccccc3C2=O)cc1S(F)(F)(F)(F)F
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
0.46 ml (8.24 mmol) of semiconcentrated sulfuric acid was slowly added dropwise at 0° C. to a solution of 1 g (2.74 mmol) of 2-(4-amino-3-pentafluorosulfanylphenyl)isoindole-1,3-dione (prepared in example 5) in acetic acid. The mixture was stirred at 0° C. for 10 min; then a solution of 189.4 mg of sodium nitrite in 2 ml of water was slowly added dropwise with stirring, and the resulting solution was stirred at 0° C. for 30 min. This solution was finally added dropwise to a solution, cooled to 0° C., of 246 mg (2.74 mmol) of copper(I) cyanide and 536 mg (8.23 mmol) of potassium cyanide in 5 ml of water. The reaction mixture was stirred at 0° C. for 30 min and afterward at room temperature for another 3 h. After the end of the reaction, the mixture was added to water and the aqueous phase extracted twice with ethyl acetate. The organic phase was dried over magnesium sulfate and filtered, the filtrate was concentrated and the residue purified chromatographically on silica gel first with toluene and then with 20/1 toluene/ethyl acetate. 4-(1,3-Dioxo-1,3-dihydroisoindol-2-yl)-2-pentafluorosulfanylbenzonitrile was obtained. 1H NMR (500 MHz; d6-dmso: δ [ppm]=8.4 (m, 2H); 8.1-7.95 (m, 5H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:14][CH:15]([CH3:21])[C:16](OCC)=[O:17].[O-]CC.[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([C:16](=[O:17])[CH:15]([CH3:21])[CH3:14])[C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCOC(=O)C(C)C
Reactant: COc1ccc(CC#N)cc1OC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(C(C#N)C(=O)C(C)C)cc1OC
Temperature: 25 °C
Yield: 30.9 %

Procedure:
To a mixture of [3,4-bis(methyloxy)phenyl]acetonitrile (2.0 g, 11 mmol) and ethyl 2-methylpropanoate (1.9 mL, 14 mmol) in ethanol (4 mL) was added a sodium ethoxide solution (21%, 8.4 mL, 23 mmol), and the resulting mixture was heated at reflux for 18 hours. After cooling to room temperature, it was poured into a mixture of ice-water (50 mL). This aqueous mixture was washed with dichloromethane (3×20 mL) then acidified to pH 1. The acidified mixture was extracted with ethyl acetate (3×30 mL). The combined extract was washed with aqueous sodium bicarbonate solution, brine, dried over sodium sulfate, filtered and concentrated to give 2-[3,4-bis(methyloxy)phenyl]-4-methyl-3-oxopentanenitrile as a brown oil (0.7 g, 3.4 mmol, 28% yield), MS (EI) for C14H17NO3: 248 (MH+).