Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([O:18][CH3:19])=[CH:11][C:12]([Br:17])=[C:13]([CH:16]=1)[CH:14]=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]1([CH3:28])[CH:25]=[CH:24][C:23]([Mg]Br)=[CH:22][CH:21]=1.[Cl-].[NH4+].Cl>C(OCC)(=O)C.O1CCCC1>[CH2:1]([O:8][C:9]1[C:10]([O:18][CH3:19])=[CH:11][C:12]([Br:17])=[C:13]([CH:14]([C:23]2[CH:24]=[CH:25][C:20]([CH3:28])=[CH:21][CH:22]=2)[OH:15])[CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc([Mg]Br)cc1
Reactant: COc1cc(Br)c(C=O)cc1OCc1ccccc1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(Br)c(C(O)c2ccc(C)cc2)cc1OCc1ccccc1
Reaction time: 0.17 h

Procedure:
To a mixture of 5-benzyloxy-2-bromo-4-methoxy-benzaldehyde (1 g) and tetrahydrofuran (10 mL) was added p-tolylmagnesium bromide (1 mol/L tetrahydrofuran solution, 3.7 mL) under ice-salt bath cooling. After stirring at same temperature for 10 minutes, to the mixture were added an aqueous solution of ammonium chloride, ethyl acetate and 2 mol/L hydrochloric acid. The separated organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 0%-50% ethyl acetate/hexane, gradient elution) to give the title compound (1.27 g).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([O:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:15]=[CH:14][N:13]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(N(CC)CC)C.[CH3:35][N:36]1[CH:40]=[C:39]([S:41](Cl)(=[O:43])=[O:42])[N:38]=[CH:37]1>CN(C=O)C>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([O:21][CH:22]3[CH2:27][CH2:26][N:25]([S:41]([C:39]4[N:38]=[CH:37][N:36]([CH3:35])[CH:40]=4)(=[O:43])=[O:42])[CH2:24][CH2:23]3)[N:15]=[CH:14][N:13]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(Nc2ncnc(OC3CCNCC3)c2[N+](=O)[O-])cc1
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cn1cnc(S(=O)(=O)N2CCC(Oc3ncnc(Nc4ccc(S(C)(=O)=O)cc4)c3[N+](=O)[O-])CC2)c1

Procedure:
Compound A31 was prepared in a similar manner as described above using (4-methanesulfonyl-phenyl)-[5-nitro-6-(piperidin-4-yloxy)-pyrimidin-4-yl]-amine (i.e., Comound A2) (15 mg, 0.035 mmol), triethylamine (20 EL), 1-methyl-1H-imidazole-4-sulfonyl chloride (9 mg, 0.050 mmol), DMF (0.6 mL), 1H NMR (CDCl3, 400 MHz) δ 2.07 (m, 4H), 3.08 (s, 3H), 3.32 (m, 2H), 3.53 (m, 2H), 3.79 (s,3H), 5.55 (m, 1H), 7.46 (s, 1H), 7.53 (s,1H), 7.85 (d,2H), 7.97 (d, 2H), 8.38 (s, 1H), 10.16 (s, 1H). Exact mass calculated for C20H23N7O7S2 537.11, found 538.4 (MH+).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([CH3:10])([CH3:9])[C:5](OC)=[O:6].CC(C)C(=O)[CH2:14][C:15]#[N:16]>>[CH3:1][O:2][CH2:3][C:4]([CH3:10])([CH3:9])[C:5](=[O:6])[CH2:14][C:15]#[N:16]
Reactant: COCC(C)(C)C(=O)OC
Reactant: CC(C)C(=O)CC#N
Product: COCC(C)(C)C(=O)CC#N
Yield: 29 %

Procedure:
Prepared from methyl 3-methoxy-2,2-dimethylpropanoate (8 g, 54.7 mmol) according to the method described in Example 122A Step 1 for 4-methyl-3-oxopentanenitrile. Purification via silica gel chromatography eluting with mixtures of petroleum ether and ethyl acetate afforded 5-methoxy-4,4-dimethyl-3-oxopentanenitrile as a yellow oil (2.5 g, 29%). 1H NMR (300 MHz, CDCl3) δ 3.72 (s, 2H), 3.32-3.33 (m, 5H), 1.18 (s, 6H).
Reaction SMILES: [CH2:1]([Li])CCC.[I-].C[S+](C)C.[O:11]1[CH2:15][CH2:14][O:13][CH:12]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]=[CH2:23])[N:17]=1>CCCCCC.O1CCCC1>[CH:22]1([C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([CH:12]3[O:13][CH2:14][CH2:15][O:11]3)[N:17]=2)[CH2:1][CH2:23]1
Reactant: [Li]CCCC
Reactant: C=Cc1cccc(C2OCCO2)n1
Agent: C[S+](C)C
Agent: [I-]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: c1cc(C2CC2)nc(C2OCCO2)c1
Temperature: -15 °C
Reaction time: 0.33 h

Procedure:
5.60 ml of a 1.6 M solution of n-butyllithium in hexane are introduced dropwise into a suspension of 2.71 g of trimethylsulfonium iodide (13.3 mmol) in 25 ml of tetrahydrofuran cooled to -15° C. The solution is stirred at -15° C. for 20 minutes under nitrogen, and then a solution of 1.57 g of 2-[1,3]dioxolan-2-yl-6-vinylpyridine (8.90 mmol) in 5 ml of tetrahydrofuran is added dropwise. After stirring for 1 hour at -15° C., the suspension is stirred for 3 hours at room temperature. The tetrahydrofuran is evaporated off, the residue is taken up in water and the mixture is extracted with ethyl acetate. The organic phase is washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated under vacuum. The title product is isolated by chromatography on a silica column (eluent: hexane/ethyl acetate; 50:50). 1.24 g of a colorless oil are obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)=[N:8][C:7](=[O:17])[C:6]=2[CH:18]=1.Br[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[OH:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][O:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)=[N:8][C:7](=[O:17])[C:6]=2[CH:18]=1
Reactant: O=c1nc(-c2ccccn2)sc2ccc(O)cc12
Reactant: OCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1nc(-c2ccccn2)sc2ccc(OCCCCCCO)cc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 95 %

Procedure:
A mixture of 6-hydroxy-2-(2-pyridyl)-4H-1,3-benzothiazine-4-one (0.35 g, 1.3 mmol), 6-bromohexanol (1.28 g, 7.0 mmol) and potassium carbonate (0.38 g, 2.7 mmol) and DMF (10 ml) was stirred at room temperature for 24 hrs. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with water and dried. The solvent was evaporated under reduced pressure. The obtained crystals were recrystallized from tetrahydrofuran-hexane to give the titled compound (0.44 g, 91%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:7]([CH3:79])([CH3:78])[C:8]3[C:13]([O:14][C:15]=2[C:16]=1[CH2:17][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])=[C:12]([CH2:28][NH:29][C:30](=[O:75])[C@H:31]([CH3:74])[NH:32][C:33](=[O:73])[C@H:34]([CH2:61][C:62]1[CH:67]=[CH:66][C:65]([O:68][C:69]([CH3:72])([CH3:71])[CH3:70])=[CH:64][CH:63]=1)[NH:35][C:36](=[O:60])[C@H:37]([C@H:56]([CH2:58][CH3:59])[CH3:57])[NH:38]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O)[C:11]([O:76][CH3:77])=[CH:10][CH:9]=3.C(NCC)C>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:7]([CH3:79])([CH3:78])[C:8]3[C:13]([O:14][C:15]=2[C:16]=1[CH2:17][C:18]([O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:19])=[C:12]([CH2:28][NH:29][C:30](=[O:75])[C@H:31]([CH3:74])[NH:32][C:33](=[O:73])[C@H:34]([CH2:61][C:62]1[CH:67]=[CH:66][C:65]([O:68][C:69]([CH3:70])([CH3:71])[CH3:72])=[CH:64][CH:63]=1)[NH:35][C:36](=[O:60])[C@H:37]([C@H:56]([CH2:58][CH3:59])[CH3:57])[NH2:38])[C:11]([O:76][CH3:77])=[CH:10][CH:9]=3
Reactant: CC[C@H](C)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N[C@@H](Cc1ccc(OC(C)(C)C)cc1)C(=O)N[C@@H](C)C(=O)NCc1c(OC)ccc2c1Oc1c(ccc(OC)c1CC(=O)OCc1ccccc1)C2(C)C
Solvent: CN(C)C=O
Solvent: CCNCC
Product: CC[C@H](C)[C@H](N)C(=O)N[C@@H](Cc1ccc(OC(C)(C)C)cc1)C(=O)N[C@@H](C)C(=O)NCc1c(OC)ccc2c1Oc1c(ccc(OC)c1CC(=O)OCc1ccccc1)C2(C)C
Yield: 85.3 %

Procedure:
A solution of 0.74 g (0.73 mmol) of benzyl 3,6-dimethoxy-9,9-dimethyl-5-[(N-(9H-fluoren-9-ylmethoxycarbonyl)-L-iso-leucyl-O-tert-butyl-L-tyrosyl-L-alanyl)aminomethyl]xanthene-4-acetate in 7 ml of dimethylformamide was stirred at 0° for 1 hour in the presence of 0.7 ml of diethylamine. The reaction mixture was brought to dryness. The residue obtained was chromatographed over silica gel in chloroform/methanol, whereby 0.53 g of benzyl 3,6-dimethoxy-9,9-dimethyl-5-[(L-isoleucyl-O-tert-butyl-L-tyrosyl-L-alanyl)aminomethyl]xanthene-4-acetate was obtained; IR 3292, 2970, 1742, 1672, 1655, 1627, 1605, 1536, 1502, 1499 cm-1.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:10]([C:12]3[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=3)=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]=[C:4]2[CH:21]=[N:22][N:23]([CH3:24])[C:3]=12.[Cl-].[NH4+].C([OH:29])C>O.[Fe]>[ClH:1].[NH2:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[C:11]3[C:2](=[O:29])[C:3]4[N:23]([CH3:24])[N:22]=[CH:21][C:4]=4[NH:5][C:6]=3[CH:7]=[CH:8][CH:9]=2)=[CH:13][CH:14]=1
Reactant: Cn1ncc2nc3cccc(-c4ccc([N+](=O)[O-])cc4)c3c(Cl)c21
Reactant: CCO
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: Cl
Product: Cn1ncc2[nH]c3cccc(-c4ccc(N)cc4)c3c(=O)c21
Temperature: 25 °C
Yield: 99 %

Procedure:
A mixture of 9-chloro-1-methyl-8-(4-nitrophenyl)-1H-pyrazolo[4,3-b]quinoline (EXAMPLE 41, step 1, 45 mg, 0.13 mmol), iron powder (37 mg, 0.67 mmol) and ammonium chloride (0.7 mg, 0.013 mmol) in a mixture of ethanol (4 ml) and water (1.5 ml) was refluxed for 8 h. After cooling to room temperature, the mixture was filtered through a pad of Celite. The filtrate was concentrated, dissolved in ethyl acetate (300 ml), washed with water (100 ml) and dried over magnesium sulfate. Removal of solvent gave 41 mg (99%) of the title compound as a solid.
Reaction SMILES: [Cl-:1].[Cl-].[Cl-].[CH:4]1([Zr+3:9])[CH:8]=[CH:7][CH:6]=[CH:5]1.[CH3:10][Si:11]([CH3:22])([CH3:21])[O:12][CH2:13][CH2:14][CH2:15][C-]1C=CC=C1.[K+].[C:24]1([CH3:30])[CH:29]=[CH:28][CH:27]=CC=1>>[Cl-:1].[Cl-:1].[CH:28]1([C:5]2[C:4]([Zr+2:9])([CH2:15][CH2:14][CH2:13][O:12][Si:11]([CH3:21])([CH3:10])[CH3:22])[CH:8]=[CH:7][CH:6]=2)[CH:27]=[CH:30][CH:24]=[CH:29]1
Reactant: Cc1ccccc1
Reactant: [Zr+3]C1C=CC=C1
Reactant: C[Si](C)(C)OCCC[c-]1cccc1
Agent: [Cl-]
Agent: [K+]
Product: C[Si](C)(C)OCCCC1([Zr+2])C=CC=C1C1C=CC=C1

Procedure:
To a suspension of 2.46 g (7 mmol) of cyclopentadienyl zirconium trichloride in toluene, a suspension of 1.6 g (7 mmol) of potassium (3-trimethylsiloxypropyl)-cyclopentadienide in toluene is added. A yellow-brown-coloured suspension immediately precipitates. The reaction is maintained for 12 hours. Subsequently, the solution is filtered and concentrated and a crystalline white solid is formed (0.8 g, 2 mmol, 28%). 1H-NMR (C6D6): 5.87 (t, 2H), 5.65 (t, 2H), 3.46 (m, 2H), 2.74 (m, 2H), 1.73 (m, 2H), 0.14 (s, 9H). 13C-NMR (C6D6): 11.6.9, 115.0, 114.7, 112.2, 61.8, 33.6, 26.8, −0.393. Mass spectrum: M+-65(356): 30%.
Reaction SMILES: [CH2:1]=[CH:2][CH:3]=[CH:4][CH2:5][CH3:6].[Cl:7][SiH:8]([Cl:10])[Cl:9]>[Cl-].C([P+](CCCC)(CCCC)CCCC)CCC>[CH3:1][CH:2]1[Si:8]([Cl:9])([Cl:7])[CH:5]([CH3:6])[CH:4]=[CH:3]1.[Cl:7][Si:8]([Cl:10])([Cl:9])[CH:2]([CH:3]=[CH:4][CH:5]([Si:8]([Cl:10])([Cl:9])[Cl:7])[CH3:6])[CH3:1]
Reactant: Cl[SiH](Cl)Cl
Reactant: C=CC=CCC
Agent: CCCC[P+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Product: CC(C=CC(C)[Si](Cl)(Cl)Cl)[Si](Cl)(Cl)Cl
Product: CC1C=CC(C)[Si]1(Cl)Cl
Temperature: 180 °C
Yield: 74 %
Yield: 10 %

Procedure:
As in Example 1, 1,3-hexadiene (1.00 g, 12.17 mmol), trichlorosilane (6.59 g, 48.65 mmol) and tetrabutylphosphonium chloride (0.36 g, 1.22 mmol) were added in a 25 mL stainless steel tube under nitrogen atmosphere. After sealing the cylinder with a cap, the reactor was maintained at 180° C. for 8 hours. The resulting mixture was distilled to yield 1.64 g (yield: 74%) of 1,1-dichloro-2,5-dimethylsilacyclo-3-pentene and 0.43 g (yield: 10%) of 2,5-bis(trichlorosilyl)-3-hexene main products.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:32])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][C:17]([CH:19]2[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]2)=[O:18])=[N:6][CH:7]=1.[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36]>ClCCl.C1(OC)C=CC=CC=1>[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:32])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][C:17]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[O:18])=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2ccccc2C(=O)Nc2ccc(Cl)cn2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: O=C(Nc1ccc(Cl)cn1)c1ccccc1NC(=O)C1CCNCC1
Reaction time: 4 h
Yield: 94.9 %

Procedure:
To a stirred solution of N-(5-chloropyridin-2-yl)-2-[(1-Boc-piperidin-4-ylcarbonyl)amino]benzamide (2 g, 4.3 mmol) in dichloromethane (80 mL) and anisole (2.4 mL) was added trifluoroacetic acid (8.4 mL, 109 mmol). After stirring for 4 h, the solvent was removed in vacuo. The residue was suspended in ether, sonicated for 0.25 h, stirred vigorously for 15 h, and filtered to give 1.93 g (94%) of a white solid.
Reaction SMILES: CN(C=O)C.C[O:7][C:8](=O)[N:9]=[C:10](SC)[C:11]([C:25]1[CH:26]=[N:27][C:28]([O:34][CH3:35])=[C:29]([O:31][CH2:32][CH3:33])[CH:30]=1)=[N:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:23]=[C:22]([CH3:24])[O:21][N:20]=2)=[CH:15][CH:14]=1.[CH2:39]([O:41][C:42]([C:44]1[S:48][CH:47]=[N:46][C:45]=1[NH:49][NH2:50])=[O:43])[CH3:40]>C(N(CC)CC)C>[CH2:39]([O:41][C:42]([C:44]1[S:48][CH:47]=[N:46][C:45]=1[N:49]1[C:8](=[O:7])[NH:9][C:10]([CH:11]([C:25]2[CH:26]=[N:27][C:28]([O:34][CH3:35])=[C:29]([O:31][CH2:32][CH3:33])[CH:30]=2)[NH:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]3[N:23]=[C:22]([CH3:24])[O:21][N:20]=3)=[CH:17][CH:18]=2)=[N:50]1)=[O:43])[CH3:40]
Reactant: CCOC(=O)c1scnc1NN
Reactant: CCOc1cc(C(=Nc2ccc(-c3noc(C)n3)cc2)C(=NC(=O)OC)SC)cnc1OC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1scnc1-n1nc(C(Nc2ccc(-c3noc(C)n3)cc2)c2cnc(OC)c(OCC)c2)[nH]c1=O
Temperature: 85 °C
Reaction time: 16 h
Yield: 45.1 %

Procedure:
To 4 ml of a DMF solution containing 117 mg of {2-(5-ethoxy-6-methoxypyridin-3-yl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester (Example 160a), 52 mg of 4-hydrazinothiazole-5-carboxylic acid ethyl ester and 0.038 ml of triethylamine were added. The mixture was stirred at 85° C. for 16 hours under a nitrogen atmosphere. The reaction mixture was concentrated. The residue was dissolved in 10 ml of methanol and 0.05 ml of acetic acid, and then 125 mg of sodium cyanotrihydroborate was further added thereto. The mixture was stirred at room temperature for 15 hours, and then 100 ml of ethyl acetate and 50 ml of water were added thereto. The organic layer was washed with 50 ml of water and then with 50 ml of saturated brine and then dried over anhydrous magnesium sulfate. The desiccating agent was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate) to give the title compound (65 mg).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([Cl:30])[CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:23]=4[CH3:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:31][NH2:32]>>[Cl:30][C:19]1[CH:20]=[C:21]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:23]=2[CH3:29])[C:15]2[O:14][CH:13]([CH2:12][NH:32][CH3:31])[CH2:17][C:16]=2[CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(Cl)cc(-c4cccc(C)c4C)c3O2)cc1
Reactant: CN
Product: CNCC1Cc2cc(Cl)cc(-c3cccc(C)c3C)c2O1

Procedure:
The title compound was prepared (0.054 g, 47%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[5-chloro-7-(2,3-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.149 g, 0.33 mmol) and methylamine (0.102 g, 3.3 mmol). mp 148-150° C.
Reaction SMILES: [Cl:1][C:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[N:3]=1.[OH-].[K+]>O.C(#N)C.[Fe-3](C#N)(C#N)(C#N)(C#N)(C#N)C#N.[K+].[K+].[K+]>[Cl:1][C:2]1[CH:6]=[CH:5][N:4]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[N:3]=1
Reactant: ClC1=NN(c2cccnc2)CC1
Agent: N#C[Fe-3](C#N)(C#N)(C#N)(C#N)C#N
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: Clc1ccn(-c2cccnc2)n1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 69.1 %

Procedure:
Crude 3-(3-chloro-4,5-dihydro-1H-pyrazol-1-yl)pyridine (54.1 g, 232 mmol, 77.8% purity) was introduced into a 3 L three-neck round bottom flask. Water (530 mL) was then added. The mixture was heated to 60° C. and a potassium hydroxide solution (165 g, 2940 mmol) in water (500 mL) was added. The dark brown mixture was heated to 90° C. A potassium ferricyanide solution (253 g, 768 mmol) in water (700 mL) was added slowly over 30 minutes leading to brown-red mixture. The mixture was stirred at 90° C. for another 1.5 hours. The reaction mixture was cooled to below 45° C. and filtered. The filter cake was washed with water (300 mL) affording crude product as a brown solid. The crude product was then dissolved in acetonitrile (400 mL) and filtered. The organic filtrate was dried and concentrated to afford the title product as a brown solid (28.8 g, 69%, 94% purity).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:14]=[C:13]2[C:15]([I:18])=[CH:16][NH:17][C:12]2=[CH:11][CH:10]=1.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.[OH-].[Na+]>C1COCC1.CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:14]=[C:13]2[C:15]([I:18])=[CH:16][N:17]([S:25]([C:22]3[CH:23]=[CH:24][C:19]([CH3:29])=[CH:20][CH:21]=3)(=[O:27])=[O:26])[C:12]2=[CH:11][CH:10]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Fc1cccc(F)c1-c1ccc2[nH]cc(I)c2n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3nc(-c4c(F)cccc4F)ccc32)cc1
Temperature: 23 °C
Reaction time: 0.75 h

Procedure:
A solution of 5-(2,6-difluorophenyl)-3-iodo-1H-pyrrolo[3,2-b]pyridine (657 mg, 1.845 mmol) in THF (18 mL) was treated with 4-toluenesulfonyl chloride (387 mg, 2.029 mmol, Aldrich) and solid NaOH (89 mg, 2.214 mmol, VWR). The reaction was stirred at 23° C. under N2. After 45 min, the solution was diluted with EtOAc (200 ml) and washed with brine (150 mL), dried over MgSO4, concentrated in vacuo and purified by silica gel chromatography (eluent: 10-30% EtOAc/hexane), affording 5-(2,6-difluorophenyl)-3-iodo-1-tosyl-1H-pyrrolo[3,2-b]pyridine.
Reaction SMILES: [F:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16](Cl)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1.CC[N:27]([CH:31]([CH3:33])C)[CH:28]([CH3:30])C.N1CC[CH:36]([C@H:39]([OH:41])C)C1>>[F:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16]([N:27]4[CH2:28][CH2:30][C@H:33]([CH2:36][CH2:39][OH:41])[CH2:31]4)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(NCC1CCC(F)(F)CC1)c1c(Cl)ccc2nc(Cl)ccc12
Reactant: C[C@@H](O)C1CCNC1
Product: O=C(NCC1CCC(F)(F)CC1)c1c(Cl)ccc2nc(N3CC[C@H](CCO)C3)ccc12

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (4,4-difluoro-cyclohexylmethyl)-amide, DIPEA and (R)-pyrrolidin-3-ylethanol. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.71 (m, 1H), 7.75 (1H), 7.48 (2H), 6.96 (1H), 4.52 (1H), 3.79 (m, 1H), 3.66 (m, 1H), 3.49 (m, 2H), 3.34 (m, 1H), 3.23 (m, 2H), 3.09 (m, 1H), 2.44 (m, 1H), 2.12 (m, 1H), 2.06 (m, 2H), 1.85 (m, 2H), 1.77 (m, 2H), 1.60 (m, 4H), 1.27-1.30 (m, 2H). m/z: 452 [M+H]
Reaction SMILES: [CH2:1]([C:3]([OH:8])([CH2:6][CH3:7])[C:4]#[CH:5])[CH3:2].C[Li].[CH3:11][S:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1>C1COCC1.CCCCCC>[CH2:4]([C:3]([OH:8])([CH2:6][CH3:7])[C:1]#[C:2][CH:17]([C:16]1[CH:19]=[CH:20][C:13]([S:12][CH3:11])=[CH:14][CH:15]=1)[OH:18])[CH3:5]
Reactant: CSc1ccc(C=O)cc1
Reactant: C#CC(O)(CC)CC
Agent: [Li]C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCC(O)(C#CC(O)c1ccc(SC)cc1)CC
Reaction time: 0.5 h

Procedure:
To a stirred solution of 3-ethyl-1-pentyn-3-ol (7.7 ml) in 300 ml anhydrous THF, was added dropwise 100 ml of 1.4 M methyllithium in hexane at −78° C. under argon. The mixture was further stirred for 30 minutes, followed by dropwise addition of 4-(methylthio)benzaldehyde (9.3 ml). The reaction mixture was stirred for another 12 hours, during which the cold bath was removed such that the reaction temperature reached room temperature slowly. Then the reaction was quenched by adding dilute aqueous HCl. The solvent was removed in vacuo and the resulting residue was extracted with brine and dichloromethane (150 ml×3). The organic layer was concentrated under reduced pressure and the resulting crude product was purified by recrystallization from hexane and ethylacetate (4:1) to give 11.8 g of 4-ethyl-1-{4-(methylthio)phenyl}-2-hexyn-1,4-diol as a low-melting solid. mp: 64-65° C. NMR: δ1.04 (t, J=7.5 Hz, 6H), 1.70 (q, J=7.5 Hz, 4H), 2.49 (s, 3H), 5.47 (s, 1H), 7.26 (d, J=8.4 Hz, 2H), 7.45 (d, J=8.4 Hz, 2H). IR (cm−1): 3368, 2970, 2207, 1637, 1589, 1262, 1093.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[C:13]([N+:18]([O-:20])=[O:19])[CH:12]=2)[CH:7]=[CH:8][C:9]=1[NH2:10])([O-:3])=[O:2].[O:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:26](Cl)=[O:27].Cl>O.N1C=CC=CC=1.CN(C)C=O>[N+:1]([C:4]1[CH:5]=[C:6]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:26]([C:22]3[O:21][CH:25]=[CH:24][CH:23]=3)=[O:27])=[C:13]([N+:18]([O-:20])=[O:19])[CH:12]=2)[CH:7]=[CH:8][C:9]=1[NH:10][C:26]([C:22]1[O:21][CH:25]=[CH:24][CH:23]=1)=[O:27])([O-:3])=[O:2]
Reactant: O=C(Cl)c1ccco1
Reactant: Nc1ccc(-c2ccc(N)c([N+](=O)[O-])c2)cc1[N+](=O)[O-]
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C(Nc1ccc(-c2ccc(NC(=O)c3ccco3)c([N+](=O)[O-])c2)cc1[N+](=O)[O-])c1ccco1
Temperature: 8.5 °C
Reaction time: 5 h
Yield: 81.2 %

Procedure:
In a 500 ml separable flask equipped with a stirrer, a reflux condenser cooled with water, a thermometer and a dropping funnel, 10.96 g of 3,3′-dinitro-4,4′-diaminobiphenyl was dissolved into 200 ml of N,N-dimethylformamide and then 20 ml of pyridine was added to the solution. While the prepared solution was cooled at 3 to 14° C., 12.53 g of 2-furoyl chloride was added dropwise to the solution. After the addition was completed, the reaction solution was warmed to the room temperature and stirred for further 5 hours. Then, 80 ml of 2N hydrochloric acid and 100 ml of water were added to the solution and the solid substance was separated by filtration. The obtained solid substance was washed well with water and dried in a reduced pressure to obtain 15.0 g of 3,3′-dinitro-4,4′-di-2-furoylaminobiphenyl. The yield was 81%.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH3:10].COC1C=CC=CC=1[Mg]Br.[CH2:21]1[O:29][C:28]2[CH:27]=[CH:26][C:25]([C:30]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[C:32](=[O:39])[C:31]=3[C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:24][C:23]=2[O:22]1>C1COCC1>[OH:39][C:32]1([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[O:9][CH3:10])[C:33]2[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:30]([C:25]2[CH:26]=[CH:27][C:28]3[O:29][CH2:21][O:22][C:23]=3[CH:24]=2)=[C:31]1[C:40]([O:42][CH2:43][CH3:44])=[O:41]
Reactant: COc1ccccc1Br
Reactant: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1=O
Agent: COc1ccccc1[Mg]Br
Agent: [Mg]
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1(O)c1ccccc1OC
Reaction time: 0.25 h

Procedure:
To dry magnesium turnings (81 mg, 3.4 mmol) under an argon atmosphere was added a solution of 2-bromoanisole (0.64 g, 3.4 mmol) in 5:1 THF/Et2 O (3 ml). A portion of the resulting 2-methoxyphenyl magnesium bromide solution (0.45 ml, 0.51 mmol) was added dropwise to a solution of ethyl 3-(3,4-methylenedioxyphenyl)-1-oxoindene-2-carboxylate (100 mg, 0.34 mmol) in THF (6 ml) under an argon atmosphere at 0° C. After stirring for 15 min, the mixture was partitioned between 3M HCl and EtOAc. The organic extract was washed successively with H2O, 5% aqueous NaHCO3, H2O and saturated aqueous NaCl. The solvent was removed in vacuo, and the residue was purified by flash chromatography, eluting with 15% EtOAc/hexanes to afford the title compound. (100 mg, 68%).