Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[S:5][C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[N:8]=1.[N+:13]([O-])([OH:15])=[O:14]>S(=O)(=O)(O)O>[CH3:1][O:2][CH2:3][C:4]1[S:5][C:6]2[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:7]=2[N:8]=1
Reactant: COCc1nc2ccccc2s1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: COCc1nc2ccc([N+](=O)[O-])cc2s1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 79 %

Procedure:
To a cooled (0° C.) solution of 2-methoxymethyl-benzothiazole (2.4 g, 13.4 mmol) in concentrated sulfuric acid (8 mL) was added a mixture of 90% fuming nitric acid (2 mL) and concentrated sulfuric acid (1.3 mL) at a rate to keep the internal temperature below 5° C. After the addition was completed, the reaction mixture was stirred for 15 min at 0° C. and then at RT for 2 h. The mixture was poured into ice cold water. Collection of the precipitated solid by filtration, washing with cold water until the pH of the eluent was neutral, afforded 2.6 g (79%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 8.8 (d, J=2.1 Hz, 1H), 8.36 (dd, J=9, 2.1 Hz, 1H), 8.08 (d, J=9 Hz, 1H), 4.90 (s, 2H), 3.59 (s, 3H).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([CH3:16])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:8][OH:9].[O:17]1[CH:22]=[CH:21][CH2:20][CH2:19][CH2:18]1>O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([CH3:16])([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH2:8][O:9][CH:18]1[CH2:19][CH2:20][CH2:21][CH2:22][O:17]1
Reactant: C1=COCCC1
Reactant: CC(CO)(CCCCCBr)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CC(CCCCCBr)(COC1CCCCO1)c1ccccc1
Yield: 73.7 %

Procedure:
According to the method described for the synthesis of 207d, 206h (51.0 g, 179 mmol) was reacted with 3,4-dihydro-2H-pyran (18.80 g, 223 mmol) and p-toluenesulfonic acid hydrate (1.21 g, 6.36 mmol). Filtration through aluminum oxide (370 g) and concentration in vacuo afforded 207h (48.75 g, 76%) as a yellowish oil. 1H NMR (CDCl3): δ 7.35-7.17 (m, 10H), 4.53 (m, 1H), 4.49 (m, 1H), 3.82 (m, 2H), 3.79 (m, 1H), 3.68-3.60 (m, 2H), 3.45-3.35 (m, 2H), 3.32 (t, 4H, J=6.9), 1.82-1.18 (m, 28H), 1.35 (s, 6H). 13C NMR (CDCl3): δ 146.12, 128.11, 126.66, 125.89, 99.18, 99.04, 76.46, 62.02, 61.83, 42.17, 42.07, 38.91, 38.73, 34.12, 32.80, 30.70, 29.04, 25.66, 23.33, 22.97, 22.89, 19.49, 19.39. HRMS (LSIMS, nba): Calcd for C19H30BrO2 (MH+): 369.1429, found: 369.1430.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH2:10][N:9](CC1C=CC(OC)=CC=1OC)[CH2:8]2)=[O:4].[C:25]1(OC)C=CC=CC=1.[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34]>>[F:36][C:35]([F:38])([F:37])[C:33]([OH:39])=[O:34].[CH2:1]([O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH2:10][NH:9][CH2:8]2)=[O:4])[CH3:25]
Reactant: COC(=O)c1ccc2c(c1)CN(Cc1ccc(OC)cc1OC)C2
Reactant: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ccc2c(c1)CNC2

Procedure:
A solution of 2-(2,4-dimethoxy-benzyl)-2,3-dihydro-1H-isoindole-5-carboxylic acid methyl ester (215 mg) and anisole (200 μl) in 1 ml of TFA was heated at 140° C. for 30 minutes in a CEM discover microwave synthesiser. The reaction was partitioned between water and DCM, the water layer was separated, washed with DCM then evaporated and re-evaporated with toluene/MeOH (×2) to give 105 mg of the title compound. 1H NMR (DMSO-d6) 9.70 (2H, br s), 8.02 (1H, s), 8.98 (1H, d), 7.57 (1H, d), 4.60 (2H, s), 4.56 (2H, s), 3.89 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.C(O)(=O)C.BrBr>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1
Reactant: O=C1CCC(c2ccc(Cl)cc2)=NN1
Agent: BrBr
Solvent: CC(=O)O
Solvent: O
Product: O=c1ccc(-c2ccc(Cl)cc2)n[nH]1
Yield: 93.1 %

Procedure:
To a solution of 6-(4-chlorophenyl)4,5-dihydropyridazinone (11.75 g) and glacial acetic acid (100 ml) was added dropwise 3 ml of bromine and the mixture was heated at 60°-70° C. for 3 h. The resulting mixture was cooled and slowly poured into 400 ml of cold water. The resulting white solid was filtered and dried to yield 10.83 g (89%) of 6-(4-chlorophenyl)pyridazinone.
Reaction SMILES: BrC1C(N2CCN(C(NC3C=CC=CC=3)=O)CC2)=C2N=C(C3C=CC(N(C)C)=CC=3)NC2=NC=1.[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]([N+:43]([O-])=O)[C:39]([NH2:42])=[N:40][CH:41]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].[N:67]1([CH2:72][C:73]2[CH:80]=[CH:79][C:76]([CH:77]=O)=[CH:75][CH:74]=2)[CH:71]=[CH:70][CH:69]=[N:68]1>C(O)C.CN(C=O)C>[N:67]1([CH2:72][C:73]2[CH:80]=[CH:79][C:76]([C:77]3[NH:42][C:39]4=[N:40][CH:41]=[C:36]([Br:35])[C:37]([N:46]5[CH2:51][CH2:50][N:49]([CH2:52][C:53]6[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=6)[CH2:48][CH2:47]5)=[C:38]4[N:43]=3)=[CH:75][CH:74]=2)[CH:71]=[CH:70][CH:69]=[N:68]1
Reactant: Nc1ncc(Br)c(N2CCN(Cc3cccnc3)CC2)c1[N+](=O)[O-]
Reactant: O=Cc1ccc(Cn2cccn2)cc1
Agent: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)Nc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: Brc1cnc2[nH]c(-c3ccc(Cn4cccn4)cc3)nc2c1N1CCN(Cc2cccnc2)CC1
Reaction time: 6 h
Yield: 40.7 %

Procedure:
This was prepared using the same procedure as for 4-(6-bromo-2-(4-(dimethylamino)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)-N-phenylpiperazine-1-carboxamide, but here using 5-bromo-3-nitro-4-(4-(pyridin-3-ylmethyl)piperazin-1-yl)pyridin-2-amine (20 mg, 0.051 mmol), DMF (0.15 mL), ethanol (0.85 mL), 1M Na2S2O4 (3 eq, 0.15 mmol, 0.15 mL) and 4-(1H-pyrazol-1-ylmethyl)benzaldehyde (1.1 eq, 0.056 mmol, 11 mg). After 6 h, concentration in vacuo and purification by preparative tlc (CH2Cl2-MeOH, 95:5) gave the product (11 mg, 41%) as a colourless solid; δH (500 MHz, DMSO-d6) 2.62 (s, br, 4H, piperazine N(CH2)2), 3.61 (s, 2H, CH2), 3.66 (s, br, 4H, piperazine N(CH2)2), 5.41 (s, 2H, PhCH2), 6.30 (t, J=2.0 Hz, pyrazole H-4), 7.34 (d, J=8.2 Hz, 2H, phenyl H-3 & H-5), 7.39 (dd, J=7.8, 4.8 Hz, 1H, pyridine H-5), 7.49 (d, J=1.8 Hz, 1H, pyrazole H-3 or H-5), 7.78 (dt, J=7.8, 1.7 Hz, 1H, pyridine H-4), 7.86 (d, J=2.2 Hz, 1H, pyrazole H-3 or H-5), 8.14 (d, J=8.2 Hz, 2H, phenyl H-2 & H-6), 8.23 (s, 1H, imidazo[4,5-b]pyridine H-5), 8.49 (dd, J=4.7, 1.7 Hz, 1H, pyridine H-6), 8.56 (d, J=1.6 Hz, 1H, pyridine H-2), 13.49 (s, br, 1H, imidazo[4,5-b]pyridine NH);
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C@:8]2([CH3:16])[C@@H:13]([F:14])[CH2:12][O:11][C:10]([NH2:15])=[N:9]2)[CH:7]=1.[Cl:18][C:19]1[C:20]([C:29](O)=[O:30])=[N:21][CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1>>[NH2:15][C:10]1[O:11][CH2:12][C@H:13]([F:14])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:29]([C:20]3[C:19]([Cl:18])=[CH:24][C:23]([C:25]([F:27])([F:26])[F:28])=[CH:22][N:21]=3)=[O:30])[CH:3]=[CH:4][C:5]=2[F:17])([CH3:16])[N:9]=1
Reactant: O=C(O)c1ncc(C(F)(F)F)cc1Cl
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OC[C@@H]1F
Product: C[C@]1(c2cc(NC(=O)c3ncc(C(F)(F)F)cc3Cl)ccc2F)N=C(N)OC[C@@H]1F

Procedure:
The condensation of (4R,5R)-4-(5-amino-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate A8.2) and 3-chloro-5-trifluoromethyl-pyridine-2-carboxylic acid (CAS 80194-68-9) following procedure I yielded the title compound as a white foam. MS (ISP): m/z=449.1 [M+H]+.
Reaction SMILES: [C:1]1([N:7]2[C:15](=[O:16])[C:14]3[C:9]([C:10]4[CH:19]=[CH:18][NH:17][C:11]=4[NH:12][CH:13]=3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.[CH3:29][N:30]=[C:31]=[O:32]>CN(C)C=O>[CH3:29][NH:30][C:31]([N:17]1[C:11]2[NH:12][CH:13]=[C:14]3[C:15](=[O:16])[N:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:8]=[C:9]3[C:10]=2[CH:19]=[CH:18]1)=[O:32]
Reactant: CN=C=O
Reactant: O=c1c2c[nH]c3[nH]ccc3c-2nn1-c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)n1ccc2c3nn(-c4ccccc4)c(=O)c-3c[nH]c21
Reaction time: 8 h

Procedure:
A solution of pyrrolo-pyridine 16 in dimethylformamide under an atmosphere of nitrogen and 3 equivalents of di-iso-propylethylamine (3 eq.) was added 3 equivalents of methylisocyanate and stirred overnight. The crude reaction mixture was concentrated to dryness and purification by column chromatography afforded the title compound 17a. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.83-3.11 (m, 3H) 6.64-6.92 (m, 1H) 7.21-7.43 (m, 1H) 7.44-7.63 (m, 2H) 7.77-8.05 (m, 3H) 8.57-8.81 (m, 1H) 9.48-9.76 (m, 1H).
Reaction SMILES: C(OC([NH:8][C@H:9]([C:11]([NH:13][CH2:14][CH:15]([CH3:17])[CH3:16])=[O:12])[CH3:10])=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH2:14]([NH:13][C:11](=[O:12])[C@H:9]([CH3:10])[NH2:8])[CH:15]([CH3:17])[CH3:16]
Reactant: CC(C)CNC(=O)[C@H](C)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)CNC(=O)[C@H](C)N

Procedure:
N2-(tert-Butoxycarbonyl)-N1-isobutyl-L-alaninamide (300 mg, 1.23 mmol) is stirred with 2 mL of TFA in 4 mL of dichloromethane for 1 h. The mixture is concentrated and neutralized with 2 mL of 1 N NaHCO3 and 2 mL of 1 N Na2CO3, and extracted into 50 mL of ethyl ether containing 2 mL of methanol. The organic phase was washed with brine and dried with Na2SO4. Concentration afforded the title compound as a colorless film (90 mg, 0.62 mmol, 51%). 1H NMR (CD3OD) δ 4.9 (s, 3H, includes water), 3.52 (q, J=7 Hz, 1H), 3.07-2.96 (m, 2H), 1.78 (m, 1H), 1.31 (d, J=7 Hz, 3H), 0.90 (m, 6H)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH2:14][C:6]3=[C:7]([C:11]([OH:13])=[O:12])[NH:8][C:9]([CH:10]=1)=[C:5]23.S(Cl)(Cl)=O.[CH3:21]O>>[Cl:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH2:14][C:6]3=[C:7]([C:11]([O:13][CH3:21])=[O:12])[NH:8][C:9]([CH:10]=1)=[C:5]23
Reactant: O=C(O)c1[nH]c2cc(Cl)cc3c2c1CCC3
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1[nH]c2cc(Cl)cc3c2c1CCC3
Yield: 37 %

Procedure:
To a solution of 7-chloro-1,3,4,5-tetrahydrobenz[cd]indole-2-carboxylic acid (8 g) in MeOH (100 mL) was added thionyl chloride (6.2 mL) at 0° C. The mixture was refluxed for 13 h, while thionyl chloride (10 mL×4) was added during the reflux. The resulting mixture was concentrated and the residue was purified by silica gel column chromatography with 15:1~1:1 hexane/ethyl acetate to give 2.47 g of the title compound (37%): 1H NMR (CDCl3) δ8.52 (bs, 1H), 7.15 (d, 1H, J=1.5 Hz), 6.84 (d, 1H, J=1.5 Hz), 3.93 (s, 3H), 3.07 (t, 2H, J=6.3 Hz), 2.90 (t, 2 H, J=6.3 Hz), 2.07 (5et, 2H, J=6.3 Hz).
Reaction SMILES: [C:1]([C:3]1([OH:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)#[CH:2].I[C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1/[C:13](=[CH:21]/[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28])/[C:14](=[O:20])[NH:15]2>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C.CCN(CC)CC>[OH:9][C:3]1([C:1]#[C:2][C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2/[C:13](=[CH:21]/[C:22]2[NH:23][CH:24]=[CH:25][C:26]=2[O:27][CH3:28])/[C:14](=[O:20])[NH:15]3)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: C#CC1(O)CCCCC1
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(I)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CC3(O)CCCCC3)c21

Procedure:
Using Method C above, 1-ethynyl-1-cyclohexanol (60 mg, 0.48 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (146 mg, 0.4 mmol) (Starting Material 2 supra) using (Ph3P)2PdCl2 (20 mg) and Cul (10 mg) as catalyst in DMF (2 mL) and Et3N (2 mL) as solvent at 70° C. for 15 h to yield (Z)-1,3-dihydro-4-[(1-hydroxycyclohexyl)ethynyl]-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 94 mg, 65%).
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]2[C:33]3[C@@H:17]([CH2:18][CH2:19][C@:20]4(O)[C:32]=3[CH2:31][CH2:30][C:22]3(OCC(C)(C)C[O:23]3)[CH2:21]4)[C@H:16]3[C@@:12]([CH3:43])([C@@:13]([C:36]([F:42])([F:41])[C:37]([F:40])([F:39])[F:38])([OH:35])[CH2:14][CH2:15]3)[CH2:11]2)=[CH:6][CH:5]=1>C(O)(=O)C>[OH:35][C@@:13]1([C:36]([F:41])([F:42])[C:37]([F:38])([F:39])[F:40])[CH2:14][CH2:15][C@H:16]2[C@H:17]3[C:33]([C@@H:10]([C:7]4[CH:6]=[CH:5][C:4]([CH:3]=[O:2])=[CH:9][CH:8]=4)[CH2:11][C@:12]12[CH3:43])=[C:32]1[C:20](=[CH:21][C:22](=[O:23])[CH2:30][CH2:31]1)[CH2:19][CH2:18]3
Reactant: COC(OC)c1ccc([C@H]2C[C@@]3(C)[C@@H](CC[C@@]3(O)C(F)(F)C(F)(F)F)[C@@H]3CC[C@@]4(O)CC5(CCC4=C32)OCC(C)(C)CO5)cc1
Solvent: CC(=O)O
Product: C[C@]12C[C@H](c3ccc(C=O)cc3)C3=C4CCC(=O)C=C4CC[C@H]3[C@@H]1CC[C@@]2(O)C(F)(F)C(F)(F)F
Temperature: 30 °C
Reaction time: 16 h

Procedure:
3.5 g of the compound described under 1b) were dissolved in 55 ml of 70% strength acetic acid. The mixture was after-stirred for 16 hours at 30° C. The reaction mixture was then poured onto water and after-stirred for a further 5 hours. It was then filtered. The residue was washed with water, dried and purified by chromatography over silica gel. This gave 2.2 g of the title compound.
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:14](Cl)=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N:26]1CCC2C(OC)=NC=NC=2C1)C1C=CC=CC=1>N.CO>[CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:14]([NH2:26])=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ncnc2c1CCN(Cc1ccccc1)C2
Reactant: Clc1ncnc2c1CCN(Cc1ccccc1)C2
Agent: N
Solvent: CO
Product: Nc1ncnc2c1CCN(Cc1ccccc1)C2
Temperature: 100 °C
Reaction time: 48 h

Procedure:
7-Benzyl-4-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (9.83 g, 38 mmol) was dissolved in solution of NH3 in MeOH (7N, 60 mL) in a re-sealable tube. The sealed tube was heated at 100° C. for 21 h. The reaction was cooled to room temperature and kept standing at room temperature for 48 h which led to the precipitation of the desired product 7-benzyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine. (5.1 g, 56%). The mother liquor was evaporated and dried under vacuum to yield a mixture of 4.12 g of desired product together with the side product 7-benzyl-4-methoxy-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([O:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([OH:37])[CH2:23][NH:24][S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[N+:34]([O-:36])=[O:35])(=[O:27])=[O:26])=[CH:18][CH:17]=1)(=[O:14])=[O:13])([O-:5])=[O:4].C([Si]([O:45][CH2:46][CH2:47]I)(C)C)(C)(C)C.C(=O)([O-])O.[Na+].Cl>CN(C)C=O.CO>[N+:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([O:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([OH:37])[CH2:23][N:24]([CH2:47][CH2:46][OH:45])[S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[N+:34]([O-:36])=[O:35])(=[O:27])=[O:26])=[CH:18][CH:17]=1)(=[O:13])=[O:14])([O-:5])=[O:4]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)NCC(O)c1ccc(OS(=O)(=O)c2ccccc2[N+](=O)[O-])cc1
Reactant: CC(C)(C)[Si](C)(C)OCCI
Agent: Cl
Agent: O=C([O-])O
Agent: [H-]
Solvent: CN(C)C=O
Solvent: CO
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)Oc1ccc(C(O)CN(CCO)S(=O)(=O)c2ccccc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.2 %

Procedure:
Sodium hydride (0.31 g, 7.0 mmol) was added to a solution of 3.0 g (5.82 mmol) of the title compound produced in step (i) of Reference Example 12 in N,N-dimethylformamide (19.1 ml), and the mixture was stirred at room temperature for 30 min. Thereafter, 1.65 g (5.82 mmol) of tert-butyl(2-iodoethoxy)dimethylsilane was added thereto, and the mixture was stirred at 100° C. for 21 hr. The reaction was stopped by adding sodium hydrogencarbonate, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine in that order, was dried over anhydrous sodium sulfate and was then filtered. The filtrate was concentrated under the reduced pressure. Methanol (48 ml) was added to the concentrate, 11.6 ml (11.6 mmol) of 1 N hydrochloric acid was added thereto, and the mixture was stirred at room temperature for 30 min. Sodium hydrogencarbonate was added to stop the reaction, and methanol as the solvent was removed under the reduced pressure, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine in that order, was dried over anhydrous sodium sulfate and was then filtered. The filtrate was concentrated under the reduced pressure, and the residue was purified by column chromatography on silica gel (chloroform:methanol=100:1) to give 2.22 g (yield 68%) of the title compound.
Reaction SMILES: [CH2:1]([N:4]([CH2:23][CH2:24][CH3:25])[CH:5]1[CH2:14][C:13]2[C:8](=[C:9]([F:22])[CH:10]=[CH:11][C:12]=2S(C(F)(F)F)(=O)=O)[O:7][CH2:6]1)[CH2:2][CH3:3].[O:26]1[CH:30]=[CH:29][CH:28]=[C:27]1B(O)O.[Cl-].[Li+].C(=O)([O-])[O-].[Na+].[Na+]>N.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O)C.C1(C)C=CC=CC=1>[CH2:1]([N:4]([CH2:23][CH2:24][CH3:25])[CH:5]1[CH2:14][C:13]2[C:8](=[C:9]([F:22])[CH:10]=[CH:11][C:12]=2[C:27]2[O:26][CH:30]=[CH:29][CH:28]=2)[O:7][CH2:6]1)[CH2:2][CH3:3]
Reactant: CCCN(CCC)C1COc2c(F)ccc(S(=O)(=O)C(F)(F)F)c2C1
Reactant: OB(O)c1ccco1
Agent: [Pd]
Agent: N
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCN(CCC)C1COc2c(F)ccc(-c3ccco3)c2C1
Reaction time: 3 h
Yield: 52.9 %

Procedure:
In a three-necked round-bottom flask (25 mL) equipped with a magnetic stirrer and a reflux condensor the following reagents were mixed under nitrogen: 3-dipropylamino-8-fluoro-5-trifluoromethanesulfonylchroman (0.104 g; 0.25 mmol), absolute ethanol (1.7 mL), toluene (3.6 mL), 2-furylboronic acid (0.071 g; 0.64 mmol), lithium chloride (0.022 g; 0.51 mmol), 2M sodium carbonate (0.7 mL) and tetrakis(triphenylphosphine)-palladium(0) (0.0073 g). The mixture was heatedon an oil--bath to a reflux temperature (75°-80° C.). After 3 hours GC-analysis indicated a partial reaction (20% product and 66% starting material). Therefore more 2-furylboronic acid (0.031 g; 0.28 mmol), absolute ethanol (0.2 mL) and tetrakis(triphenylphosphine)-palladium(0) (0.009 g) were added. The mixture was stirred at 75°-80° C. over night, then poured in 2M ammonia (40 mL) and extracted with ether (2×40 mL). The collected ether phases were dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by flash-chromatography on a silica column with ethyl acetate/n-hexane (2:98). Relevant fractions were pooled and concentrated to give an oil consisting of impure product (72% GC). This material was purified in a second run by flash-chromatography on a silica column eluted with eluted with ethyl acetate/methylene chloride (1:99) to give 0.042 g (51% yield) of 3-dipropylamino-8-fluoro-5-(2furyl)chroman as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([O:9][CH2:10][CH:11]2[CH2:13][CH2:12]2)[CH:3]=1.Cl[CH:15]([F:17])[F:16]>[N+](CCCC)(CCCC)(CCCC)CCCC.[Br-].O1CCOCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:15]([F:17])[F:16])=[C:4]([O:9][CH2:10][CH:11]2[CH2:12][CH2:13]2)[CH:3]=1
Reactant: Oc1ccc(Br)cc1OCC1CC1
Reactant: FC(F)Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: C1COCCO1
Product: FC(F)Oc1ccc(Br)cc1OCC1CC1
Temperature: 65 °C
Reaction time: 1.17 h

Procedure:
A mixture of crude 4-bromo-2-cyclopropylmethoxyphenol (388 g) and (n-Bu)4NBr (20 g) in dioxane (2.0 L) was heated to 65° C. Aqueous caustic solution (40%, 294 g) was added and the temperature was raised to 80° C. Chlorodifluoromethane was added below the surface via a 12 gauge needle and CF2HCl was rapidly absorbed. After about 70 minutes, the absorption of gas ceased and reaction temperature dropped to 77° C. About 184 g of chlorodifluoromethane (Fw=86.47, 2.128 mol) had been added. GC analysis of an aliquot indicated the disappearance of the starting material. The mixture was cooled to room temperature and was quenched with water (1.2 L) under CF2HCl atmosphere. Extraction with hexanes (2×750 mL) and the combined hexanes extracts were washed with water (1 L). The aqueous layer was back-extracted with hexanes (500 mL) and the combined organic extracts were dried (MgSO4) and filtered. Evaporation of the solvent under reduced pressure gave a brown oil (about 457 g). GC analysis showed 75 area % purity. The crude yield was 98% or 86% adjusted to GC area %. The crude product was distilled over a 5-plate, Older-Shaw column at 1.0 mm-Hg at 107-113° C. (overhead). Results and conditions are given in Table 3.
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[O:13][C:12]([CH2:14]O)=[CH:11][CH:10]=2)[O:8][CH2:7][CH2:6][O:5]1.CCN(CC)CC.S([Cl:27])(C)(=O)=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:27][CH2:14][C:12]1[O:13][C:9]([C:4]2([CH3:3])[O:8][CH2:7][CH2:6][O:5]2)=[CH:10][CH:11]=1
Reactant: CC1(c2ccc(CO)o2)OCCO1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(c2ccc(CCl)o2)OCCO1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-yl]-methanol (3.50 g, 19.00 mmol) in dry CH2Cl2 (35.0 mL) was treated at 0° C. with Et3N (3.44 mL, 22.80 mmol) followed by DMAP (232 mg, 1.90 mmol) and Ms-Cl (1.77 mL, 22.80 mmol). After stirring at rt for 2 h, the reaction mixture was quenched with water (40 mL), extracted with CH2Cl2 (40 mL) and the combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced. Purification of the residue by FC (8:2:0.1 hept-EA-Et3N) gave the title compound as a yellow oil: TLC: rf (4:1 hept-EA)=0.35.
Reaction SMILES: C(O)(C(F)(F)F)=O.COC1C=CC(C[O:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]([C:36]3[CH:40]=[CH:39][O:38][N:37]=3)[CH2:23][C:24]([O:26][CH2:27][C:28]3C=CC(OC)=CC=3)=[O:25])=[CH:18][CH:17]=2)=CC=1>C(Cl)Cl>[OH:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([C:36]2[CH:40]=[CH:39][O:38][N:37]=2)[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:18][CH:17]=1
Reactant: COc1ccc(COC(=O)CC(c2ccc(OCc3ccc(OC)cc3)cc2)c2ccon2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)CC(c1ccc(O)cc1)c1ccon1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 79 %

Procedure:
TFA (10 mL) was added to 6.4 (940 mg) in DCM (10 mL). The mixture was stirred at room temperature for 1.5 hours. TFA and DCM were removed under vacuum, and the residue was treated with EtOH (50 mL). The insoluble solid was removed by filtration. To the filtrate was added concentrated sulfuric acid (2 drops). The mixture was stirred at 80° C. overnight. After concentration, the crude product was purified by flash chromatography to give 6.5 (410 mg). MS ESI (pos.) m/e: 262 (M+H). 1HNMR (CDCl3) δ 8.29 (d, 1H), 7.12 (d, 2H), 6.76 (d, 2H), 6.10 (d, 1H), 4.56 (t, 1H), 4.10 (q, 2H), 3.27 (dd, 1H), 2.97 (dd, 1H), 1.19 (t, 3H). The racemic compound 6.5 was separated into two enantiomers 6.6 and 6.7 using chiral preparative AD-H column (8% IPA/92% hexanes). The stereochemistry of 6.6 and 6.7 was assigned arbitrarily.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH:21]=NO)[CH:19]=3)[CH:14]=[CH:13]2)[CH2:8][CH2:7]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH2:34].[OH-].[Na+]>O1CCCC1>[F:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH:21]=[O:34])[CH:19]=3)[CH:14]=[CH:13]2)[CH2:8][CH2:7]1
Reactant: ON=Cc1ccc2ccn(C3CCN(CCc4ccccc4F)CC3)c2c1
Reactant: O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=Cc1ccc2ccn(C3CCN(CCc4ccccc4F)CC3)c2c1
Yield: 49.1 %

Procedure:
A solution of 1-[1-(2-fluorophenethyl)piperidin-4-yl]-6-hydroxyiminomethylindole (1.95 g) in tetrahydrofuran (50 ml) was added dropwise at room temperature under ice cooling and stirring into a suspension of lithium aluminum hydride (0.4 g) in tetrahydrofuran (100 ml). Then the resultant mixture was heated under reflux for 3 hr. Under ice watar cooling, water (1 ml), a 5 N aqueous solution of sodium hydroxide (3 ml) and further water (1 ml) were carefully added dropwise into the reaction mixtures and the mixture was further vigorously stirred. The resulting precipitate was collected by filtration and washed with tetrahydrofuran. The filtrate was concentrated under reduced pressure. The residue was purified by NH-silica gel column chromatography (ethyl acetate) to give the title compound (0.92 g) as a brown wax (yield: 49.1%).