Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:12]([N:15]2[CH:21]3[CH2:22][CH2:23][N:18]([CH2:19][CH2:20]3)[CH2:17][CH2:16]2)=[CH:11][C:3]=1[C:4]([NH:6][CH2:7][C:8]([OH:10])=[O:9])=[O:5].[OH-].[Li+].C(O[C:29](OCC)(OCC)[CH2:30][CH3:31])C>CO>[N:18]12[CH2:23][CH2:22][CH:21]([CH2:20][CH2:19]1)[N:15]([C:12]1[CH:11]=[C:3]3[C:2](=[CH:14][CH:13]=1)[N:1]=[C:29]([CH2:30][CH3:31])[N:6]([CH2:7][C:8]([OH:10])=[O:9])[C:4]3=[O:5])[CH2:16][CH2:17]2
Reactant: CCOC(CC)(OCC)OCC
Reactant: Nc1ccc(N2CCN3CCC2CC3)cc1C(=O)NCC(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CCc1nc2ccc(N3CCN4CCC3CC4)cc2c(=O)n1CC(=O)O
Temperature: 160 °C
Reaction time: 8 h

Procedure:
2-(2-Amino-5-(1,4-diazabicyclo[3.2.2]nonan-4-yl)benzamido)acetic acid (85.3 mg, 0.27 mmol) (Intermediate 9A) (100 mg, 0.36 mmol) was dissolved in triethoxypropane (1 mL), and heated in the microwave at 160° C. for 10 minutes. Reaction allowed to cool to room temperature and lithium hydroxide solution added (0.5 mL, 1M in methanol) and reaction stirred overnight. Organic layer purified using a 1 g SCX cartridge, followed by preparative-HPLC. Purified sample was free-based using 500 mg SCX cartridge to afford 2-(6-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-2-ethyl-4-oxoquinazolin-3(4H)-yl)acetic acid (76 mg, 0.21 mmol).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH2:9][C:10](=[O:16])[NH:11]2.[CH2:17]([O:19][C:20]([C:22]1[C:26]([CH2:27][CH2:28][CH2:29][N:30]2[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]2)=[C:25]([CH:37]=O)[NH:24][C:23]=1[CH3:39])=[O:21])[CH3:18].N1CCCCC1>C(O)C>[CH2:17]([O:19][C:20]([C:22]1[C:26]([CH2:27][CH2:28][CH2:29][N:30]2[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]2)=[C:25]([CH:37]=[C:9]2[C:8]3[C:12](=[CH:13][CH:14]=[CH:15][C:7]=3[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[NH:11][C:10]2=[O:16])[NH:24][C:23]=1[CH3:39])=[O:21])[CH3:18]
Reactant: CCOC(=O)c1c(C)[nH]c(C=O)c1CCCN1CCN(C)CC1
Reactant: O=C1Cc2c(cccc2-c2ccccn2)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3cccc(-c4ccccn4)c32)c1CCCN1CCN(C)CC1
Temperature: 70 °C

Procedure:
A mixture of 4-pyridin-2-yl-1,3-dihydroindol-2-one (31.5 mg, 0.15 mmol), 5-formyl-2-methyl-4-[3-(4-methylpiperazin-1-yl)-propyl]-1H-pyrrole-3-carboxylic acid ethyl ester (48.2 mg, 0.15 mmol) and piperidine (0.1 mL) in ethanol (1 mL) was heated in a sealed tube at 70° C. for 6 hours. The reaction was concentrated and the residue was re-crystallized from ethyl acetate and hexane to give the title compound.
Reaction SMILES: [C:1]([O:7][C@H:8]1[C@@H:20]([O:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[C@H:19]([O:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])[C@@H:18]([CH2:35][O:36][C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39])[O:17][C@@H:9]1[S:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].C1C=C(Cl)C=C(C(OO)=[O:51])C=1.CSC>C(Cl)Cl>[C:1]([O:7][C@H:8]1[C@@H:20]([O:21][C:22](=[O:27])[C:23]([CH3:24])([CH3:26])[CH3:25])[C@H:19]([O:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])[C@@H:18]([CH2:35][O:36][C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39])[O:17][C@@H:9]1[S:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:51])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)C(=O)OC[C@H]1O[C@H](Sc2ccccc2)[C@@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Solvent: ClCCl
Solvent: CSC
Product: CC(C)(C)C(=O)OC[C@H]1O[C@H](S(=O)c2ccccc2)[C@@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Temperature: -15 °C
Yield: 75.4 %

Procedure:
To a solution of 36 (1.38 g, 2.27 mmol) in 65 mL of CH2Cl2 at -78° C. is added m-CPBA (612 mg, 64%, 2.27 mmol). The reaction mixture is allowed to warm to -15° C. and then quenched with dimethyl sulfide (1 mL, 13.6 mmol) and allowed to warm to room temperature. The reaction mixture is diluted with 50 mL of CH2Cl2, extracted with H2O (100 mL), saturated NaHCO3 (100 mL), saturated NaCl (100 mL), dried over Na2SO4, filtered, and concentrated to afford a white solid. The sulfoxide is purified using flash chromatography (30% EtOAc/hexane) to afford 1.07 g (76%) of the title compound 37 as a mixture of diastereomers: Rf 0.35 and 0.38 (30% EtOAc/hexane).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:19])OC2C=CC=CC=2)[N:7]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[CH3:35][O:36][C:37]1[CH:38]=[C:39]2[C:44](=[CH:45][C:46]=1[O:47][CH3:48])[N:43]=[CH:42][N:41]=[C:40]2[S:49][C:50]1[CH:51]=[C:52]([CH:54]=[CH:55][CH:56]=1)[NH2:53]>C1COCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:53][C:52]2[CH:54]=[CH:55][CH:56]=[C:50]([S:49][C:40]3[C:39]4[C:44](=[CH:45][C:46]([O:47][CH3:48])=[C:37]([O:36][CH3:35])[CH:38]=4)[N:43]=[CH:42][N:41]=3)[CH:51]=2)=[O:19])[N:7]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[N:6]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: COc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Reactant: CC(C)(C)c1cc(NC(=O)Oc2ccccc2)n(C2CCCCC2)n1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)nn4C4CCCCC4)c3)c2cc1OC
Temperature: 60 °C
Yield: 18 %

Procedure:
A stirred solution of phenyl 3-tert-butyl-1-cyclohexyl-1H-pyrazol-5-ylcarbamate prepared as described in Example 330A (200 mg, 0.59 mmol), N,N-diisopropylethylamine (67 mg, 0.52 mmol) and 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline (prepared as described in Example 115B) (85 mg, 0.27 mmol) in THF (1.0 mL) was heated at 60° C. for 15 h. After cooling to rt, the reaction solution was partitioned between dichloromethane and a saturated aqueous solution of sodium carbonate. The organic phase was separated and concentrated under reduced pressure. The crude product was purified via silica gel column chromatography (eluting with a gradient of 40:1 to 20:1 dichloromethane:methanol) then reverse-phase preparative HPLC to afford 1-(3-tert-butyl-1-cyclohexyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)urea (52 mg, 18%) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 9.17 (s, 1H), 8.71 (s, 1H), 8.53 (s, 1H), 7.84 (s, 1H), 7.26-7.55 (m, 5H), 6.06 (s, 1H), 4.00 (s, 6H), 3.94 (m, 1H), 1.62-1.81 (m, 7H), 1.24-1.36 (m, 12H); LC-MS (ESI) m/z 561 (M+H)+.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[CH2:14][C@@H:13]([N:15]2[CH:23]=[N:22][C:21]3[C:16]2=[N:17][CH:18]=[N:19][C:20]=3Cl)[CH2:12][C@@H:11]1[OH:25])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:33]1([C:39]#[CH:40])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CN(C=O)C.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.[Cu]I>[Si:1]([O:8][CH2:9][C@H:10]1[CH2:14][C@@H:13]([N:15]2[CH:23]=[N:22][C:21]3[C:16]2=[N:17][CH:18]=[N:19][C:20]=3[C:40]#[C:39][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:12][C@@H:11]1[OH:25])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1C[C@@H](n2cnc3c(Cl)ncnc32)C[C@@H]1O
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC[C@H]1C[C@@H](n2cnc3c(C#Cc4ccccc4)ncnc32)C[C@@H]1O
Reaction time: 3 h
Yield: 82.3 %

Procedure:
A solution of (1S,2R,4R)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-(6-chloro-9H-purin-9-yl)cyclopentanol (0.1 g, 0.26 mmol), Pd(PPh3)2Cl2 (0.006 g, 0.0089 mmol), CuI (0.004 g, 0.02 mmol) and triethylamine (0.145 mL, 1.04 mmol) in DMF (5 mL) was heated at 70° C. under argon for 1 h. Phenylacetylene (0.057 mL, 0.52 mmol) was added, the reaction mixture was stirred for 3 h, and the reaction was concentrated. The residue was dissolved in DCM and washed with saturated aq NaHCO3 and saturated aq EDTA.Na2 acid. The organic layer was dried (Na2SO4), concentrated and purified by flash chromatography (0 to 50% EtOAc/DCM) to afford the title compound (0.096 g, 82%).
Reaction SMILES: Cl[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9]([NH:17][CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])[CH:10]=[CH:11][CH:12]=3)[C:7](=[O:23])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:24]([CH2:26][NH2:27])[OH:25]>C(Cl)Cl>[CH3:21][N:20]([CH3:22])[CH2:19][CH2:18][NH:17][C:9]1[C:8]2[C:7](=[O:23])[C:6]3[C:15](=[C:2]([NH:27][CH2:26][CH2:24][OH:25])[CH:3]=[CH:4][CH:5]=3)[C:14](=[O:16])[C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: NCCO
Reactant: CN(C)CCNc1cccc2c1C(=O)c1cccc(Cl)c1C2=O
Solvent: ClCCl
Product: CN(C)CCNc1cccc2c1C(=O)c1cccc(NCCO)c1C2=O
Temperature: -150 °C
Yield: 38.8 %

Procedure:
A mixture of Compound 17 (0.87 g, 2.7 mmol) and ethanolamine (0.8 mL, 13.23 mmol) was heated in an oil bath (−150° C.) for 18 hours. The mixture was cooled to room temperature, dissolved in 100 mL CH2Cl2 and extracted with water and brine. The organic layer was dried (Na2SO4) and evaporated to provide Compound 21 (370 mg). This product was used in the next step without any purification. Rf (9:1 CHCl3/MeOH) 0.19. The structure of Compound 21 is given below:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:15]=[C:16]([C@@H:20]([OH:33])[CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]([OH:32])([CH3:31])[CH3:30])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1.[C:34]([Si:38](Cl)([CH3:40])[CH3:39])([CH3:37])([CH3:36])[CH3:35].N1C=CN=C1.C1(C)C=CC=CC=1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:15]=[C:16]([C@@H:20]([O:33][Si:38]([CH3:40])([CH3:39])[C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]([OH:32])([CH3:31])[CH3:30])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(O)c1ccccc1CC[C@H](O)c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(C)(O)c1ccccc1CC[C@H](O[Si](C)(C)C(C)(C)C)c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To the diol of Step 3 (36.56 g, 79.8 mmol) in 400 mL of CH2Cl2 was added tert-butyl-chlorodimethylsilane (18.21 g, 121 mmol), imidazole (10.97 g, 161 mmol) and 4-(dimethylamino)pyridine (0.988 g, 8.1 mmol) and the mixture was stirred at r.t. for 3 days. Toluene (400 mL) was then added and the product was filtered through silica with EtOAc:toluene 0:100 to 5:95. The title product was concentrated and stripped with toluene to remove any remaining silyl chloride.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][C:4]([CH2:7][CH2:8][CH2:9][CH2:10][PH:11](=[O:15])[O:12][CH2:13][CH3:14])=[CH:3]1.[Si:16](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17].C(N(CC)CC)C>CN(C=O)C.CN(C1C=CN=CC=1)C>[Si:16]([O:1][CH:2]1[CH2:6][CH2:5][C:4]([CH2:7][CH2:8][CH2:9][CH2:10][PH:11](=[O:15])[O:12][CH2:13][CH3:14])=[CH:3]1)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: CCO[PH](=O)CCCCC1=CC(O)CC1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCO[PH](=O)CCCCC1=CC(O[Si](C)(C)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.2 %

Procedure:
A solution of (±)-ethyl (3-hydroxycyclopentenyl)butylphosphinate (7) (3.66 g, 15.8 mmol) in anhydrous DMF (100 cm3) was treated with t-butyldimethylsilyl chloride (2.62 g, 17.4 mmol), triethylamine (4.55 cm3) and DMAP (425 mg). The reaction mixture was stirred at room temperature for 16 h, after which time the solvent was removed in vacuo. The residue was partitioned between DCM (50 cm3) and water (30 cm3) and the aqueous layer was further extracted with DCM (3×20 cm3). The combined organic layers were washed with water (2×30 cm3) and brine (40 cm3), dried over anhydrous sodium sulfate, filtered and the solvent removed under reduced pressure. The crude product was purified by short column vacuum chromatography on silica gel (15% ethanol/ethyl acetate) to yield the desired title compound (8) as a colourless oil (3.35 g, 61%): 1H-NMR (300 MHz, CDCl3) δH 0.09 (6H, s, Si(CH3)2), 0.89 (9H, s, SiC(CH3)3), 0.91 and 0.93 (3H, 2×d, J=7.2 and 7.2 Hz, PCH2CH2CH2CH3), 1.22-1.83 (9H, m, POCH2CH3, PCH2CH2CH2CH3, PCH2CH2CH2CH3, PCH2CH2CH2CH3), 2.26-2.72 (4H, m, C(4)—H, C(4)—H′, C(5)—H and C(5)—H′), 3.84-4.19 (2H, m, POCH2CH3), 4.97 (1H, m, C(3)—H), 6.50 and 6.54 (1H, 2×d, J=9.6 and 9.6 Hz, C(2)—H); 13C-NMR (75 MHz, CDCl3) δC −4.81 and −4.74 (d, 6JPC=5.7 Hz, Si(CH3)2), 13.48 (s, PCH2CH2CH2CH3), 16.43 and 16.51 (d, 6JPC=6.23 Hz, SiC(CH3)3), 18.08 (s, POCH2CH3), 23.43 (t, 2JPC=3.15 and 3.15 Hz, PCH2CH2CH2CH3), 23.69 and 23.90 (d, 3JPC=15.90 Hz, PCH2CH2CH2CH3), 25.75 (s, SiC(CH3)3), 27.22 and 28.54 (2×d, JPC=99.6 and 99.0 Hz, PCH2CH2CH2CH3), 31.55 and 31.70 (2×d, 3JPC=11.63 and 11.63 Hz, C(4)), 34.54 (t, 2JPC=8.25 and 8.55 Hz, C(5)), 60.15 (2×d, 2JPOC=6.30 and 6.83 Hz, POCH2CH3), 77.97 and 78.22 (d, 3JPC=18.45 Hz, C(3)), 136.64 and 138.24 (2×d, JPC=119.78 and 120.08 Hz, C(1)), 148.51 (d, 2JPC=9.38 Hz, C(2)); 31P-NMR (121 MHz, CDCl3) δP 42.77 and 43.15; MS (CI, CH4) m/z 347.2 (16%) (MH+), 215.1 (100), 375.3 (44), 289.2 (39). Synthesis of (±)-cis-ethyl [3(t-butyldimethylsilyloxy)cyclopentanyl]butylphosphinate (9)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl[S:15]([OH:18])(=[O:17])=[O:16]>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:13]([S:15]([OH:18])(=[O:17])=[O:16])=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(-c2ccccc2)cc1
Reactant: O=S(=O)(O)Cl
Solvent: ClC(Cl)Cl
Product: O=S(=O)(O)c1ccccc1-c1ccc(F)cc1
Reaction time: 4 h

Procedure:
4′-Fluorobiphenyl (5 g) was dissolved in chloroform (100 mL) at room temperature. Chlorosulfonic acid (5 g) was added dropwise and stirring was continued for a further 4 hours, after which the solvent was allowed to slowly evaporate until precipitation was seen. The mixture was left to recrystallised overnight and the solid was collected by filtration. Further crops of crystals were collected from the filtrate.
Reaction SMILES: [CH2:1]([OH:5])[C@H:2]([OH:4])[CH3:3].C(N(CC)CC)C.Cl[C:14]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1(C)C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:15]1([C:14]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[O:5][CH2:1][C@H:2]([OH:4])[CH3:3])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C[C@@H](O)CO
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C[C@@H](O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a suspension of (2R)-1,2-propanediol (1.9 mL) in toluene (20 mL) was added triethylamine (8.3 mL) and 4-dimethylaminopyridine (32 mg). The mixture was ice-cooled and 1,1′,1″-(chloromethylidyne)tris-benzene (6.6 g) was added and the mixture stirred at ambient temperature for 20 h. The reaction mixture was diluted with toluene then extracted with ammonium chloride solution (×2), then brine (×1) and the organic layer was dried (MgSO4), filtered and evaporated. The resulting oil was triturated with iso-hexane to give subtitle compound as a white solid. Yield: 4 g
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:17])[CH:5]=[C:6]([O:15][CH3:16])[C:7]=1[CH2:8][N:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.N1C=CC=CC=1.[F:24][C:25]([F:31])([F:30])[S:26](Cl)(=[O:28])=[O:27]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([O:17][S:26]([C:25]([F:31])([F:30])[F:24])(=[O:28])=[O:27])[CH:5]=[C:6]([O:15][CH3:16])[C:7]=1[CH2:8][N:9]1[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: COc1cc(O)cc(Cl)c1CN1CCCCC1
Reactant: O=S(=O)(Cl)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc(OS(=O)(=O)C(F)(F)F)cc(Cl)c1CN1CCCCC1
Temperature: 25 °C
Yield: 101.1 %

Procedure:
To a stirred solution of 3-chloro-5-methoxy-4-piperidin-1-ylmethylphenol (223 mg, 0.87 mmol) and pyridine (0.28 mL, 3.5 mmol) in DCM (10 mL) at −20° C. was added trifluoromethanesulfonyl chloride (0.29 mL, 1.7 mmol). After the addition was complete the reaction mixture was allowed to warm to ambient temperature then diluted with DCM (20 mL) then washed with water (10 mL). The organic phase was separated, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to afford an oil that was purified by flash chromatography (silica, 12 g column, ISCO, 0-100% ethyl acetate in cyclohexane) to afford the title compound as a red oil (341 mg, 73%). 1H NMR (CDCl3, 300 MHz): 7.06 (d, J=2.3 Hz, 1H), 6.85 (d, J=2.3 Hz, 1H), 4.40 (s, 2H), 4.05 (s, 3H), 3.72-3.42 (m, 1H), 3.06-2.72 (m, 1H), 2.23-1.75 (m, 4H), 1.73-1.36 (m, 4H).
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3]([C:5]1[CH:6]=[C:7]([OH:22])[C:8]2[N:12]=[C:11]([CH3:13])[N:10](C(OC(C)(C)C)=O)[C:9]=2[CH:21]=1)=[O:4].[O:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27](O)[CH2:26][CH2:25]1>>[O:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]([O:22][C:7]2[C:8]3[N:12]=[C:11]([CH3:13])[NH:10][C:9]=3[CH:21]=[C:5]([C:3]([N:2]([CH3:1])[CH3:23])=[O:4])[CH:6]=2)[CH2:26][CH2:25]1
Reactant: Cc1nc2c(O)cc(C(=O)N(C)C)cc2n1C(=O)OC(C)(C)C
Reactant: OC1CCOc2ccccc21
Product: Cc1nc2c(OC3CCOc4ccccc43)cc(C(=O)N(C)C)cc2[nH]1
Yield: 53 %

Procedure:
The title compound was prepared as a white solid (58 mg, 53% yield for 2 steps) from 1,1-dimethylethyl 6-[(dimethylamino)carbonyl]-4-hydroxy-2-methyl-1H-benzimidazole-1-carboxylate (100 mg, 0.313 mmol, STEP 2 in Example 9) and 3,4-dihydro-2H-chromen-4-ol (141 mg, 0.939 mmol) by the same manner in STEP 3-2 of Example 9:
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][N:5]([CH2:7][CH3:8])[N:6]=1.[CH3:9][O:10][C:11]1[CH:24]=[CH:23][C:22]2[O:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]([C:25](Cl)=[O:26])[C:13]=2[CH:12]=1>>[CH2:7]([N:5]1[N:4]=[N:3][C:2]([NH:1][C:25]([CH:14]2[C:13]3[CH:12]=[C:11]([O:10][CH3:9])[CH:24]=[CH:23][C:22]=3[O:21][C:20]3[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:26])=[N:6]1)[CH3:8]
Reactant: COc1ccc2c(c1)C(C(=O)Cl)c1ccccc1O2
Reactant: CCn1nnc(N)n1
Product: CCn1nnc(NC(=O)C2c3ccccc3Oc3ccc(OC)cc32)n1

Procedure:
The title compound, white solid, m.p. 208-210° C. (dec.) and MS: (pos. ions): m/e=352.3 (M++H) was prepared in accordance with the general method of example 1 from 5-amino-2-ethyl-2H-tetrazole and (RS)-2-methoxy-9H-xanthene-9-carbonyl chloride.
Reaction SMILES: Cl[C:2]1[C:15]2[C:14](=O)[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([Cl:17])[CH:12]=3)[S:7][C:6]=2[C:5]([CH3:18])=[CH:4][CH:3]=1.[CH2:19]([N:21]([CH2:26][CH3:27])[CH2:22][CH2:23][NH:24][NH2:25])[CH3:20]>>[Cl:17][C:11]1[CH:10]=[CH:9][C:8]2[S:7][C:6]3[C:15]4[C:14](=[N:25][N:24]([CH2:23][CH2:22][N:21]([CH2:26][CH3:27])[CH2:19][CH3:20])[C:2]=4[CH:3]=[CH:4][C:5]=3[CH3:18])[C:13]=2[CH:12]=1
Reactant: CCN(CC)CCNN
Reactant: Cc1ccc(Cl)c2c(=O)c3cc(Cl)ccc3sc12
Product: CCN(CC)CCn1nc2c3c(c(C)ccc31)Sc1ccc(Cl)cc1-2

Procedure:
By condensation of 1,7-dichloro-4-methyl-9-thioxanthenone with 2-(diethylamino)ethyl hydrazine was obtained 9-chloro-2-(2-(diethylamino)ethyl)-5-methyl-2H-(1)benzothiopyrano[4,3,2-cd]indazole. To 0.13 g. of this base in acetone (3 ml.) was added 30% aqueous hydrogen peroxide (0.2 ml.). After 18 hours at room temperature the solution was evaporated to dryness under reduced pressure and the residue crystallized from acetone to give 9-chloro-2-(2-diethylamino)ethyl)-5-methyl-2H(1)-benzothiopyrano[4,3,2-cd]indazole N-oxide monohydrate, m.p. 134° - 135° (decomp.).
Reaction SMILES: [CH2:1]([O:7][C:8]1[C:13]([F:14])=[C:12]([F:15])[CH:11]=[C:10]([F:16])[C:9]=1[F:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C([Li])CCC.CCCCCC.[C:29](=[O:31])=[O:30].Cl>C1COCC1>[CH2:1]([O:7][C:8]1[C:9]([F:17])=[C:10]([F:16])[C:11]([C:29]([OH:31])=[O:30])=[C:12]([F:15])[C:13]=1[F:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: O=C=O
Reactant: CCCCCCOc1c(F)c(F)cc(F)c1F
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCCCOc1c(F)c(F)c(C(=O)O)c(F)c1F
Temperature: -78 °C
Reaction time: 2 h

Procedure:
27.5 g of the compound (4) dissolved in 250 mL of THF were cooled at −78° C. in an argon atmosphere; thereto were then dripped 82 mL of a 1.6 M/L n-butyllithium/hexane solution, with stirring for 2 hours at the same temperature. After addition of a suitable amount of crushed dry ice, the temperature was raised to room temperature, followed by stirring overnight. 200 mL of 3N hydrochloric acid were then added under ice cooling, the organic layer was separated, and the aqueous layer was extracted with diethyl ether. The organic layers were combined, were washed with saturated brine, and were then dried over anhydrous magnesium sulfate. After evaporating the solvent, the organic layer was recrystallized from hexane to yield 25.9 g (88 mmol) of 4-hexyloxy-2,3,5,6-tetrafluorobenzoic acid (5).
Reaction SMILES: [H-].[Na+].CS(C)=O.[Cl:7][C:8]1[CH:9]=[C:10]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH:11]=[CH:12][C:13]=1[Cl:14].[C:23]([O:27][C:28]([N:30]1[CH2:34][CH2:33][CH:32](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>C(OCC)(=O)C>[C:23]([O:27][C:28]([N:30]1[CH2:34][CH2:33][CH:32]([N:15]([C:10]2[CH:11]=[CH:12][C:13]([Cl:14])=[C:8]([Cl:7])[CH:9]=2)[C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH2:31]1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: Cc1ccc(S(=O)(=O)OC2CCN(C(=O)OC(C)(C)C)C2)cc1
Reactant: Fc1ccc(Nc2ccc(Cl)c(Cl)c2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(N(c2ccc(F)cc2)c2ccc(Cl)c(Cl)c2)C1
Temperature: 60 °C
Reaction time: 1 h
Yield: 17.5 %

Procedure:
Sodium hydride (0.19 g, 60% in oil) was added to 10 ml of dimethyl sulfoxide (DMSO) and stirred at 60° C. for one hour. Subsequently, 1.0 g of (3,4-dichlorophenyl)-(4-fluorophenyl)amine was added to the mixture and stirred at 60° C. for one hour. A DMSO solution containing 2.0 g of 3-(toluene-4-sulfonyloxy)pyrrolidine-1-carboxylic acid tert-butyl ester was gradually added to the mixture and stirred at 60° C. for 15 hours. Ethyl acetate was added to the reaction solution. The solution was then washed with water, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=20:1). The eluent solvent was distilled off under reduced pressure to thereby obtain 0.29 g of oily brown 3-[(3,4-dichlorophenyl)-(4-fluorophenyl)amino]pyrrolidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:4]=1[C:5](Cl)=[O:6].[NH2:27][C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[C:30]([C:36]([F:39])([F:38])[F:37])[CH:29]=1.C(N(CC)CC)C>ClCCl>[C:32]([C:31]1[CH:34]=[CH:35][C:28]([NH:27][C:5](=[O:6])[C:4]2[C:8]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:9][CH:10]=[CH:11][C:3]=2[O:2][CH3:1])=[CH:29][C:30]=1[C:36]([F:37])([F:38])[F:39])#[N:33]
Reactant: CCCCCCCCCCCCCCCc1cccc(OC)c1C(=O)Cl
Reactant: N#Cc1ccc(N)cc1C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCc1cccc(OC)c1C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1

Procedure:
2-Methoxy-6-pentadecyl-benzoyl chloride was condensed with 4-Amino-2-trifluoromethyl benzonitrile in dichloromethane in presence of triethylamine as acid scavenger to yield N-(4-Cyano-3-trifluoromethyl-phenyl)-2-methoxy-6-pentadecyl-benzamide. The reaction mixture was then concentrated in vacuo and the residue was extracted into ethyl acetate. The ethyl acetate layer was washed with water and with cold aqueous hydrochloric acid, then dried over sodium sulphate and finally concentrated in vacuo. The residue obtained was chromatographed over silica gel to afford the desired product.