Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[CH2:4][CH2:5][CH:6]=[O:7].[O:12]=[C:13]([CH3:20])/[CH:14]=[CH:15]/[C:16]([O:18][CH3:19])=[O:17]>C(Cl)(Cl)Cl>[CH2:4]([C@H:5]1[C@@H:15]([C:16]([O:18][CH3:19])=[O:17])[CH:14]=[C:13]([CH3:20])[O:12][C:6]1=[O:7])[C:3]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:2]=1
Reactant: O=CCCc1ccccc1Cl
Reactant: COC(=O)/C=C/C(C)=O
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@H]1C=C(C)OC(=O)[C@H]1Cc1ccccc1
Yield: 88 %

Procedure:
Prepared according to the general procedure from 2-chloro-hydrocinnamaldehyde and (E)-methyl 4-oxopent-2-enoate using 0.5 mol % 1 as the catalyst in 88% yield as a single diasteromer (colorless oil). [α]D20 (c 1.10, CHCl3)=+218.7; 1H NMR (400 MHz, CDCl3) δ 7.32-7.23 (m, 3H), 7.12 (d, 2H, J=7.2 Hz), 5.02 (d, 1H, J=7.2 Hz), 3.73 (s, 3H), 3.48 (dd, 1H, J=14.3, 4.6 Hz), 3.02 (t, 1H, J=6.0 Hz), 2.89-2.84 (m, 1H), 2.66 (dd, 1H, J=14.3, 10.1 Hz), 1.89 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 171.3, 169.3, 152.6, 138.3, 129.2, 129.0, 127.0, 98.7, 52.6, 42.8, 40.3, 33.4, 19.0; IR (thin film) ν 3062, 2954, 1780, 1732, 1496, 1435, 1362, 1164 cm−1; HRMS (ESI) calcd for C15H16O4 [M+Na]+ 283.0940, found 283.0944; 99% ee (3S,4S)-isomer as determined by HPLC (AD-H, 9:1 hexanes/i-PrOH), tr (3S,4S)=12.0 min, tr (3R,4R)=9.40 min.
Reaction SMILES: [CH:1]1([N:5]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=2)[S:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][CH:10]=2)(=[O:8])=[O:7])[CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40].O>C(Cl)Cl>[CH:1]1([N:5]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=2)[S:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]3[CH2:17][CH2:18][N:19]([S:39]([CH3:38])(=[O:41])=[O:40])[CH2:20][CH2:21]3)=[CH:11][CH:10]=2)(=[O:8])=[O:7])[CH2:4][CH2:3][CH2:2]1
Reactant: O=S(=O)(c1ccc(OC2CCNCC2)cc1)N(c1cccc(F)c1)C1CCC1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)N1CCC(Oc2ccc(S(=O)(=O)N(c3cccc(F)c3)C3CCC3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-{4-[cyclobutyl-(3-fluoro-phenyl)-sulfamoyl]-phenoxy}-piperidine-1-carboxylic acid tert-butyl ester (330 mg, 655 μmol) in DCM (9 mL) was added TFA (1 mL) and then the reaction was stirred at room temperature for 30 minutes. The reaction was concentrated and then purified by SCX eluting with 2 M NH3 in MeOH to give N-cyclobutyl-N-(3-fluoro-phenyl)-4-(piperidin-4-yloxy)-benzenesulfonamide (195 mg, 483 μmol). To a solution of N-cyclobutyl-N-(3-fluoro-phenyl)-4-(piperidin-4-yloxy)-benzenesulfonamide in DCM (10 mL) was added DIPEA (168 μL, 965 μmol) and methanesulfonyl chloride (41 μL, 531 μmol) and the reaction was stirred at room temperature for 30 minutes. Water was added and then extracted with DCM, filtered through a phase separator and concentrated. Purification by silica gel column chromatography (0-50% EtOAc in cyclohexane) followed by preparative reverse a phase HPLC gave the title compound (169 mg). 1H NMR δ (DMSO): 7.46 (2H, d, J=8.8 Hz), 7.38-7.39 (1H, m), 7.16-7.17 (3H, m), 6.77-6.78 (2H, m), 4.69-4.71 (1H, m), 4.20-4.22 (1H, m), 3.33-3.38 (4H, m), 3.13 (2H, ddd, J=12.1, 8.09, 3.4 Hz), 2.91 (3H, s), 2.03-2.06 (4H, m), 1.77-1.81 (4H, m), 1.53-1.56 (2H, m). LCMS (m/z, Method B) ES+ 482.9 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[C:20](=O)([O-])[O-].[Cs+].[Cs+].CI>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:13]([CH3:20])[CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(Cl)cc(NC2CCOCC2)c1C
Agent: [Cs+]
Solvent: CC#N
Solvent: CI
Product: COC(=O)c1cc(Cl)cc(N(C)C2CCOCC2)c1C
Temperature: 80 °C
Yield: 65.2 %

Procedure:
To a stirred solution of methyl 5-chloro-2-methyl-3-((tetrahydro-2H-pyran-4-yl)amino)benzoate (700 mg, 2.473 mmol) in acetonitrile (10 mL), cesium carbonate (1.61 g, 4.946 mmol) and methyl iodide (1.82 g, 0.8 ml, 12.36 mmol) were added; resulting reaction mass was heated at 80° C. for 13 h. On completion, reaction mass was cooled to room temperature and filtered, residue was washed with ethyl acetate and filtrate was concentrated and then purified by column chromatography to afford desired compound (480 mg, 65%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>CN(C1C=CN=CC=1)C.CCCCCC>[CH3:22][C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH:1][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[N:10]=[CH:9][CH:8]=[CH:7]3)(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1cccc2cccnc12
Agent: CN(C)c1ccncc1
Solvent: CCCCCC
Product: Cc1ccc(S(=O)(=O)Nc2cccc3cccnc23)cc1
Yield: 64.5 %

Procedure:
In the similar fashion using route 14 general procedure 27, 8-aminoquinoline (200 mg, 1.38 mmol), p-toluenesulfonyl chloride (260 mg, 1.3 mmol) and DMAP (cat.) gave the title compound (250 mg, 60%) after trituration from n-hexane.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9]2)(=[O:5])=[O:4].[N:17]1([CH2:22][CH2:23][NH:24][C:25]([C:27]2[C:31]([CH3:32])=[C:30]([CH:33]=O)[NH:29][C:28]=2[CH3:35])=[O:26])[CH2:21][CH2:20][CH2:19][CH2:18]1>>[N:17]1([CH2:22][CH2:23][NH:24][C:25]([C:27]2[C:31]([CH3:32])=[C:30]([CH:33]=[C:9]3[C:8]4[C:12](=[CH:13][CH:14]=[C:6]([S:3](=[O:5])(=[O:4])[N:2]([CH3:16])[CH3:1])[CH:7]=4)[NH:11][C:10]3=[O:15])[NH:29][C:28]=2[CH3:35])=[O:26])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCN1CCCC1
Reactant: CN(C)S(=O)(=O)c1ccc2c(c1)CC(=O)N2
Product: Cc1[nH]c(C=C2C(=O)Nc3ccc(S(=O)(=O)N(C)C)cc32)c(C)c1C(=O)NCCN1CCCC1
Yield: 54.2 %

Procedure:
2-Oxo-2,3-dihydro-1H-indole-5-sulfonic acid dimethylamide (90 mg, 0.38 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-ylethyl)amide (100 mg) to give 100 mg (54%) of the title compound as a yellow solid.
Reaction SMILES: C(O[C@H]1C2C(=CC(Br)=CC=2)[C@@H](NC[C@@H](O)[C@@H](N)CC2C=C(F)C=C(F)C=2)C1)C=C.[O-]P([O-])([O-])=O.[K+].[K+].[K+].N1CCC[C@H]1C(O)=O.[CH2:46]1[CH:50]2[CH2:51][NH:52][CH2:53][CH:49]2[CH2:48][N:47]1[C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55].Br[C:62]1[CH:63]=[CH:64][C:65]2[C@H:66]3[CH2:83][C@@H:80]([C:81]=2[CH:82]=1)[NH:79][CH2:78][C@@H:77]([OH:84])[C@H:76]([CH2:85][C:86]1[CH:91]=[C:90]([F:92])[CH:89]=[C:88]([F:93])[CH:87]=1)[NH:75][C:74](=[O:94])[CH2:73][CH2:72][CH2:71][CH:70]=[CH:69][CH2:68][O:67]3>O.CCOC(C)=O.[Cu]I.CS(C)=O>[C:57]([O:56][C:54]([N:47]1[CH2:48][CH:49]2[CH:50]([CH2:51][N:52]([C:62]3[CH:63]=[CH:64][C:65]4[C@H:66]5[CH2:83][C@@H:80]([C:81]=4[CH:82]=3)[NH:79][CH2:78][C@@H:77]([OH:84])[C@H:76]([CH2:85][C:86]3[CH:87]=[C:88]([F:93])[CH:89]=[C:90]([F:92])[CH:91]=3)[NH:75][C:74](=[O:94])[CH2:73][CH2:72][CH2:71][CH:70]=[CH:69][CH2:68][O:67]5)[CH2:53]2)[CH2:46]1)=[O:55])([CH3:60])([CH3:59])[CH3:58]
Reactant: O=C1CCCC=CCO[C@@H]2C[C@H](NC[C@@H](O)[C@H](Cc3cc(F)cc(F)c3)N1)c1cc(Br)ccc12
Reactant: CC(C)(C)OC(=O)N1CC2CNCC2C1
Agent: [Cu]I
Agent: C=CCO[C@@H]1C[C@H](NC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c2cc(Br)ccc21
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CC2CN(c3ccc4c(c3)[C@@H]3C[C@H]4OCC=CCCCC(=O)N[C@@H](Cc4cc(F)cc(F)c4)[C@H](O)CN3)CC2C1
Temperature: 25 °C
Yield: 61.6 %

Procedure:
Step FF (1): Copper(I) iodide (20 mg, 0.104 mmol), K3PO4 (67 mg, 0.316 mmol), L-proline (9.2 mg, 0.080 mmol), and DMSO (1 mL) were combined in a 1 dram vial. tert-Butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (40.7 mg, 0.192 mmol) and (1S,4R,5S,15R)-19-bromo-5-(3,5-difluoro-benzyl)-4-hydroxy-14-oxa-2,6-diaza-tricyclo[13.6.1.016,21]docosa-11,16(21),17,19-tetraen-7-one (39 mg, 0.073 mmol, TFA salt of Example 68) were added to the mixture. The vial was capped, shaken, and placed into a heating block preheated to 90° C. The reaction was allowed to stir magnetically for 16 h at 90° C. The reaction was cooled to rt, and diluted with water and EtOAc. The mixture was extracted with EtOAc. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under vacuo. The crude residue was purified by flash column chromatography on a small pre-packed silica gel column, eluted with 30% EtOAc/hexane, then 5-10% methanol/DCM. The pure fractions were pooled (Rf=0.54 in 5% methanol/DCM) and concentrated in vacuo to afford 30 mg (55% yield) of the title compound as a brown solid/residue. This material was determined to be a mixture of cis and trans isomers by proton NMR. Analytical HPLC conditions (methanol/0.1% TFA water, 4.6×50 mm, 5 micron, Waters X-Bridge C18 column, 5 mL/min, 254 nm wavelength) showed a purity of 90% and a Rt of 4.79 min.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[C:3]=1[CH3:19].CC(C)([O-])C.[Na+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[CH3:60][O:61][C:62]1[CH:69]=[CH:68][C:65]([CH2:66][NH2:67])=[CH:64][CH:63]=1>CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[F:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:67][CH2:66][C:65]3[CH:68]=[CH:69][C:62]([O:61][CH3:60])=[CH:63][CH:64]=3)=[C:3]([CH3:19])[C:4]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:5]2)=[CH:10][CH:9]=1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1Cl
Reactant: COc1ccc(CN)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1ccc(CNc2c(C)c(-c3ccccn3)nc3cc(F)ccc23)cc1
Temperature: 110 °C
Reaction time: 3 h

Procedure:
A mixture of 4-chloro-7-fluoro-3-methyl-2-(pyridin-2-yl)quinoline (2.0 g, 7.33 mmol), sodium tert-butoxide (1.41 g, 14.67 mmol), tris(dibenzylideneacetone)-dipalladium (0) (0.504 g, 0.550 mmol), XPhos (0.52 g, 1.100 mmol), 4-methoxybenzylamine (0.95 mL, 7.33 mmol), and toluene (15 mL) was stirred at 110° C. under nitrogen for 3 h. Upon completion, the reaction was cooled to 23° C. and concd. The resulting crude residue was taken up in EtOAc, filtered through Celite, and washed with water and brine. The organic phase was dried over magnesium sulfate and concd, affording a crude material that was purified by column chromatography (silica; 0-50% EtOAc in hexanes) to yield 7-fluoro-N-(4-methoxybenzyl)-3-methyl-2-(pyridin-2-yl)quinolin-4-amine as an orange oil. Mass Spectrum (ESI) m/e=374.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[NH:11][C:10]([CH3:13])(C)[C:9]2[C:8](=[O:14])[CH2:7][CH:6]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3Br)[CH2:5][C:4]=2[N:3]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24](B(O)O)[CH:23]=1.NC1N=C(C)C2C(=O)CC(C3C=CC=CC=3C3C=CC=CC=3)CC=2N=1>>[NH2:1][C:2]1[N:11]=[C:10]([CH3:13])[C:9]2[C:8](=[O:14])[CH2:7][CH:6]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:24]3[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=3)[CH2:5][C:4]=2[N:3]=1
Reactant: CC1(C)NC(N)=NC2=C1C(=O)CC(c1ccccc1Br)C2
Reactant: OB(O)c1cccnc1
Agent: Cc1nc(N)nc2c1C(=O)CC(c1ccccc1-c1ccccc1)C2
Product: Cc1nc(N)nc2c1C(=O)CC(c1ccccc1-c1cccnc1)C2

Procedure:
The title compound was prepared from 2-amino-4-methyl-7-(2-bromo-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one (example 3/i stage 2/3) and pyridin-3-ylboronic acid, following the procedure describing the synthesis of 2-amino-7-biphenyl-2-yl-4-methyl-7,8-dihydro-6H-quinazolin-5-one (example 5/a stage 1).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([NH:8][CH2:9][C:10]2[C:11]([CH3:25])=[CH:12][C:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[N:14][C:15]=2[CH3:16])=[O:7])[CH:3]=[N:2]1.CS(O[CH2:31][C:32]1[CH:33]=[C:34]2[C:39](=[CH:40][CH:41]=1)[N:38]=[CH:37][C:36]([Cl:42])=[CH:35]2)(=O)=O.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Cl:42][C:36]1[CH:37]=[N:38][C:39]2[C:34]([CH:35]=1)=[CH:33][C:32]([CH2:31][N:1]1[CH:5]=[C:4]([C:6]([NH:8][CH2:9][C:10]3[C:11]([CH3:25])=[CH:12][C:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[N:14][C:15]=3[CH3:16])=[O:7])[CH:3]=[N:2]1)=[CH:41][CH:40]=2
Reactant: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CNC(=O)c1cn[nH]c1
Reactant: CS(=O)(=O)OCc1ccc2ncc(Cl)cc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CNC(=O)c1cnn(Cc2ccc3ncc(Cl)cc3c2)c1

Procedure:
A solution of tert-Butyl 5-((1H-pyrazole-4-carboxamido)methyl)-4,6-dimethylpyridin-2-ylcarbamate (145 mg, 0.421 mmol), (3-Chloroquinolin-6-yl)methyl methanesulfonate (143 mg, 0.421 mmol 80%) and K2CO3 (291 mg, 2.105 mmol) in Acetone (3 ml) was stirred for 20 h at 50° C. The reaction was quenched with H2O and extracted twice with DCM. The organic layer was dried with Na2SO4, filtered and evaporated to dryness to afford crude title compound. The crude product was purified by preparative HPLC (Macherey-Nagel Nucleosil 250×40 mm, 5 to 100% ACN and 0.1% TFA, flow 40 ml/min) to afford pure title compound. MS (Method V) [M+H]+=521.4.
Reaction SMILES: [F:1][CH:2]1C(=O)[CH2:6][CH2:5][N:4]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[CH2:3]1.[CH3:18][O:19][CH:20](OC)[O:21][CH3:22].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:18][O:19][C:20]1([O:21][CH3:22])[CH2:6][CH2:5][N:4]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[CH2:3][CH:2]1[F:1]
Reactant: COC(OC)OC
Reactant: O=C1CCN(c2ccc([N+](=O)[O-])cc2)CC1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: COC1(OC)CCN(c2ccc([N+](=O)[O-])cc2)CC1F
Temperature: 45 °C
Yield: 91 %

Procedure:
The mixture of 4-(3-fluoro-4-oxo-piperidin-1-yl)-nitrobenzene (51 mmol), trimethylorthoformate (103 mmol), p-toluene-sulphonic acid monohydrate (51 mmol) in methanol (100 ml) was heated at 45° C. for 24 hours. Solvent was removed and residual mass was taken into ethyl acetate and saturated sodium bicarbonate solution mixture. The organic layer was dried and removal of the solvent afforded title compound as a solid in 91% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][C:14]([C:20]([CH:22]2[CH2:24][CH2:23]2)=[O:21])=[C:13]3[NH:25][C@H:26]2[CH2:31][CH2:30][C@H:29]([N:32](C)[C:33](=O)OC(C)(C)C)[CH2:28][CH2:27]2)[CH:5]=[C:6]([F:9])[C:7]=1[OH:8].C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][C:14]([C:20]([CH:22]2[CH2:24][CH2:23]2)=[O:21])=[C:13]3[NH:25][C@H:26]2[CH2:31][CH2:30][C@H:29]([NH:32][CH3:33])[CH2:28][CH2:27]2)[CH:5]=[C:6]([F:9])[C:7]=1[OH:8]
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(F)c(O)c(Cl)c4)cc23)CC1
Solvent: O=C(O)C(F)(F)F
Product: CN[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(F)c(O)c(Cl)c4)cc23)CC1

Procedure:
Following general procedure A-2, tert-butyl trans-4-[6-(3-chloro-5-fluoro-4-hydroxyphenyl)-3-(cyclopropanecarbonyl)quinolin-4-ylamino]cyclohexyl(methyl)carbamate (0.125 mmol) was reacted with TFA (2 mL) to afford the desired product (32 mg, 55% over two steps) as a yellow solid: 1H NMR (300 MHz, DMSO-d6) δ 9.80 (s, 1H), 9.8 (s, 1H), 8.25 (s, 1H), 7.99 (d, J=8.7 Hz, 1H), 7.83 (d, J=8.7 Hz, 1H), 7.49-7.34 (m, 2H), 4.00-3.94 (s, 1H), 3.00-2.85 (m, 1H), 2.85-2.74 (m, 1H), 2.44 (s, 3H), 2.25-2.04 (m, 4H), 1.60-1.30 (m, 4H), 1.15-0.98 (m, 4H); ESI MS m/z 468 [C26H27ClFN3O2+H]+; HPLC>99% (AUC), tR=10.03 min.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:20])[O:17][CH2:18][CH3:19])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1>>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([N:20]=[C:16]([N:7]2[CH2:6][C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=3[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8]2)[O:17][CH2:18][CH3:19])=[O:30])=[CH:24][CH:23]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Product: CCOC(=NC(=O)Nc1ccc(Cl)cc1)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from ethyl 5,7-dihydro-6H-dibenz[c,e]-azepine-6-carboximidate and p-chlorophenyl isocyanate, there is obtained ethyl N-[(p-chlorophenyl)carbamoyl]-5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate, m.p. 154°-156° C.;
Reaction SMILES: NC1C=C(C=CC=1NC)OC1C=CN=C(C(NC)=O)C=1.N([C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=1)=C=S.IC>CO>[C:28]([OH:30])(=[O:29])[C:27]1[CH:31]=[CH:32][CH:24]=[CH:25][CH:26]=1
Reactant: O=C(O)c1ccc(N=C=S)cc1
Agent: CNC(=O)c1cc(Oc2ccc(NC)c(N)c2)ccn1
Solvent: CI
Solvent: CO
Product: O=C(O)c1ccccc1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To {4-[3-amino-4-(methylamino)phenoxy](2-pyridyl)}-N-methylcarboxamide (1 eq) in methanol was added 4-isothiocyanatobenzoic acid (1 eq) and stirred at 60° C. for 3 h. To it was then added iodomethane (1 eq) and heated to 60° C. for 3 h. and concentrated the solvent and purified on silica gel to yield 4-({1-methyl-5-[2-(N-methylcarbamoyl)(4-pyridyloxy))]benzimidazol-2-yl}amino)benzoic acid. MS: MH+=417.
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[C:22]([C:29]#[CH:30])[CH:23]=[CH:24][CH:25]=4)[O:20][C:19]=3[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[N:38]([Si](C)(C)C)=[N+:39]=[N-:40]>CO.CN(C=O)C.CCOC(C)=O.[Cu]I>[C:1]([O:5][C:6](=[O:37])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[C:22]([C:29]5[N:38]=[N:39][NH:40][CH:30]=5)[CH:23]=[CH:24][CH:25]=4)[O:20][C:19]=3[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[CH:14][CH:13]=2)[CH2:9][CH2:10][CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C#Cc1cccc2c(=O)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)oc12
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(-c5c[nH]nn5)cccc4c3=O)cc2)CCC1
Temperature: 100 °C
Reaction time: 3.75 h

Procedure:
A solution of {1-[4-(8-Ethynyl-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (34 mg, 0.069 mmol) in MeOH (0.2 mL) and DMF (1.8 mL) was treated with copper(I) iodide (1 mg, 0.003 mmol) and azido trimethylsilane (0.014 ml, 0.104 mmol). The reaction mixture was the stirred at 100° C. for 3.75 h. The resultant mixture was allowed to cool to RT, diluted with EtOAc, washed with brine. The aqueous extracts were further washed with EtOAc (×2). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0 to 30% EtOAc in DCM) to give the title compound. LCMS (Method G) RT=3.88 min, [M+H]+=535.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:33][CH2:34][CH3:35])[CH2:9][CH2:10][S:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH:20]([O:22][CH2:23][CH2:24][CH2:25][O:26][PH:27]([C:29]([O:31][OH:32])=[O:30])=[O:28])[CH3:21])=[CH:4][CH:3]=1.[CH3:36]OC(P(Cl)(Cl)=O)=O.[OH-].[Na+]>>[CH:5]1([CH:8]([CH2:33][CH2:34][CH2:35][CH3:36])[CH2:9][CH2:10][S:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH:20]([O:22][CH2:23][CH2:24][CH2:25][O:26][PH:27]([C:29]([O:31][OH:32])=[O:30])=[O:28])[CH3:21])[CH2:6][CH2:7][CH2:2][CH2:3][CH2:4]1
Reactant: CCCC(CCSCCCCCCCCC(C)OCCCO[PH](=O)C(=O)OO)c1ccc(Cl)cc1
Reactant: COC(=O)P(=O)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Product: CCCCC(CCSCCCCCCCCC(C)OCCCO[PH](=O)C(=O)OO)C1CCCCC1
Yield: 71 %

Procedure:
1.70 g (81%) R,S-((3-(12-cyclohexyldodecylthio)-2-decyloxy)-propoxy)-hydroxy-phosphinyl-formic acid methyl ester (example 12.28) was obtained analogously to example 1 as a colourless oil from 0.55 g (3.10 mmol) 16 and 1.50 g (3.10 mmol) R,S-2-decyloxy-3-(12-cyclohexyldodecylthio)-1-propanol. Saponification of 1.50 g of this ester with sodium hydroxide solution (example 1) yielded 1.10 g (71%) 8 with a melting point of 105-107° C.
Reaction SMILES: Br[C:2]([F:15])([F:14])[C:3]([F:13])([F:12])[CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].CO.[BH4-].[Na+]>O1CCCC1>[F:12][C:3]([F:13])([CH:2]([F:14])[F:15])[CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)CCCC(F)(F)C(F)(F)Br
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)CCCC(F)(F)C(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
Under a nitrogen atmosphere, 1 g (3.39 millimoles) of ethyl 6-bromo-5,5,6,6-tetrafluorohexanoate was dissolved in 10 mL of tetrahydrofuran and 1 mL of methanol and then 129 mg (3.39 millimoles) of sodium borohydride was added thereto, followed by stirring at room temperature for 1 hour. A reaction solution was extracted with ethyl acetate after the addition of a sulfuric acid aqueous solution, followed by concentrating a solvent. With this, ethyl 5,5,6,6-tetrafluorohexanoate was obtained at a yield of 50%. There cannot be confirmed production of 6-bromo-5,5,6,6-tetrafluorohexan-1-ol.
Reaction SMILES: CC(C)([O-])C.[K+].F[C:8]1[CH:26]=[N:25][CH:24]=[CH:23][C:9]=1[C:10]([CH:12]([C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:11].O>CN1C(=O)CCC1>[OH:11][C:10]1[C:9]2[CH:23]=[CH:24][N:25]=[CH:26][C:8]=2[C:19]([CH3:21])([CH3:20])[C:18](=[O:22])[C:12]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)C(C(=O)c1ccncc1F)C(=O)C(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCOC(=O)C1=C(O)c2ccncc2C(C)(C)C1=O
Temperature: 25 °C
Yield: 76.5 %

Procedure:
A mixture of potassium t-butoxide (0.34 g, 3.0 mmol) in 8 mL NMP stirred at room temperature was treated with a solution of ethyl 2-(3-fluoroisonicotinoyl)-4-methyl-3-oxopentanoate (0.28 g, 1.00 mmol) in 1 mL NMP drop wise. The dark red solution was stirred at room temperature for 15 hours, M+1=262. There were two spots that had the MS=262. The mixture was poured into 200 mL water. The mixture was extracted with DCM (3×50 mL). The combined organic layers were washed with brine (20 mL), dried, and concentrated. The crude product was purified by column eluting with 10-50% EtOAc/hexane to give 0.2 g oil. MS m/e: (M+H)+ 262.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[S:7][C:8]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[CH:9][CH:10]=1.C1C(=O)N([Br:23])C(=O)C1>CN(C=O)C.C(Cl)Cl>[Br:23][C:13]1[S:12][C:11]([C:8]2[S:7][C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[CH:10][CH:9]=2)=[CH:15][CH:14]=1
Reactant: c1csc(-c2ccc(-c3cccs3)s2)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Brc1ccc(-c2ccc(-c3cccs3)s2)s1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 92 %

Procedure:
Using 2,2′:5′,2″-terthiophene (7, FIG. 3): N-Bromosuccimide (3.147 mg, 17.681 mmol) were added portion in portions during 5 hours to an solution of 2,2′:5′,2″-terthiophene (4.315 g, 17.373 mmol) in 10 ml DMF at −20° C. After about 90 min, a precipitate was formed. After stirring for 14 hours at room temperature, the reaction mixture was dissolved in 300 ml CH2Cl2 and washed twice with 100 ml 1N HCl. The aqueous layers were extracted with CH2Cl2 and the organic layers were dried (MgSO4) and concentrated. Purification by FC (hexanes) gave 5.222 g (56 mmol, 92%) 5-bromo-2,2′:5′,2″-terthiophene, 92%) as yellow solid.