Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[N:3]=[C:4]([CH:12]2[CH:15]([N:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)[CH2:14][CH2:13]2)[N:5]2[CH:10]=[CH:9][N:8]=[C:7]([NH2:11])[C:6]=12.[C:23]1([C:29]2[CH:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[C:36]3[C:31](=[CH:32][C:33](B4OC(C)(C)C(C)(C)O4)=[CH:34][CH:35]=3)[N:30]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:22][N:19]1[CH2:20][CH2:21][N:16]([CH:15]2[CH:12]([C:4]3[N:5]4[CH:10]=[CH:9][N:8]=[C:7]([NH2:11])[C:6]4=[C:2]([C:33]4[CH:32]=[C:31]5[C:36]([C:37]([C:39]([F:42])([F:40])[F:41])=[CH:38][C:29]([C:23]6[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=6)=[N:30]5)=[CH:35][CH:34]=4)[N:3]=3)[CH2:13][CH2:14]2)[CH2:17][CH2:18]1
Reactant: CC1(C)OB(c2ccc3c(C(F)(F)F)cc(-c4ccccc4)nc3c2)OC1(C)C
Reactant: CN1CCN(C2CCC2c2nc(I)c3c(N)nccn23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Product: CN1CCN(C2CCC2c2nc(-c3ccc4c(C(F)(F)F)cc(-c5ccccc5)nc4c3)c3c(N)nccn23)CC1
Temperature: 75 °C
Reaction time: 8 h

Procedure:
1-Iodo-3-[4-(4-methyl-piperazin-1-yl)-cyclobutyl]-imidazo[1,5-a]pyrazin-8-ylamine (120 mg, 0.00029 mole), 2-phenyl-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-4-trifluoromethyl-quinoline (230 mg, 0.00058 mole), cesium carbonate (330 mg, 0.0010 mole), 1,2-dimethoxyethane (6 mL, 0.06 mole) and water (1 mL) were combined in a 25 ml round bottom flask with a magnetic stir bar. The flask was subjected to three vacuum, argon cycles and charged with tetrakis(triphenylphosphine)palladium(0) (35 mg, 0.000030 mole). The flask was subjected to three vacuum, argon cycles again. The reaction was stirred under argon at 75° C. (external temperature) overnight. The product mixture was concentrated in vacuo, then allowed to stand under vacuum for 1 h. The product mixture was then chromatographed on silica gel with methylene chloride, methanol, concentrated ammonium hydroxide (140:10:1). Only the purest fractions were combined and concentration in vacuo, and placement under high vacuum for 30 minutes afforded the title compound as a yellow solid. The solid was re-crystallized from hexanes/ether to afford the title compound as a yellow solid; 1H NMR (CD3OD, 400 MHz) δ 2.14-2.62 (m, 15H), 2.78-2.82(Q, 1H, J=7.9 Hz), 3.62-3.67 (Q, 1H, J=7.9H), 6.32 (bs, 2H), 7.12-7.14 (d, 1H, J=4.8 Hz), 7.58-7.64 (m, 4H), 8.16-8.22 (m, 2H), 8.39-8.42 (m, 3H), 8.48 (s, 1H); 19F NMR (DMSO, 400 MHz) δ-60.15; MS(ES+): 557.98 (10) [MH+]; HPLC TR3.408 min. (100%) (polar—15 min).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[CH2:12][C:13]([OH:15])=[O:14].[C:16]1(C)C=CC=CC=1.CO.C[Si](C=[N+]=[N-])(C)C>CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[CH2:12][C:13]([O:15][CH3:16])=[O:14]
Reactant: O=C(O)Cc1c(Br)cccc1C(F)(F)F
Reactant: Cc1ccccc1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)Cc1c(Br)cccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a mixture of 2-(2-bromo-6-(trifluoromethyl)phenyl)acetic acid (0.306 g, 1.08 mmol) in 4:1 toluene/MeOH (8 mL) was added trimethylsilyldiazomethane (2.0 M in Et2O; 0.80 mL, 1.6 mmol). The resulting mixture was stirred at room temperature for 20 hours before diluting with EtOAc (40 mL) and washing with saturated aqueous NaHCO3 (3×40 mL). The organics were passed through a phase separation cartridge then concentrated under reduced pressure to give the title compound A91 (0.293 g, 91%); 1H NMR (400 MHz, CDCl3) δ 7.80 (d, J=8.3 Hz, 1H), 7.65 (d, J=7.8 Hz, 1H), 7.29 (m, 1H), 4.04 (m, 2H), 3.72 (s, 3H).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[C:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=O.[NH2:30][CH2:31][C:32]([OH:34])=[O:33].C[O-].[Na+]>>[CH2:16]([N:10]1[C:9](=[O:23])[C:8]2[C:7]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[N:6][C:5]([C:3]([NH:30][CH2:31][C:32]([OH:34])=[O:33])=[O:2])=[C:14]([OH:15])[C:13]=2[CH:12]=[CH:11]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NCC(=O)O
Reactant: COC(=O)c1nc(-c2ccccc2)c2c(=O)n(Cc3ccccc3)ccc2c1O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CNC(=O)c1nc(-c2ccccc2)c2c(=O)n(Cc3ccccc3)ccc2c1O
Temperature: 25 °C
Yield: 74.5 %

Procedure:
A mixture of 7-benzyl-4-hydroxy-8-oxo-1-phenyl-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (29 mg, 0.075 mmol), glycine (750 mg, 10 mmol) and NaOMe solution (15 mL, 7.5 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., solvent was evaporated in vacuo. The residue was partitioned between water and EtOAc. 1 M HCl was added with vigorous stirring until pH was about 2. The organic layer was dried over MgSO4 and concentrated. The crude was chromatographed (5-70% EtOAc/hexanes+2% AcOH) to give 24 mg of the title compound as a pale yellow solid. MS: (+) m/z 429.99 (M+1).
Reaction SMILES: [Br:1]CC[C:4]12[CH2:10][CH:7]([CH2:8][CH2:9]1)[CH:6]=[CH:5]2.[CH3:11][N:12]([CH3:14])[CH3:13].O1[CH2:19][CH2:18]CC1>>[Br-:1].[CH:4]12[CH2:10][CH:7]([CH:6]=[CH:5]1)[CH2:8][CH:9]2[CH2:18][CH2:19][N+:12]([CH3:14])([CH3:13])[CH3:11]
Reactant: C1CCOC1
Reactant: CN(C)C
Reactant: BrCCC12C=CC(CC1)C2
Product: C[N+](C)(C)CCC1CC2C=CC1C2
Product: [Br-]
Reaction time: 48 h

Procedure:
An appropriately sized container was charged under nitrogen with tetrahydrofuran (180 g, 202 mL), 2-bromoethyl norbornene (20.11 g, 100 mmol) and a stock solution of trimethylamine (45% aqueous 65.7 g 79.1 ml). The contents were stirred for 48 hours, at which time the solvents were removed under reduced pressure. A portion of drum grade toluene (200 ml, 173 g) was added. The solvents were then removed once again under reduced pressure with the toluene being useful to promote the azeotropic removal of water. The azeotropic removal of water was repeated with toluene (200 ml 173 g) and subsequently with heptane (200 ml, 136 g). The resulting powder was dried under vacuum for 18 hours.
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].C(N(CC)CC)C.C(=O)=O.[N+](C1C=CC([O:28][C:29](=O)[C@@H:30]2[CH2:34][CH2:33][CH2:32][N:31]2[C:35]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:36])=CC=1)([O-])=O.Cl>O1CCOCC1.O>[C:35]([N:31]1[CH2:32][CH2:33][CH2:34][C@H:30]1[C:29]([NH:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4])=[O:28])([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36]
Reactant: CC(C)[C@H](N)C(=O)O
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: Cl
Agent: O=C=O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)[C@H](NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1)C(=O)O
Reaction time: 20 h
Yield: 68.4 %

Procedure:
L-Valine (30 mmol, 3.52 g) and triethylamine (60 mmol, 8.36 mL) were combined in 275 mL of 1:1 dioxane-water. Solid carbon dioxide pieces were added with stirring to achieve pH 8.5, and then N-CBZ-L-proline 4-nitrophenyl ester (Sigma, 30 mmol, 11.11 g) was added to the solution with stirring at room temperature. After 20 hours, the clear yellow solution was acidified by gradual addition of 1N HCl, concentrated by rotary evaporation at reduced pressure, and diluted with ethyl acetate. The organic phase was separated, washed with water (5×) and brine (2×), dried (MgSO4), and rotovapped to give an oil residue. Crystallization of this residue from hot ethyl acetate-hexane afforded 7.15 g (68%) of N-CBZ-L-prolyl-L-valine as a white solid, m.p. 132°-134° C., lit. m.p. 134°-136° C.; G. R. Pettit, "Synthetic Peptides," Vol. 1, 154 (1970).
Reaction SMILES: [CH2:1]([C:8]1[N:12]=[C:11]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])=[C:16]([Br:27])[CH:15]=2)[O:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28]([O:35][C:36]([N:38]1[CH2:42][CH2:41][CH2:40][C@@H:39]1[CH:43]=[CH:44][CH2:45]O)=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:28]([O:35][C:36]([N:38]1[CH2:42][CH2:41][CH2:40][C@@H:39]1[CH:43]=[CH:44][CH2:45][N:20]([C:17]1[CH:18]=[CH:19][C:14]([CH2:13][C:11]2[O:10][N:9]=[C:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[N:12]=2)=[CH:15][C:16]=1[Br:27])[C:21](=[O:26])[C:22]([F:25])([F:23])[F:24])=[O:37])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C(Nc1ccc(Cc2nc(Cc3ccccc3)no2)cc1Br)C(F)(F)F
Reactant: O=C(OCc1ccccc1)N1CCC[C@@H]1C=CCO
Product: O=C(OCc1ccccc1)N1CCC[C@@H]1C=CCN(C(=O)C(F)(F)F)c1ccc(Cc2nc(Cc3ccccc3)no2)cc1Br
Yield: 90 %

Procedure:
4-(3-Benzyl-1,2,4-oxadiazol-5-ylmethyl)-2-bromo-1-trifluoroacetylaminobenzene and (R)-1-(N-benzyloxycarbonylpyrrolidin-2-yl)-3-hydroxypropene were used. Chromatography using elution with 5% either in methylene chloride afforded the title compound (90%) as a thick yellow oil: R1 =0.75 (CHCl3 --CH3OH 20:1); LRMS (m/z, relative intensity) 683 (M+,18).
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.FC(F)(F)C(O)=O.[C:50]1([C:56]2[CH:61]=[C:60]([CH:62]3[CH2:67][CH2:66][NH:65][CH2:64][CH2:63]3)[CH:59]=[CH:58][C:57]=2[NH:68][C:69]([C:71]2[NH:72][CH:73]=[C:74]([C:76]#[N:77])[N:75]=2)=[O:70])[CH2:55][CH2:54][CH2:53][CH2:52][CH:51]=1>C(Cl)Cl>[C:4]([O:3][C:1](=[O:2])[NH:8][CH2:9][C:10]([N:65]1[CH2:66][CH2:67][CH:62]([C:60]2[CH:59]=[CH:58][C:57]([NH:68][C:69]([C:71]3[NH:72][CH:73]=[C:74]([C:76]#[N:77])[N:75]=3)=[O:70])=[C:56]([C:50]3[CH2:55][CH2:54][CH2:53][CH2:52][CH:51]=3)[CH:61]=2)[CH2:63][CH2:64]1)=[O:12])([CH3:5])([CH3:6])[CH3:7]
Reactant: N#Cc1c[nH]c(C(=O)Nc2ccc(C3CCNCC3)cc2C2=CCCCC2)n1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(=O)N1CCC(c2ccc(NC(=O)c3nc(C#N)c[nH]3)c(C3=CCCCC3)c2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 47.2 %

Procedure:
A solution of N-BOC-glycine (0.29 g, 1.63 mmol) in CH2Cl2 (10 mL) was treated with DIEA (0.85 mL, 4.90 mmol), HOBt (0.26 g, 1.96 mmol), and EDCI (0.38 g, 1.96 mmol). The mixture was stirred at room temperature for 10 min and added to a suspension of 4-cyano-1H-imidazole-2-carboxylic acid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide trifluoroacetic acid salt (as prepared in Example 14, step (b), 0.80 g, 1.63 mmol) in CH2Cl2 (20 mL). The solution was stirred at room temperature for 17 h. Solvents were evaporated in vacuo. Silica gel chromatography (50% EtOAc in hexanes) afforded the title compound (0.41 g, 47%) as a white solid. 1H-NMR (CDCl3; 400 MHz): δ 9.53 (s, 1H), 8.26 (d, 1H, J=8.4 Hz), 7.80-7.78 (m, 1H), 7.71 (s, 1H), 7.45-7.43 (m, 1H), 7.06 (d, 1H, J=8.4 Hz), 7.00 (s, 1H), 5.83 (br s, 1H), 5.76 (br s, 1H), 4.78-4.68 (m, 1H), 3.96-3.85 (m, 2H), 3.17-3.03 (m, 1H), 2.78-2.63 (m, 2H), 2.29 (br s, 2H), 2.22 (br s, 2H), 1.95-1.87 (m, 2H), 1.86-1.72 (m, 4H), 1.70-1.55 (m, 2H), 1.44 (s, 9H). LC-MS (ESI, m/z): Calcd. for C29H36N6O4 533.3 (M+H), found 532.9.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:17]=[C:16]([CH3:18])[C:15]([S:19]([N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][C@H:23]2[CH2:28][O:29][CH2:30][C:31]([OH:33])=O)(=[O:21])=[O:20])=[C:14]([CH3:34])[CH:13]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[N:58]1[CH:63]=[CH:62][CH:61]=[C:60]([C:64]2([O:71][CH2:72][CH2:73][N:74]3[CH2:78][CH2:77][CH2:76][CH2:75]3)[CH2:70][CH2:69][CH2:68][NH:67][CH2:66][CH2:65]2)[CH:59]=1>C(Cl)Cl>[CH3:10][O:11][C:12]1[CH:17]=[C:16]([CH3:18])[C:15]([S:19]([N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][C@H:23]2[CH2:28][O:29][CH2:30][C:31]([N:67]2[CH2:68][CH2:69][CH2:70][C:64]([C:60]3[CH:59]=[N:58][CH:63]=[CH:62][CH:61]=3)([O:71][CH2:72][CH2:73][N:74]3[CH2:78][CH2:77][CH2:76][CH2:75]3)[CH2:65][CH2:66]2)=[O:33])(=[O:21])=[O:20])=[C:14]([CH3:34])[CH:13]=1
Reactant: c1cncc(C2(OCCN3CCCC3)CCCNCC2)c1
Reactant: COc1cc(C)c(S(=O)(=O)N2CCCC[C@H]2COCC(=O)O)c(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C)c(S(=O)(=O)N2CCCC[C@H]2COCC(=O)N2CCCC(OCCN3CCCC3)(c3cccnc3)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 46 %

Procedure:
DIPEA (2.5 eq.) was added to a cooled solution (0° C.) of (S)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)acetic acid [acid D] in methylene chloride (5 ml/mmol), followed by HOBt (1 eq.) and EDCl (1.5 eq.). The reaction mixture was stirred at room temperature for 10 min and cooled to 0° C. and 4-(pyridin-3-yl)-4-(2-(pyrrolidin-1-yl)ethoxy)azepan hydrochloride [amine K] (1.2 eq.) was added. The reaction mixture was then stirred at room temperature for 16 h. In this time, the educts reacted completely (TLC control). The reaction mixture was diluted with methylene chloride (20 ml) and washed with saturated ammonium chloride solution, saturated sodium chloride solution, saturated sodium bicarbonate solution and finally with sat. sodium chloride solution again. The organic phase was dried over sodium sulfate and concentrated to dryness on a rotary evaporator. The crude product was purified by means of column chromatography (silica gel, 2% methanol in methylene chloride). Yield: 46%. MS, Rt=2.8 min, m/z=643.4 [MH]+
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:5]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][N:19]=3)=[O:17])[CH2:12][CH2:11]2)=[N:6][CH:7]=[CH:8][CH:9]=1)[CH3:2].[CH:27]1([NH2:32])[CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH:27]1([NH:32][C:22]([C:21]2[CH:25]=[CH:26][C:18]([C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:5]4[C:4]([NH:3][CH2:1][CH3:2])=[CH:9][CH:8]=[CH:7][N:6]=4)[CH2:11][CH2:12]3)=[O:17])=[N:19][CH:20]=2)=[O:24])[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: NC1CCCC1
Reactant: CCNc1cccnc1N1CCN(C(=O)c2ccc(C(=O)O)cn2)CC1
Product: CCNc1cccnc1N1CCN(C(=O)c2ccc(C(=O)NC3CCCC3)cn2)CC1
Yield: 76 %

Procedure:
By the same procedure as described in the example 24, the synthesis was carried out starting with 6-[1-[3-(ethylamino)-2-pyridyl]piperazin-4-yl-carbonyl]nicotinic acid and using cyclopentylamine. And then, the product was recrystallized with isopropanol and ether to give a desired compound.
Reaction SMILES: [CH2:1]([N:3]([CH2:30][CH2:31]O)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]([CH3:29])[S:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:11][CH2:10]1)[CH3:2].CCN(S(F)(F)[F:39])CC.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([N:3]([CH2:30][CH2:31][F:39])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]([CH3:29])[S:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:11][CH2:10]1)[CH3:2]
Reactant: CCN(CCO)CCCCC[C@H]1CC[C@H](N(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCN(CCF)CCCCC[C@H]1CC[C@H](N(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C

Procedure:
To 500 mg (10.5 mmol) trans-N-(4-{5-[Ethyl-(2-hydroxy-ethyl)-amino]-pentyl}-cyclohexyl)-N-methyl-4-trifluoromethyl-benzenesulfonamide in 6 ml CH2Cl2 were added 0.2 ml (1.6 mmol) DAST at −78° C. After 3.5 h at that temperature additional 0.2 ml (1.6 mmol) DAST were added and the mixture was slowly warmed to RT over night. The solution was added to a cooled aqueous solution of Na2CO3 and extracted with EtOAc. The organic phase was washed with brine and dried over Na2SO4. Column chromatography CH2Cl2/MeOH 98:2 yielded 125.4 mg (25%) trans-N-(4-{5-[Ethyl-(2-fluoro-ethyl)-amino]-pentyl}-cyclohexyl)-N-methyl-4-trifluoromethyl-benzenesulfonamide as brown oil, MS: 481 (MH+).
Reaction SMILES: Cl.O1CCOCC1.C(O[C:13](=O)[N:14]([CH2:16][CH2:17][O:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[C:26]([N:28]1[CH2:42][C:31]2=[C:32]3[N:37]([N:38]=[C:30]2[CH2:29]1)[C:36]([CH3:39])=[C:35]([Cl:40])[C:34]([CH3:41])=[N:33]3)=[O:27])C)(C)(C)C>C(Cl)Cl.CC(OC)(C)C>[ClH:40].[Cl:40][C:35]1[C:34]([CH3:41])=[N:33][C:32]2[N:37]([N:38]=[C:30]3[CH2:29][N:28]([C:26]([C:20]4[CH:21]=[CH:22][C:23]([F:25])=[CH:24][C:19]=4[O:18][CH2:17][CH2:16][NH:14][CH3:13])=[O:27])[CH2:42][C:31]3=2)[C:36]=1[CH3:39]
Reactant: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccc(F)cc1OCCN(C)C(=O)OC(C)(C)C)C3
Agent: Cl
Solvent: ClCCl
Solvent: COC(C)(C)C
Solvent: C1COCCO1
Product: CNCCOc1cc(F)ccc1C(=O)N1Cc2nn3c(C)c(Cl)c(C)nc3c2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 139 %

Procedure:
A 4M solution of HCl in 1,4-dioxane (0.72 mL; 2.9 mmol; 15 eq.) was added to a solution of {2-[2-(6-chloro-5,7-dimethyl-1H,3H-2,4,7a,8-tetraaza-cyclopenta[a]indene-2-carbonyl)-5-fluoro-phenoxy]-ethyl}-methyl-carbamic acid tert-butyl ester (100 mg; 0.19 mmol; 1 eq.) in DCM (5 mL) and the reaction mixture was stirred at room temperature for 2 hours. The residue was suspended in hot MTBE, filtered and dried to afford the title compound (60 mg, 68%) as a pale yellow solid. 1H NMR (DMSO-d6) δ 8.92-8.69 (m, 2H), 7.50-7.38 (m, 1H), 7.24-7.13 (m, 1H), 7.00-6.90 (td, J=8.5, 8.0, 2.2 Hz, 1H), 4.89-4.77 (d, J=8.6 Hz, 2H), 4.65-4.51 (m, 2H), 4.41-4.32 (m, 2H), 3.27 (br s, 2H), 2.85 (s, 1.7H), 2.81 (s, 1.3H), 2.62 (s, 1.3H), 2.57 (s, 1.7H), 2.53 (s, 3H). HPLC (max plot) 97.0%, Rt 2.73 min. UPLC/MS: (MS+) 418.3 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[Cl-].[Al+3].[Cl-].[Cl-].[Cl:19][CH2:20][CH2:21][CH2:22][C:23](Cl)=[O:24]>C(Cl)Cl>[Cl:19][CH2:20][CH2:21][CH2:22][C:23]([C:7]1[CH:8]=[CH:9][C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:12]([O:13][CH3:14])[CH:11]=2)[CH:6]=1)=[O:24]
Reactant: O=C(Cl)CCCCl
Reactant: COc1cc2ccccc2cc1OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1cc2ccc(C(=O)CCCCl)cc2cc1OC

Procedure:
This product was prepared from 2,3-dimethoxynaphthalene (3.76 g), aluminium chloride (2.93 g) and 4-chlorobutanoylchloride (2.96 g) in methylene chloride (100 ml) as described in example 9(a) above.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH2:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20])=[O:12].[CH3:21][O:22][C:23](=[O:33])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30](O)=[O:31].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.C(OCC)(=O)C>[CH3:21][O:22][C:23](=[O:33])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30](=[O:31])[NH:9][CH2:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20])=[O:12]
Reactant: COc1ccccc1C(=O)CN
Reactant: COC(=O)CCCCCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CCCCCCC(=O)NCC(=O)c1ccccc1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.5 %

Procedure:
Add triethylamine (8.1 g, 79.9 mmol) dropwise to a solution of 2-amino-1-(2-methoxyphenyl)ethanone hydrochloride (13.6 g, 67.4 mmol) and octanedioic acid monomethyl ester (14.0 g, 74.2 mmol) in methylene chloride (600 mL) at 0° C. under nitrogen, and then add EDC HCl (15.5 g, 81.0 mmol). Stir the mixture for 4 hours and warm to room temperature with stirring for an additional 18 hours. Dilute the mixture in ethyl acetate (1.2 L), wash sequentially with water (300 mL), 1 N HCl (300 mL), brine (300 mL), saturated sodium, bicarbonate solution (300 mL) and brine (300 mL), and dry over sodium sulfate. Remove the solvent under reduced pressure to afford 7-[2-(2-methoxyphenyl)-2-oxoethylcarbamoyl]heptanoic acid methyl ester (20.0 g, 88%), which is used in the next step without further purification.
Reaction SMILES: [OH:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[C:3]([OH:5])=[O:4].[CH2:12](O)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>S(=O)(=O)(O)O>[OH:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[C:3]([O:5][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:4]
Reactant: CCCCCCCCCCO
Reactant: CCCCCCC(O)C(=O)O
Agent: O=S(=O)(O)O
Product: CCCCCCCCCCOC(=O)C(O)CCCCCC
Yield: 77.2 %

Procedure:
A 250 ml one neck round bottom flask equipped with a Dean Stark trap, condenser and nitrogen inlet/outlet was charged with 20.0 g (0.125 moles) 2-hydroxyoctanoic acid, 79.0 g (0.499 moles) decyl alcohol, and 0.062 g sulfuric acid. The mixture was heated to 140° for 8 hours and water was collected as the reaction proceeded. The acid was neutralized by washing three times with 50 ml saturated sodium bicarbonate solution. Approximately 50 ml ether was needed to break the emulsion. The organic layer was collected and dried over magnesium sulfate. Excess decyl alcohol was removed by high vacuum distillation to yield 28.99 g (77.3% yield) of clear pale yellow liquid. According to GC the product is 99.6% pure.
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])[C:2](OCC)=O.[Cl:11][C:12]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:13]=1[CH:14]=[C:15]([C:23]([NH2:25])=[O:24])[C:16]([NH2:22])=[N:17]2>CCCCCC>[Cl:11][C:12]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:13]=1[CH:14]=[C:15]1[C:23](=[O:24])[NH:25][C:2]([C:1]([O:8][CH2:9][CH3:10])=[O:7])=[N:22][C:16]1=[N:17]2
Reactant: CCOC(=O)C(=O)OCC
Reactant: NC(=O)c1cc2c(Cl)cccc2nc1N
Solvent: CCCCCC
Product: CCOC(=O)c1nc2nc3cccc(Cl)c3cc2c(=O)[nH]1

Procedure:
Diethyl oxalate (350 ml.) and 5-chloro-2-aminoquinoline-3-carboxamide (5.9 g., 0.0267 mole) are heated together at 170° C. for 4 hours. By-product water and ethanol are distilled from the reaction mixture. The dark reaction mixture is cooled, treated with hexane (300 ml.) and filtered. The brown solid is dissolved in methylene chloride:ethanol (1:1), decolorized with charcoal and concentrated to give a tan solid. The solid is recrystallized from methylene chloride-hexane. It is purified further by chromatography on silica gel using methylene chloride:ethanol (9:1) as eluant. The product, recovered by evaporation of the eluate, is recrystallized from methylene chloride-ethanol. Yield = 0.756 g. (9.3%). M.P. 278°-279° C. (dec.).
Reaction SMILES: [CH3:1][CH2:2][CH:3]([OH:10])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].C(N(CC)CC)C.[S:18](Cl)([CH3:21])(=[O:20])=[O:19]>ClCCl>[CH3:21][S:18]([O:10][CH:3]([CH2:2][CH3:1])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])(=[O:20])=[O:19]
Reactant: CCCCCCC(O)CC
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCC(CC)OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
20 g (138.6 mmol) of 3-nonanol and 15.43 g of triethylamine are dissolved in 150 ml of dichloromethane and admixed dropwise with 17.47 g (152.5 mmol) of mesyl chloride. The mixture is stirred at room temperature for 4 hours. The organic phase is extracted twice with water and dried over sodium sulphate and the solvent is removed under reduced pressure. This gives 30.7 g (95%) of a yellow liquid.