Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:31](Cl)=[CH:30][C:29]2[C:4](=[N:5][C:6]3[C:7]4[C:16]([C:17]5[C:26]([C:27]=3[N:28]=2)=[N:25][C:24]2[C:19](=[CH:20][C:21](Cl)=[C:22](Cl)[CH:23]=2)[N:18]=5)=[N:15][C:14]2[C:9](=[CH:10][C:11](Cl)=[C:12](Cl)[CH:13]=2)[N:8]=4)[CH:3]=1.[CH2:37]([SH:47])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:37]([S:47][C:2]1[C:31]([S:47][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])=[CH:30][C:29]2[C:4](=[N:5][C:6]3[C:7]4[C:16]([C:17]5[C:26]([C:27]=3[N:28]=2)=[N:25][C:24]2[C:19](=[CH:20][C:21]([S:47][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])=[C:22]([S:47][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH:23]=2)[N:18]=5)=[N:15][C:14]2[C:9](=[CH:10][C:11]([S:47][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])=[C:12]([S:47][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH:13]=2)[N:8]=4)[CH:3]=1)[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46]
Reactant: Clc1cc2nc3c4nc5cc(Cl)c(Cl)cc5nc4c4nc5cc(Cl)c(Cl)cc5nc4c3nc2cc1Cl
Reactant: CCCCCCCCCCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCSc1cc2nc3c4nc5cc(SCCCCCCCCCC)c(SCCCCCCCCCC)cc5nc4c4nc5cc(SCCCCCCCCCC)c(SCCCCCCCCCC)cc5nc4c3nc2cc1SCCCCCCCCCC
Temperature: 80 °C
Reaction time: 72 h
Yield: 55.5 %

Procedure:
A mixture of 2,3,8,9,14,15-hexachloro-5,6,11,12,17,18-hexaazatrinaphthylene (3.00 g, 5.08 mmol), 1-decanethiol (13.74 mL, 66.75 mmol) and K2CO3 (25.55 g, 185.00 mmol) in DMF (250 mL) was stirred at 80° C. for 72 hrs under nitrogen. After cooled down to room temperature, solvent was removed in vacuo. To the solid residue, water and dichloromethane was added. The organic layer was separated and the aqueous layer was extracted with dichloromethane (100 mL) twice. The combined organic layer was dried over magnesium sulfate and filtered. Solvent was evaporated under reduced pressure to give a yellow solid. The yellow solid was purified by flash chromatography on silica gel eluting with hexane:dichloromethane (1:1) to give a solid (4.00 g, 56% yield). The yellow product was washed with hot acetone in a Soxhlet extractor for 12 hrs before sending for elemental analysis. 1H (300 MHz, CD2Cl2) δ 7.49 (s, 6H), 2.81 (t, J=6.8 Hz, 12H), 1.55 (p, J=6.6 Hz, 12H), 1.50-1.25 (m, 84H), 0.93 (t, J=6.3 Hz, 18H). 13C NMR (75 MHz, CD2Cl2): 143.36, 141.84, 140.42, 122.26, 33.22, 32.36, 30.14, 30.07, 29.91, 29.82, 28.24, 23.13, 14.32. HRMS MALDI-TOF (with CHCA as matrix), 1417.8975; calcd. For C84H133N6S6 (M+H), 1417.8911. Anal. Calcd. For C84H132N6S6: C, 71.13; H, 9.38; N, 5.93. Found: C, 70.92; H, 9.38; N, 5.90.
Reaction SMILES: [C:1]1([Li])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:8]1([O:13][C:14]2[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=2[O:22][CH3:23])[CH:17]=[O:18])[CH2:12][CH2:11][CH2:10][CH2:9]1>O1CCCC1>[C:1]1([CH:17]([OH:18])[C:16]2[CH:19]=[CH:20][C:21]([O:22][CH3:23])=[C:14]([O:13][CH:8]3[CH2:9][CH2:10][CH2:11][CH2:12]3)[CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Reactant: [Li]c1ccccc1
Solvent: C1CCOC1
Product: COc1ccc(C(O)c2ccccc2)cc1OC1CCCC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 91.9 %

Procedure:
Phenyllithium (1.8M solution in cyclohexane/diethyl ether, 25.5 milliliters, 46 mmol) was added dropwise over 15 minutes to a stirred solution of 3-cyclopentyloxy-4-methoxybenz-aldehyde (6 grams, 27 mmol) in dry tetrahydrofuran (20 milliliters) at -78° C. The resulting solution was stirred at -78° C. for 30 minutes and quenched at -78° C. by the rapid addition of aqueous saturated NH4Cl (70 milliliters). After warming to room temperature, water was added to dissolve the solids and volatiles were removed in vacuo. The residue was partitioned between water (250 milliliters) and ethyl acetate (250 milliliters), the aqueous phase was extracted with ethyl acetate (3×250 milliliters) and the combined organic layers washed with water (200 milliliters). The organics were dried over Na2SO4 and concentrated in vacuo to give a light yellow oil. The oil was purified by flash chromatography (SiO2 :hexane/ethyl acetate (4:1)) to afford the title compound as a pale yellow oil (7.4 grams).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][C:6]([NH2:12])=[CH:7][CH:8]=2)[N:3]=1.[CH3:13][O-:14].[Na+]>CO>[CH3:13][O:14][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][C:6]([NH2:12])=[CH:7][CH:8]=2)[N:3]=1
Reactant: Nc1ccc2ccc(Cl)nc2n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc2ccc(N)nc2n1

Procedure:
A mixture of 2-chloro-7-amino-1,8-napthyridine (Newkome, G. R. et al, J. Org. Chem., 1981, 46, 833-39) (180 mg, 1 mmol) and a methanolic solution of sodium methoxide (458 μL, 25 wt. %) in methyl alcohol (2 mL) was heated at 50° C. for 19 hours. The reaction mixture was allowed to cool, filtered through Celite using dichloromethane, concentrated in vacuo and the residue purified on Silica gel (1:9:0.2 methyl alcohol/dichloromethane/ammonium hydroxide) to afford 2-methoxy-7-amino1,8-naphthyridine as a pale yellow solid.
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:13][O:14][C:15](=[O:24])[C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[C:18]([Cl:23])[CH:17]=1.CCN(CC)CC>C(Cl)Cl>[CH3:13][O:14][C:15](=[O:24])[C:16]1[CH:21]=[CH:20][C:19]([N:22]=[C:2]=[O:4])=[C:18]([Cl:23])[CH:17]=1
Reactant: COC(=O)c1ccc(N)c(Cl)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(N=C=O)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 260 %

Procedure:
To an ice cold solution of triphosgene (59 mg, 200 μmol) in CH2Cl2 (1.5 ml) was added 4-amino-3-chloro-benzoic acid methyl ester (100 mg, 540 μmol; [84228-44-4]) and a solution of Et3N (150 μl, 1.1 mmol) in CH2Cl2 (0.5 ml) under an argon atmosphere. The reaction mixture was stirred at ambient temperature for 30 min. The solvent was removed under reduced pressure. The residue was triturated with EtOAc, the solid was filtered off and the filtrate was evaporated to dryness under reduced pressure to give the title compound (111 mg, 520 μmol; 97%) as brown solid which was used in the next step without further purification. MS: m/e=228.9 [M+H+].
Reaction SMILES: [F:1][C:2]1([F:18])[CH2:6][CH2:5][C@@H:4]([C@@:7]([OH:17])([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([OH:10])=[O:9])[CH2:3]1.O[CH2:20][C@@H:21]1[CH2:26][CH2:25][NH:24][C:23](=[S:27])[NH:22]1>>[F:1][C:2]1([F:18])[CH2:6][CH2:5][C@@H:4]([C@@:7]([OH:17])([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:8]([O:10][CH2:20][C@@H:21]2[CH2:26][CH2:25][NH:24][C:23](=[S:27])[NH:22]2)=[O:9])[CH2:3]1
Reactant: O=C(O)[C@](O)(c1ccccc1)[C@@H]1CCC(F)(F)C1
Reactant: OC[C@@H]1CCNC(=S)N1
Product: O=C(OC[C@@H]1CCNC(=S)N1)[C@](O)(c1ccccc1)[C@@H]1CCC(F)(F)C1

Procedure:
Using (2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylacetic acid and (4S)-4-(hydroxymethyl)tetrahydropyrimidine-2(1H)-thione, the title compound was prepared by a method similar to Step 2 of Referential Example 12.
Reaction SMILES: Cl[CH2:2][C:3]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:11](=[O:20])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH3:21])[N:4]=1.[N:22]1[C:30]([NH2:31])=[C:29]2[C:25]([N:26]=[CH:27][NH:28]2)=[N:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:31][C:30]1[N:22]=[CH:23][N:24]=[C:25]2[C:29]=1[N:28]=[CH:27][N:26]2[CH2:2][C:3]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:11](=[O:20])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH3:21])[N:4]=1
Reactant: Nc1ncnc2nc[nH]c12
Reactant: Cc1cccc2nc(CCl)n(-c3ccccc3Cl)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc2nc(Cn3cnc4c(N)ncnc43)n(-c3ccccc3Cl)c(=O)c12
Yield: 28.4 %

Procedure:
Prepared according to Procedure C using Intermediate 2g (250 mg, 0.783 mmol), adenine (116 mg, 0.862 mmol), K2CO3 (119 mg, 0.862 mmol), and DMF (4 mL). The crude product was recrystallized from EtOH to provide 93 mg of a pale yellow solid (28%), mp 190.7-190.9° C. 1H NMR (DMSO-d6) δ: 8.05 (s, 1H); 8.03 (s, 1H); 7.76-7.79 (m, 1H); 7.71-7.74 (m, 1H); 7.59-7.67 (m, 1H); 7.34 (d, J=7.4 Hz, 1H); 7.28 (d, J=8.2 Hz, 1H); 7.24 (br s, 2H); 5.07 (d, J=17 Hz, 1H); 4.92 (d, J=17 Hz, 1H); 2.73 (s, 3H). 13C NMR (DMSO-d6) ppm: 161.1, 156.2, 152.8, 150.9, 150.1, 148.3, 141.9, 141.0, 134.6, 133.6, 132.2, 131.9, 131.3, 130.8, 130.3, 129.3, 125.9, 119.1, 118.4, 44.8, 22.8. MS (ES): m/z 418.1 (M+). Anal. calcd. for C21H16ClN7O.H2O: C, 57.87; H, 4.16; Cl, 8.13; N, 22.49. Found: C, 57.78; H, 3.99; Cl, 8.38; N, 22.32.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[N:44]6[C:45]([CH3:49])=[CH:46][CH:47]=[CH:48][C:43]6=[N:42][CH:41]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:50]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:59])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[N:44]6[C:45]([CH3:49])=[CH:46][CH:47]=[CH:48][C:43]6=[N:42][CH:41]=5)=[O:59])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:50]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4cnc5cccc(C)n45)cc2)CCN3CC(C)C)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4cnc5cccc(C)n45)cc2)CCN3CC(C)C)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 88.7 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(5-methylimidazo[1,2-a]pyridin-3-yl)methyl]thio]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (1.157 g) in dichloromethane (10 ml) was added 3-chloroperbenzoic acid (70%, 0.50 g) in dichloromethane (10 ml) at −78° C. The mixture was stirred for 1 hour at −78° C., an aqueous solution of sodium thiosulfate was added to the mixture, and the mixture was stirred at room temperature for 10 minutes. The mixture was extracted with ethyl acetate, and the organic layer was washed with sodium bicarbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (basic silica gel, ethyl acetate:hexane 3:1→ethyl acetate), to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(5-methylimidazo[1,2-a]pyridin-3-yl)methyl]sulfinyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 407) (1.05 g) as yellow amorphous.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:4][C:3]=1[F:15]>CC(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:4][C:3]=1[F:15]
Reactant: O=C(O)CC/C=C/c1ccc(Br)c(F)c1
Solvent: CC(C)O
Product: O=C(O)CCCCc1ccc(Br)c(F)c1
Reaction time: 3 h
Yield: 95 %

Procedure:
To a solution of (E)-5-(4-bromo-3-fluorophenyl)pent-4-enoic acid from step L1 (420 mg, 1.54 mmol) in 2-propanol (5 mL), was added sulfide platinum 5 weight % on carbon (100 mg, 0.513 mmol). The mixture was stirred under a hydrogen filled balloon for 3 h. The solid was filtered off. The filtrate concentrated in vacuo to afford 5-(4-bromo-3-fluorophenyl)pentanoic acid (400 mg, 1.45 mmol, 95% yield). 1H NMR (500 HMz, chloroform-d) δ 7.45 (dd, J=8.0, 7.4 Hz, 1H), 6.96 (dd, J=9.7, 1.9 Hz, 1H), 6.86 (dd, J=8.1, 1.5 Hz, 1H), 2.66-2.60 (m, 2H), 2.43-2.38 (m, 2H), 1.72-1.64 (m, 4H).
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=O)(=[O:4])=[O:3].[NH2:15][C@@H:16]1[CH2:25][CH2:24][C:23]2[C:18](=[C:19]([N:26]3[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]3)[CH:20]=[CH:21][CH:22]=2)[CH2:17]1.C(N(CC)CC)C>S(Cl)(Cl)=O.C(Cl)Cl>[CH3:32][N:29]1[CH2:30][CH2:31][N:26]([C:19]2[CH:20]=[CH:21][CH:22]=[C:23]3[C:18]=2[CH2:17][C@H:16]([NH:15][C:9](=[O:11])[C:8]2[CH:12]=[CH:13][CH:14]=[C:6]([O:5][S:2]([CH3:1])(=[O:3])=[O:4])[CH:7]=2)[CH2:25][CH2:24]3)[CH2:27][CH2:28]1
Reactant: CS(=O)(=O)Oc1cccc(C(=O)O)c1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)c2cccc(OS(C)(=O)=O)c2)CC3)CC1
Temperature: 40 °C
Reaction time: 0.25 h

Procedure:
A suspension of 3-methanesulfonyloxybenzoic acid (0.20 g, 0.90 mmol; described in: Looker, J. H.; Hayes, C. H.; Thatcher, D. N. J. Am. Chem. Soc. 1957, 79, 741-4) in thionyl chloride (5 mL) was heated at 40° C. for 45 min (the solution became homogeneous). The excess of thionyl chloride was evaporated in vacuo, the residue was treated with toluene and again the solvent was removed in vacuo. Crude acid chloride (120 mg, 0.50 mmol) was dissolved in methylene chloride (5 mL) and added dropwise to an ice-cooled solution of (R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (120 mg, 0.48 mmol) and triethylamine (100 μL, 0.72 mmol) in methylene chloride (20 mL). After the addition, the reaction was allowed to stir at ambient temperature for 15 min and was then washed with dilute aqueous sodium hydrogen carbonate. The phases were separated and the organic phase was dried (Na2SO4), filtered and evaporated in vacuo to give a crude product which was purified on a silica gel column using chloroform/ethanol saturated with NH3 (100:4) as the eluent. Yield: 87 mg (41%) of the title compound as white crystals: mp 159-160° C.; [α]21D -27° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 443 (21, M+).
Reaction SMILES: C([C@@H]1COC(=O)N1[C:14](=[O:34])[C@H:15]([O:24][C:25]1[CH:30]=[CH:29][C:28]([CH:31]([CH3:33])[CH3:32])=[CH:27][CH:26]=1)[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)C1C=CC=CC=1.[OH-:35].[Li+].OO>>[OH:23][C:20]1[CH:19]=[CH:18][C:17]([CH2:16][C@@H:15]([O:24][C:25]2[CH:26]=[CH:27][C:28]([CH:31]([CH3:32])[CH3:33])=[CH:29][CH:30]=2)[C:14]([OH:34])=[O:35])=[CH:22][CH:21]=1
Reactant: [OH-]
Reactant: CC(C)c1ccc(O[C@H](Cc2ccc(O)cc2)C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)cc1
Agent: OO
Agent: [Li+]
Product: CC(C)c1ccc(O[C@H](Cc2ccc(O)cc2)C(=O)O)cc1

Procedure:
In a similar manner to that described in Reference example 29(e), a reaction was carried out using (R)-4-benzyl-3-[(R)-3-(4-hydroxyphenyl)-2-(4-isopropylphenoxy)propionyl]oxazolidine-2-one (3.78 g), which is the product of Reference example 30(d), aqueous lithium hydroxide solution (1N, 20.6 ml) and aqueous hydrogen peroxide solution (31%, 2.26 ml) and the reaction mixture was treated to afford (R)-3-(4-hydroxyphenyl)-2-(4-isopropylphenoxy)propionic acid (2.18 g) as a white powder. This acid (1.95 g) was reacted with oxalyl chloride (2.73 ml) and 2-trimethylsilylethanol (4.66 ml) and the reaction mixture was treated in a similar manner to that described Reference example 29(e) to afford the desired compound (2.26 g) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:20])[C:10]([C:15]1[CH:19]=CN[N:16]=1)=[CH:11][N:12]([CH3:14])[CH3:13].ClC1C=C(Cl)C=CC=1C(=O)[CH2:30][C:31]1[N:32]=C(C)NC=1>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:20])[C:10]([C:15]1[N:16]=[C:31]([CH3:30])[NH:32][CH:19]=1)=[CH:11][N:12]([CH3:13])[CH3:14]
Reactant: Cc1nc(CC(=O)c2ccc(Cl)cc2Cl)c[nH]1
Reactant: CN(C)C=C(C(=O)c1ccc(Cl)cc1Cl)c1cc[nH]n1
Product: Cc1nc(C(=CN(C)C)C(=O)c2ccc(Cl)cc2Cl)c[nH]1

Procedure:
Made using the same procedure as for 1-(2,4-dichlorophenyl)-3-(dimethylamino)-2-pyrazolylprop-2-en-1-one except that 1-(2,4-dichlorophenyl)-2-(2-methylimidazolyl)ethan-1-one (VI, 1.0 g, 3.7 mmol) was used. The crude residue was used without purification.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[N:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:10]=[C:11]3[C:16]=2[CH2:15][CH2:14][CH2:13][CH2:12]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:23]1([N:29]=[C:30]=[O:31])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[CH:1]1([N:7]([C:8]2[N:9]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:10]=[C:11]3[C:16]=2[CH2:15][CH2:14][CH2:13][CH2:12]3)[C:30]([NH:29][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:31])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C=NC1CCCCC1
Reactant: c1ccc(-n2nc3c(c2NC2CCCCC2)CCCC3)cc1
Product: O=C(NC1CCCCC1)N(c1c2c(nn1-c1ccccc1)CCCC2)C1CCCCC1

Procedure:
In analogy to the procedure described in example 1.2, cyclohexyl-(2-phenyl-4,5,6,7-tetrahydro-2H-indazol-3-yl)-amine (example 45) was reacted with cyclohexylisocyanate ([3173-53-3]) to give the title compound as colorless oil. MS: m/e=421.3 [M+H+].
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]([C:9]2[C:10]3[S:21][CH:20]=[CH:19][C:11]=3[N:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:14]=2)=[O:8])=[CH:4][CH:3]=1.C[O-].[Na+].[O:25]1CCOC[CH2:26]1.O>CO>[CH3:26][O:25][C:2]1[S:6][C:5]([C:7]([C:9]2[C:10]3[S:21][CH:20]=[CH:19][C:11]=3[N:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:14]=2)=[O:8])=[CH:4][CH:3]=1
Reactant: C1COCCO1
Reactant: O=C(c1ccc(Br)s1)c1nc(C(F)(F)F)nc2ccsc12
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc(C(=O)c2nc(C(F)(F)F)nc3ccsc23)s1
Yield: 71 %

Procedure:
A suspension of 5-bromo-2-thienyl 2-trifluoromethylthieno[3,2-d]pyrimidin-4-ylmethanone (0.2 g, 0.51 mmol) in MeOH (15 mL) was treated with sodium methoxide (0.11 g, 2.04 mmol), refluxed for 1 h, treated with dioxane (0.1 mL) to aid dissolution, refluxed for 18 h, cooled, treated with water (15 mL) and concentrated in vacuo. The resulting aqueous mixture was extracted with EtOAc (2×25 mL), the combined extracts washed with brine (25 mL), dried (MgSO4), concentrated in vacuo and the resulting red oil dissolved in heptane-EtOAc (50:50), filtered through a pad of SiO2, concentrated in vacuo and the resulting solid recrystallised [heptane-EtOAc (19:1)] to give the title compound (0.124 g, 71%) as a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[O:13]([CH2:20][C:21]([NH:23][C:24]1[C:25]2[N:26]=[CH:27][N:28]([C:37]=2[N:38]=[CH:39][N:40]=1)[C@@H:29]1[O:36][C@H:33]([CH2:34][OH:35])[C@@H:31]([OH:32])[CH2:30]1)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([O:35][CH2:34][C@H:33]2[O:36][C@@H:29]([N:28]3[C:37]4[N:38]=[CH:39][N:40]=[C:24]([NH:23][C:21](=[O:22])[CH2:20][O:13][C:14]5[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=5)[C:25]=4[N:26]=[CH:27]3)[CH2:30][C@@H:31]2[OH:32])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(COc1ccccc1)Nc1ncnc2c1ncn2[C@H]1C[C@H](O)[C@@H](CO)O1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: O=C(COc1ccccc1)Nc1ncnc2c1ncn2[C@H]1C[C@H](O)[C@@H](COC(=O)c2ccc([N+](=O)[O-])cc2)O1

Procedure:
The synthesis of this product is carried out by reacting 1.1 eq of p-nitrobenzoyl chloride with 6-N-phenoxyacetyldeoxyadenosine for 4 hours in pyridine. After hydrolysis of the excess reagent, almost complete evaporation of the pyridine, and ethyl acetate/sodium bicarbonate extraction, the ethyl acetate phase is evaporated to dryness. The product is obtained by column chromatography with a gradient of methanol in chloroform (elution 4% methanol).
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]=[C:17]([CH2:22][N:23]2[CH2:26][CH:25]([C:27]([OH:29])=[O:28])[CH2:24]2)[CH:16]=[C:15]3[C:30]([F:33])([F:32])[F:31])[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[C:34](O)(C(F)(F)F)=O>>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]=[C:17]([CH2:22][N:23]2[CH2:34][CH2:24][CH:25]([C:27]([OH:29])=[O:28])[CH2:26]2)[CH:16]=[C:15]3[C:30]([F:33])([F:32])[F:31])[CH2:7][CH2:6]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3nc(CN4CC(C(=O)O)C4)cc(C(F)(F)F)c3c2)CC1
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3nc(CN4CCC(C(=O)O)C4)cc(C(F)(F)F)c3c2)CC1

Procedure:
Synthesized as per 1-[6-(trans-4-tert-Butyl-cyclohexyloxy)-4-trifluoromethyl-quinolin-2-ylmethyl]-azetidine-3-carboxylic acid (Example 168) using the appropriate amine. ESI-MS(M+H+): 479.2; 1H NMR (400 MHz, METHANOL-d4) Shift 8.17 (d, J=9.29 Hz, 1H), 7.85 (s, 1H), 7.58 (dd, J=2.38, 9.41 Hz, 1H), 7.39 (br. s., 1H), 4.85 (br. s., 2H), 4.32-4.44 (m, 1H), 3.39-3.53 (m, 1H), 2.51 (br. s., 1H), 2.41 (br. s., 1H), 2.27 (d, J=10.79 Hz, 2H), 1.86-1.99 (m, 2H), 1.34-1.55 (m, 2H), 1.19-1.34 (m, 2H), 1.03-1.19 (m, 1H), 0.91 (s, 9H). 1.3 TFA per molecule.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:13])[NH:7]2.[H-].[Na+].[CH2:16]([O:23][C:24]([NH:26][C@@H:27]1[CH2:32][CH2:31][N:30]([CH2:33][CH2:34]Cl)[CH2:29][C@@H:28]1[C:36]([O:38][CH3:39])=[O:37])=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(OC(=O)NC1CCN(CCN2C3C(=CC=C(F)C=3F)C=CC2=O)CC1)(C)(C)C>>[CH2:16]([O:23][C:24]([NH:26][C@@H:27]1[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][N:7]2[C:8]3[C:3](=[C:2]([F:1])[CH:11]=[C:10]([F:12])[CH:9]=3)[CH:4]=[CH:5][C:6]2=[O:13])[CH2:29][C@@H:28]1[C:36]([O:38][CH3:39])=[O:37])=[O:25])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=c1ccc2c(F)cc(F)cc2[nH]1
Reactant: COC(=O)[C@H]1CN(CCCl)CC[C@H]1NC(=O)OCc1ccccc1
Agent: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)ccc3ccc(F)c(F)c32)CC1
Agent: [H-]
Agent: [Na+]
Product: COC(=O)[C@H]1CN(CCn2c(=O)ccc3c(F)cc(F)cc32)CC[C@H]1NC(=O)OCc1ccccc1

Procedure:
5,7-Difluoroquinolin-2(1H)-one (Intermediate 25) (350 mg, 1.93 mmol) was deprotonated with sodium hydride (85 mg, 60% in oil, 2.13 mmol) and alkylated with methyl (3S,4R)-4-{[(benzyloxy)carbonyl]amino}-1-(2-chloroethyl)piperidine-3-carboxylate (Intermediate 36) (1.93 mmol) as described for Intermediate 20. Colorless hard foam, 604 mg (63%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1>C1COCC1.O>[F:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:1][CH2:2][CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:20])[CH3:21])[CH:14]=[CH:15][CH:16]=3)[CH2:7][CH2:6]2)=[O:32])=[CH:26][CH:25]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: O=C=Nc1ccc(F)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)Nc3ccc(F)cc3)CC2)c1
Yield: 10.9 %

Procedure:
A solution of N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide (26.4 mg, 0.0870 mol), 1-fluoro-4-isocyanatobenzene (11.9 mg, 0.0870 mmol), in THF (1.00 mL) was stirred for 12 h at 25° C. The resulting crude mixture was diluted with water (10 mL), the aqueous layer was extracted with CH2Cl2 (3×20 mL). The combined organic layers were concentrated in vacuo and the residue was purified by preparative TLC using 2.5% of NH3 (2.0 M in methanol) in CH2Cl2 to give the desired product N-{3-[1-(3-{[(4-fluoroanilino)carbonyl]amino}propyl)-4-piperidinyl]phenyl}-2-methylpropanamide (4.18 mg, 10.9%): 1H NMR (400 MHz, CDCl3) 7.45 (q, 2H, J=4.7 Hz), 7.23-7.21 (m, 4H), 7.05 (t, 4H, J=7.8 Hz), 6.75 (m, 1H), 4.05 (m, 1H), 3.19 (s, 1H), 2.71 (m, 1H), 2.53 (m, 1H), 2.26-2.21 (m, 3H), 1.80-1.60 (m, 9H), 1.25 (d, 6H, J=6.4 Hz); ESMS m/e: 439.4 (M+H)+.