Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@H:5]3[NH2:12])[CH2:3]1)[CH2:9]2.[NH:13]1[C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([C:22](O)=[O:23])[C:16]=2[CH:15]=[N:14]1.N>>[ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@H:5]3[NH:12][C:22]([C:17]3[C:16]4[CH:15]=[N:14][NH:13][C:21]=4[CH:20]=[CH:19][CH:18]=3)=[O:23])[CH2:3]1)[CH2:9]2
Reactant: O=C(O)c1cccc2[nH]ncc12
Reactant: NC1C2CC3CC1CN(C3)C2
Agent: Cl
Agent: N
Product: O=C(NC1C2CC3CC1CN(C3)C2)c1cccc2[nH]ncc12

Procedure:
Prepared from (4r)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine hydrochloride and 1H-indazole-4-carboxylic acid according to methods A and C. 1H NMR (300 MHz, methanol-d4) δ ppm 2.08-2.34 (m, 5H), 2.51 (s, 2H), 3.42-3.64 (m, 4H), 3.88 (d, J=12.5 Hz, 2H), 4.33 (s, 1H), 7.42-7.52 (m, 1H), 7.58-7.64 (m, 1H), 7.72 (d, J=8.5 Hz, 1H), 8.33 (s, 1H). MS (DCI/NH3) m/z 297.
Reaction SMILES: [F:1][CH:2]([F:32])[C:3]1[N:7]([C:8]2[CH:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([NH:20][CH2:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:9]=2)[C:6]2[CH:28]=[CH:29][CH:30]=[CH:31][C:5]=2[N:4]=1.Br[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>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].COCCOC>[F:32][CH:2]([F:1])[C:3]1[N:7]([C:8]2[CH:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([NH:20][CH2:21][CH:22]3[CH2:23][CH2:24][N:25]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[CH2:26][CH2:27]3)[N:9]=2)[C:6]2[CH:28]=[CH:29][CH:30]=[CH:31][C:5]=2[N:4]=1
Reactant: FC(F)c1nc2ccccc2n1-c1cc(N2CCOCC2)nc(NCC2CCNCC2)n1
Reactant: Brc1ccccc1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: COCCOC
Product: FC(F)c1nc2ccccc2n1-c1cc(N2CCOCC2)nc(NCC2CCN(c3ccccc3)CC2)n1
Temperature: 130 °C
Reaction time: 1 h

Procedure:
To a mixture of 4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-morpholin-4-yl-N-(piperidin-4-ylmethyl)pyrimidin-2-amine (50 mg) and 1,2-dimethoxyethane (1 mL) were added bromobenzene (24 μL), tris(dibenzylideneacetone)dipalladium (0) (6.5 mg), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (11 mg), and potassium phosphate (96 mg), and the mixture was stirred in a microwave reactor at 130° C. for 1 hour. The reaction mixture was filtered through celite, and to the filtrate was added silica gel, followed by concentrating under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate) to obtain 4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(morpholin-4-yl)-N-[(1-phenylpiperidin-4-yl)methyl]pyrimidin-2-amine (39 mg) as a white powder.
Reaction SMILES: [ClH:1].[CH2:2]([N:9]1[C:17]2[C:12](=[CH:13][C:14]([NH:18][C:19]3[C:28]4[C:23](=[CH:24][C:25](I)=[CH:26][CH:27]=4)[N:22]=[CH:21][N:20]=3)=[CH:15][CH:16]=2)[CH:11]=[N:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[O:30]1[CH:34]=[CH:33][CH:32]=[C:31]1[Sn](CCCC)(CCCC)CCCC>>[ClH:1].[CH2:2]([N:9]1[C:17]2[C:12](=[CH:13][C:14]([NH:18][C:19]3[C:28]4[C:23](=[CH:24][C:25]([C:31]5[O:30][CH:34]=[CH:33][CH:32]=5)=[CH:26][CH:27]=4)[N:22]=[CH:21][N:20]=3)=[CH:15][CH:16]=2)[CH:11]=[N:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Ic1ccc2c(Nc3ccc4c(cnn4Cc4ccccc4)c3)ncnc2c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Agent: Cl
Product: c1ccc(Cn2ncc3cc(Nc4ncnc5cc(-c6ccco6)ccc45)ccc32)cc1

Procedure:
Prepared according to Procedure B from (1-benzyl-1H-indazol-5-yl)-(7-iodoquinazolin-4-yl)-amine hydrochloride and (furan-2-yl)-tri-n-butylstannane; δH [2H6]DMSO 9.94(1H, bs), 8.61 (1H, d), 8.55(1H, s), 8.21 (2H, d), 8.00(3H, m), 7.73(2H, s), 7.30(6H, s), 6.74(1H, s), 5.72(2H, s); m/z (M+1+) 418.
Reaction SMILES: CS[C:3]([N:7]1[CH2:11][CH:10]([CH2:12][CH3:13])[CH:9]=[N:8]1)=[N:4][CH2:5][CH3:6].[C:14]1(/[CH:20]=[CH:21]/[S:22]([NH2:25])(=[O:24])=[O:23])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(#N)C>[CH2:5]([NH:4][C:3]([N:7]1[CH2:11][CH:10]([CH2:12][CH3:13])[CH:9]=[N:8]1)=[N:25][S:22](/[CH:21]=[CH:20]/[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:23])=[O:24])[CH3:6]
Reactant: NS(=O)(=O)/C=C/c1ccccc1
Reactant: CCN=C(SC)N1CC(CC)C=N1
Solvent: CC#N
Product: CCNC(=NS(=O)(=O)/C=C/c1ccccc1)N1CC(CC)C=N1
Yield: 0.3 %

Procedure:
0.70 g (1 mol equiv.) 4,N-Diethyl-4,5-dihydro-pyrazole-1-carboximidothioic acid methyl ester and 0.68 g (1.05 mol equiv.) trans-2-phenyl-ethenesulfonic acid amide were added to 7 mL acetonitrile, and the reaction mixture was refluxed overnight. Volatiles were removed under reduced pressure, and the residue was taken up in ethyl acetate and extracted with 2N NaOH. The organic layer was dried over Na2SO4, filtered and evaporated to dryness. Purification by flash chromatography on silica gel (Et2O:PA=2:1) afforded 1.00 g (81%) trans-2-phenyl-ethenesulfonic acid ethylamino-(4-ethyl-4,5-dihydro-pyrazol-1-yl)-methyleneamide. 1H NMR (400 MHz, CDCl3) δ 0.98 (t, J=7.5 Hz, 3H), 1.21 (t, J=7.2 Hz, 3H), 1.46-1.70 (m, 2H), 3.06-3.16 (m, 1H), 3.51-3.59 (m, 2H), 3.74 (dd, J=11.3, 7.5 Hz, 1H), 4.13 (t, J=11.3 Hz, 1H), 6.70-6.92 (m, 1H), 6.92 (d, J=1.3 Hz, 1H), 6.97 (d, J=15.4 Hz, 1H), 7.35-7.41 (m, 3H), 7.44 (d, J=15.4 Hz, 1H), 7.46-7.50 (m, 2H).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.C(N(CC)CC)C.[CH2:18]([C:20]1[N:25]=[C:24]([Cl:26])[N:23]=[C:22](Cl)[CH:21]=1)[CH3:19]>CN(C)C=O>[CH2:18]([C:20]1[N:25]=[C:24]([Cl:26])[N:23]=[C:22]([N:2]2[CH2:3][CH2:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:1]2)[CH:21]=1)[CH3:19]
Reactant: CCc1cc(Cl)nc(Cl)n1
Reactant: c1ccc2c(c1)CCNC2
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCc1cc(N2CCc3ccccc3C2)nc(Cl)n1
Yield: 65.9 %

Procedure:
In accordance with the same procedure as in Step 1 of Example 1, except that 1,2,3,4-tetrahydroisoquinoline(3.5 ml, 28 mmol), triethylamine(3.9 ml, 28 mmol),N,N-dimethylformamide (20 ml) and 6-ethyl-2,4-dichloropyrimidine(4.9 g, 27.7 mmol) prepared in Preparation 2 were used as starting materials, 5.0 g of the titled compound was prepared. (Yield: 66%)
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([N+:23]([O-])=O)=[C:11]([CH:16]=[CH:17]N2CCCC2)[C:12]([Br:15])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CC(O)=O.[Fe]>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[C:11]2[C:10]=1[NH:23][CH:17]=[CH:16]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1c(OCc2ccccc2)ccc(Br)c1C=CN1CCCC1
Agent: [Fe]
Solvent: CC(=O)O
Product: Brc1ccc(OCc2ccccc2)c2[nH]ccc12
Reaction time: 2 h

Procedure:
1-[-2-(3-Benzyloxy-6-bromo-2-nitro-phenyl)-vinyl]-pyrrolidine (10 g, 24.8 mmol; Intermediate 82) suspended in HOAc (25 mL) was added to a boiling mixture of iron (4.15 g, 74.4 mmol) in HOAc. After 2 h boiling TLC indicated that no starting material is left. The reaction mixture was filtered while still warm. The residue was evaporated and dissolved in toluene. The toluene slurry was applied to a silica column and eluted with toluene/hexane 1/1. Obtained 3.1 g. MS (ESI+) for C15H12BrNO m/z 302, 304 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:11]2[CH:12]=[C:13]([C:16]([F:19])([F:18])[F:17])[CH:14]=[CH:15][C:10]=2[O:9][C:8]([CH2:22][F:23])([CH2:20][F:21])[CH:7]=1)=[O:5])C.[OH-].[K+].Cl>C(O)C>[F:23][CH2:22][C:8]1([CH2:20][F:21])[CH:7]=[C:6]([C:4]([OH:5])=[O:3])[C:11]2[CH:12]=[C:13]([C:16]([F:19])([F:17])[F:18])[CH:14]=[CH:15][C:10]=2[O:9]1
Reactant: CCOC(=O)C1=CC(CF)(CF)Oc2ccc(C(F)(F)F)cc21
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C1=CC(CF)(CF)Oc2ccc(C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
A mixture of 0.51 g of 2,2-bis(fluoromethyl)-6-trifluoromethyl-2H-1-benzopyran-4-carboxylic acid ethyl ester, 0.13 g of potassium hydroxide and 10 ml of ethyl alcohol was stirred at room temperature for 2 hours. To the reaction mixture was added ice water and hydrochloric acid and crystals separated out were filtered to obtain 0.43 g of 2,2-bis(fluoromethyl)-6-trifluoromethyl-2H-1-benzopyran-4-carboxylic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:11][CH:12]([C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1)[OH:13]>C(O)(=O)C.O=[Pt]=O>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:11][CH:12]([CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)[OH:13]
Reactant: COc1cccc(CC(O)c2ccncc2)c1OC
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: COc1cccc(CC(O)C2CCNCC2)c1OC
Yield: 167.9 %

Procedure:
4-[2-(2,3-dimethoxyphenyl)-1-hydroxyethyl]pyridine (20.0 g, 0.077 mol) in acetic acid (170 ml) over 1.5 g of PtO2 was hydrogenated for 45 minutes on a Parr shaker. The reaction was filtered through Celite and filtrate combined with another run of 21.0 g (0.08 mol). The combined filtrates were concentrated in vacuo and the resulting oil was diluted with water. The aqueous solution was made basic with 50% aqueous NaOH, and the basic mixture extracted with EtOAc. The organic extract was washed with water, dried (magnesium sulfate) and then concentrated to afford 34.3 g of an oil that solidified upon standing. The solid was removed and recrystallized twice from isopropyl ether at 5° C. to afford the piperidine as a white solid, mp 82-84° C.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[C:6]([N:8]1[C@H:13]([CH2:14][C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)[CH2:12][N:11]2[CH2:24][C:25](=[O:28])[CH2:26][CH2:27][C@@H:10]2[CH2:9]1)=[O:7].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C(O)(=O)C.O>[F:37][C:2]([F:1])([F:36])[C:3]1[CH:4]=[C:5]([C:6]([N:8]2[C@H:13]([CH2:14][C:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[NH:17][CH:16]=3)[CH2:12][N:11]3[CH2:24][C@@H:25]([OH:28])[CH2:26][CH2:27][C@@H:10]3[CH2:9]2)=[O:7])[CH:29]=[C:30]([C:32]([F:35])([F:33])[F:34])[CH:31]=1
Reactant: O=C1CC[C@@H]2CN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@H](Cc3c[nH]c4ccccc34)CN2C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1C[C@H]2CC[C@H](O)CN2C[C@H]1Cc1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.4 %

Procedure:
To a suspension of (3R,9aR)-2-[3,5-bis(trifluoromethyl)benzoyl]-3-(1H-indol-3-ylmethyl)-octahydro-2H-pyrido[1,2-a]pyrazin-7-one (5.6 g) in acetic acid (75 mL) was added sodium triacetoxyborohydride (6.78 g). The resulting mixture was stirred for one hour at room temperature then poured in water and basified with 2M sodium hydroxide (aq.). The formed precipitate was collected by filtration, washed with water, suspended in toluene and concentrated in vacuo to afford 3,5-bis(trifluoromethyl) phenyl-[(3R,7S,9aR)-7-hydroxy-3-(1H-indol-3-ylmethyl)-octahydropyrido[1,2-a]pyrazin-2-yl]-methanone (5.7 g). Rf 0.35 (CH2Cl2/MeOH 9:1) (compound 12).
Reaction SMILES: [NH:1]([C:8]1[N:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16](OC=O)(=[O:18])C>>[CH3:14][C:12]1[CH:11]=[C:10]([CH3:15])[N:9]=[C:8]([N:1]([CH:16]=[O:18])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[N:13]=1
Reactant: CC(=O)OC=O
Reactant: Cc1cc(C)nc(Nc2ccccc2)n1
Product: Cc1cc(C)nc(N(C=O)c2ccccc2)n1
Reaction time: 96 h

Procedure:
2-Anilino-4,6-dimethylpyrimidine (10 g) was added to formic-acetic anhydride (prepared from formic acid (5 ml) and acetic anydride (12 ml)) and the mixture heated gently to 40° to give a clear solution. After standing for 4 days, a crystalline solid separated and toluene was added to give a clear solution again. The mixture was evaporated to dryness, more toluene added and reevaporated. The product was recrystallised from ethyl acetate/light petroleum to give N-(4,6-dimethylpyrimidin-2-yl)-formanilide, m.p. 134°-5°. (Compound 3).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:31])=[C:4]([C:11](/[C:13](=[CH:29]/[CH3:30])/[CH:14]=[C:15]2\[C:16](=C)[N:17]=C(C3C=CC=CC=3)[O:19][C:20]\2=[O:21])=[O:12])[N:5]2[C:10]=1[CH:9]=[CH:8][CH:7]=[CH:6]2.[OH-].[K+].Cl>O.CN1C(=O)CCC1>[NH2:17][C:16]1[CH:30]=[CH:29][C:13]([C:11]([C:4]2[N:5]3[C:10]([CH:9]=[CH:8][CH:7]=[CH:6]3)=[C:2]([Br:1])[C:3]=2[CH3:31])=[O:12])=[CH:14][C:15]=1[C:20]([OH:19])=[O:21]
Reactant: C=c1nc(-c2ccccc2)oc(=O)/c1=C/C(=C\C)C(=O)c1c(C)c(Br)c2ccccn12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1c(Br)c2ccccn2c1C(=O)c1ccc(N)c(C(=O)O)c1
Temperature: 25 °C
Yield: 109.4 %

Procedure:
The (5E)-5-{(2E)-2-[(1-bromo-2-methylindolizin-3-yl)carbonyl]but-2-en-1-ylidene}-4-methylidene-2-phenyl-4,5-dihydro-6H-1,3-oxazin-6-one (18.6 g; 40.4 mmol) is added portionwise to potassium hydroxide (22.7 g; 0.40 mol) in 100 mL of water and 140 mL of NMP. The reaction mixture is heated at reflux for 18 h, cooled to ambient temperature and poured into a hydrochloric acid solution (1 M). The yellow precipitate formed is filtered off and dried under vacuum to give 16.5 g (99%) of a yellow powder.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[S:24][C:23]4[C:18](=[N:19][CH:20]=[CH:21][C:22]=4[O:25][C:26]4[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=4)[CH:17]=3)=[CH:12][CH:11]=2)[CH2:3][CH2:2]1.FC1C=C(N[C:66]([NH:68][C:69](=[O:77])[CH2:70][C:71]2[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=2)=[S:67])C=CC=1OC1C=CN=C2C=C(C3C=CC=C(OCCN4CCOCC4)C=3)SC=12>>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[S:24][C:23]4[C:18](=[N:19][CH:20]=[CH:21][C:22]=4[O:25][C:26]4[CH:27]=[CH:28][C:29]([NH:32][C:66]([NH:68][C:69](=[O:77])[CH2:70][C:71]5[CH:72]=[CH:73][CH:74]=[CH:75][CH:76]=5)=[S:67])=[CH:30][CH:31]=4)[CH:17]=3)=[CH:12][CH:11]=2)[CH2:3][CH2:2]1
Reactant: Nc1ccc(Oc2ccnc3cc(-c4ccc(OCCN5CCOCC5)cc4)sc23)cc1
Reactant: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ccnc3cc(-c4cccc(OCCN5CCOCC5)c4)sc23)c(F)c1
Product: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ccnc3cc(-c4ccc(OCCN5CCOCC5)cc4)sc23)cc1
Yield: 30 %

Procedure:
Starting from the compound 202 and following the procedure described above for the compound 163a (scheme 31), title compound 203 was obtained in 30% yield. 1H NMR (400 MHz, DMSO-d6) δ ppm: 12.38 (s, 1H), 11.73 (s, 1H), 8.47 (d, 1H, J=5.5 Hz), 7.90 (s, 1H), 1H), 7.79 (s, 2H, J=9.0), 7.36 (d, 2H, J=9.0 Hz), 7.43-7.27 (m, 7H), 7.05 (d, 2H, J=9.0 Hz), 6.63 (d, 1H, J=5.3 Hz), 4.15 (t, 2H, J=5.6 Hz), 3.82 (s, 2H), 3.58 (t, 4H, J=4.6 Hz), 2.71 (t, 2H, J=5.7 Hz), 2.51-2.46 (m, 4H). LRMS (M+1) 625.2 (100%).
Reaction SMILES: [NH:1]([C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13](O)=[O:14])[C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C1COCC1.[H-].CN1CCN([Al+]N2CCN(C)CC2)CC1.C(OCC)C>O>[NH:1]([C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[CH:13]=[O:14])[C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH:4]=[O:5]
Reactant: O=C(O)c1ccccc1Nc1ccccc1C(=O)O
Agent: CN1CCN([Al+]N2CCN(C)CC2)CC1
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: O=Cc1ccccc1Nc1ccccc1C=O
Temperature: -20 °C
Reaction time: 24 h
Yield: 33.4 %

Procedure:
To a 500-ml reactor thoroughly dried and purged with argon, 2.3 g (8.94 mmol) of 2,2′-iminodibenzoic acid and 50 ml of THF were introduced, and they were cooled to −20° C. At that temperature, 90 ml of a THF solution (0.3 M) of bis(1-methylpiperazine-4-yl)aluminum hydride was dropwise added with stirring. Then, the temperature of the system was raised, and the reaction was conducted for 24 hours under reflux. The reaction solution was allowed to stand for cooling to room temperature. To the solution, 100 ml of diethyl ether was added, and 150 ml of water was further added slowly with ice cooling. The oil layer obtained by phase separation was concentrated and subjected to isolation by means of silica gel column chromatography to obtain 673 mg of 2,2′-iminodibenzaldehyde. To a 100-ml reactor thoroughly dried and purged with argon, 650 mg (2.89 mmol) of the 2,2′-iminodibenzaldehyde, 699 mg (5.77 mmol) of 2,6-dimethylaniline, 50 ml of dehydrated methanol and 0.2 ml of acetic acid were introduced, and they were reacted at room temperature for 12 hours. From the reaction solution, the solvent was distilled off, and the remainder was subjected to isolation by means of silica gel column chromatography to obtain 237 mg (yield: 6.1%) of a compound represented by the following formula (L6).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][NH2:12])=[CH:2]1.CCN(CC)CC.[F:20][C:21]([F:36])([F:35])[C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[C:25](Cl)=[O:26]>C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][NH:12][C:25](=[O:26])[C:24]2[CH:28]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:30]=[C:22]([C:21]([F:20])([F:35])[F:36])[CH:23]=2)=[CH:2]1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: NCCc1c[nH]c2ccccc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCc1c[nH]c2ccccc12)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 16 h

Procedure:
To a solution of 2-(1H-indol-3-yl)-ethylamine (1.0 g) in CH2Cl2 was added at 22° C. NEt3 (1.74 ml) and 3,5-bis-trifluoromethyl-benzoyl chloride (1.24 ml) and stirring was continued at 22° C. for 16 h. The mixture was washed with aqueous NaHCO3 and brine and the organic layer was dried and evaporated to give the title compound as a brown solid. MS: 401.3 ([M+H]+).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:38])[CH2:18][CH:19]2[CH2:24][C:23](=[O:25])[N:22]([CH2:26][C:27]([O:29]CC3C=CC=CC=3)=[O:28])[C:21](=[O:37])[CH2:20]2)[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C.[OH-].[Pd+2].[OH-]>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:38])[CH2:18][CH:19]2[CH2:24][C:23](=[O:25])[N:22]([CH2:26][C:27]([OH:29])=[O:28])[C:21](=[O:37])[CH2:20]2)[CH2:13][CH2:12]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccccc1N1CCN(C(=O)CC2CC(=O)N(CC(=O)OCc3ccccc3)C(=O)C2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)CC2CC(=O)N(CC(=O)O)C(=O)C2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.7 %

Procedure:
A suspension of benzyl (4-{2-[4-(2-tert-butylphenyl)piperazin-1-yl]-2-oxoethyl}-2,6-dioxopiperidin-1-yl)acetate (Example 78, 0.28 g, 0.539 mmol) and palladium hydroxide (20% on carbon, wetted with ca. 50% water, 30 mg) in ethyl acetate (25 mL) was stirred under hydrogen atmosphere at room temperature for 3 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to provide (4-{2-[4-(2-tert-butylphenyl)piperazin-1-yl]-2-oxoethyl}-2,6-dioxopiperidin-1-yl)acetic acid (0.21 g, 91%) as a white powder.
Reaction SMILES: CC(C)([O-])C.[Na+].[F:7][C:8]1[CH:9]=[CH:10][C:11]([O:52][CH3:53])=[C:12]([C:14]([CH3:51])([CH3:50])[CH2:15][C:16]([OH:49])([C:45]([F:48])([F:47])[F:46])[CH2:17][NH:18][C:19]2[CH:27]=[C:26]([CH3:28])[CH:25]=[C:24]3[C:20]=2[CH:21]=[N:22][N:23]3[C:29]2[CH:30]=[C:31]([CH:42]=[CH:43][CH:44]=2)[C:32]([O:34][CH2:35][C:36]2C=CC=CC=2)=[O:33])[CH:13]=1>C(O)C>[F:7][C:8]1[CH:9]=[CH:10][C:11]([O:52][CH3:53])=[C:12]([C:14]([CH3:50])([CH3:51])[CH2:15][C:16]([OH:49])([C:45]([F:46])([F:48])[F:47])[CH2:17][NH:18][C:19]2[CH:27]=[C:26]([CH3:28])[CH:25]=[C:24]3[C:20]=2[CH:21]=[N:22][N:23]3[C:29]2[CH:30]=[C:31]([CH:42]=[CH:43][CH:44]=2)[C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:13]=1
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cc(C)cc2c1cnn2-c1cccc(C(=O)OCc2ccccc2)c1)C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cccc(-n2ncc3c(NCC(O)(CC(C)(C)c4cc(F)ccc4OC)C(F)(F)F)cc(C)cc32)c1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 58.3 %

Procedure:
Sodium tert-butoxide (4 mg, 0.042 mmol) was added to a solution of phenylmethyl 3-(4-{[4-[5-fluoro-2-(methyloxy)phenyl]-2-hydroxy-4-methyl-2-(trifluoromethyl)pentyl]amino}-6-methyl-1H-indazol-1-yl)benzoate (Intermediate 30, 23 mg, 0.035 mmol) in ethanol (3 mL) and the mixture stirred at room temperature for 75 min. The mixture was then partitioned between dichloromethane (20 mL) and aqueous ammonium chloride (20 mL). The organic layer was separated, passed through a hydrophobic frit and evaporated and the residue purified by mass-directed autopreparation to give the title compound (12 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)=[N:11][C:10]([C:23]([F:26])([F:25])[F:24])=[N:9]2)=[CH:4][CH:3]=1.[OH-].[K+].[CH2:29](OS(OCC)(=O)=O)[CH3:30].[NH4+].[OH-]>O.CN(C=O)C>[CH2:29]([O:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]3[CH:14]=[CH:15][C:16]([S:19]([CH3:22])(=[O:20])=[O:21])=[CH:17][CH:18]=3)=[N:11][C:10]([C:23]([F:24])([F:25])[F:26])=[N:9]2)=[CH:6][CH:7]=1)[CH3:30]
Reactant: CCOS(=O)(=O)OCC
Reactant: CS(=O)(=O)c1ccc(-c2nc(C(F)(F)F)nn2-c2ccc(O)cc2)cc1
Agent: [K+]
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccc(-n2nc(C(F)(F)F)nc2-c2ccc(S(C)(=O)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.5 %

Procedure:
A mixture of 1-(4-hydroxy-phenyl)-5-(4-methylsulfonyl-phenyl)-3-trifluoromethyl-1H-1,2,4-triazole (4 g, 10.4 mmol), KOH (1.5 g, 26.8 mmol) and DMF (40 ml) was stirred at room temperature for 1 h. Then diethylsulfate (1.6 ml, 12.2 mmol) was added, the reaction mixture stirred at room temperature for 13 h, NH4OH (20 ml) added and the mixture poured into water (1 l). The precipitate was filtered, washed several times with water and dried. Recrystallization from ethanol yielded a white solid (3.7 g, 88%).
Reaction SMILES: [OH:1][CH:2]([CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:16][CH:15]=1)[CH2:3][C:4]#[C:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].[CH3:25]O>C1(C)C=CC=CC=1>[OH:1][CH:2]([CH2:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:18][CH:19]=1)[CH2:3][C:4]#[C:5][CH2:6][CH2:7][CH2:8][C:9]([O:11][CH3:25])=[O:10]
Reactant: CCCCCc1ccc(OCC(O)CC#CCCCC(=O)O)cc1
Reactant: CO
Solvent: Cc1ccccc1
Product: CCCCCc1ccc(OCC(O)CC#CCCCC(=O)OC)cc1

Procedure:
A solution of 3 g of 8-hydroxy-9-(4-pentylphenoxy)-5-nonynoic acid, the product of Example 7b, 40 ml of MeOH, 40 ml of toluene and 3 drops of BF3 ·Et2O was heated for 12 hr to reflux with a Dean Stark trap to remove water. Solvent was removed and the residue was dissolved in Et2O and was washed NaHCO3 solution and NaCl solution. The ether solution was dried over MgSO4 and removed solvent to give the title compound, an oil.
Reaction SMILES: [CH:1]1([N:7]([CH2:23][CH:24]([O:27][CH3:28])[O:25][CH3:26])[C:8](=[O:22])[CH2:9][CH2:10][O:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]=[O:21])[CH:15]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C)C(S([CH2:38][N+:39]#[C-:40])(=O)=O)=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>CO>[CH:1]1([N:7]([CH2:23][CH:24]([O:27][CH3:28])[O:25][CH3:26])[C:8](=[O:22])[CH2:9][CH2:10][O:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[O:21][CH:40]=[N:39][CH:38]=3)[CH:15]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccccc1C
Reactant: COC(CN(C(=O)CCOCCc1cccc(C=O)c1)C1CCCCC1)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(CN(C(=O)CCOCCc1cccc(-c2cnco2)c1)C1CCCCC1)OC
Temperature: 80 °C

Procedure:
To N-cyclohexyl-N-(2,2-dimethoxyethyl)-3-(3-formylphenethoxy)propanamide [Example 10, Step ii)] (600 mg) in a 10 ml microwave vial was added toluenesulfonylmethyl isocyanide (329 mg), potassium carbonate (233 mg) and methanol (2 mL). The vial was sealed and heated at 80° C. for 40 min within a microwave before cooling to room temperature. The solvents were evaporated under vacuum followed by the addition of water, which was extracted once with ethyl acetate. The organic phase was washed once with water, dried over sodium sulphate, filtered and the solvent removed to afford desired material, which was carried onto the next step directly. MS [M+H-MeOH]+=399 (MultiMode+)