Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH:6]=[CH:5][C:4]([OH:7])=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].[H][H]>C(O)(C)C.O1CCCC1.[Pd]>[CH2:6]1[CH:1]([CH:8]2[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]2)[CH2:2][CH2:3][CH:4]([OH:7])[CH2:5]1
Reactant: [H][H]
Reactant: Oc1ccc(-c2ccc(O)cc2)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: C1CCOC1
Product: OC1CCC(C2CCC(O)CC2)CC1

Procedure:
In 1 l of isopropanol was dissolved 100 g (0.54 mol) of biphenyl-4,4'-diol, and 5 g of anhydrous sodium carbonate and 5 g of 5% palladium-on-carbon were added to the solution. The mixture was subjected to reduction reaction in an autoclave at 100° C. and at a hydrogen pressure of 5 kg/cm2 for 25 to 30 hours. After completion of the reaction, the reaction mixture was filtered, and the isopropanol was removed from the filtrate by distillation under reduced pressure to recover a part of dicyclohexyl-4,4'-diol. The crystals obtained as a filter cake were dissolved in 500 ml of tetrahydrofuran while hot and filtered. The tetrahydrofuran was removed from the filtrate by distillation under reduced pressure to obtain dicyclohexyl-4,4'-diol. Both crystals were combined, suspended in 1 l of n-hexane while hot, and allowed to stand at 5° to 6° C. for 1 hour. The precipitated crystals were collected by filtration and dried under reduced pressure to obtain 93 g (0.47 mol) of a compound of formula: ##STR28## Melting Point: 179°-181° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:16][C:15]3[CH:14]=[CH:13][NH:12][C:11](=[O:17])[C:10]=3[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.F[C:19]1[CH:20]=[CH:21][C:22]([N+:26]([O-:28])=[O:27])=[C:23]([CH3:25])[CH:24]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:16][C:15]3[CH:14]=[CH:13][N:12]([C:19]4[CH:20]=[CH:21][C:22]([N+:26]([O-:28])=[O:27])=[C:23]([CH3:25])[CH:24]=4)[C:11](=[O:17])[C:10]=3[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=c1[nH]ccc2oc(-c3cccc(Cl)c3)cc12
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1cc(-n2ccc3oc(-c4cccc(Cl)c4)cc3c2=O)ccc1[N+](=O)[O-]
Temperature: 120 °C
Reaction time: 48 h
Yield: 78.5 %

Procedure:
To a solution of 2-(3-chlorophenyl)-5H-furo[3,2-c]pyridine-4-one (1.00 g, 4.08 mmol) in DMF (9.46 mL) was added 5-fluoro-2-nitrotoluene (0.57 mL, 4.7 mmol) and Cs2CO3 (1.32 g, 4.08 mmol). After stirring at 120° C. for 48 h, the reaction mixture was cooled and the solids were collected by filtration. The solids were washed with EtOAc (300 ml) to yield the title compound (1.22 g, 78%) as a golden yellow solid: 1H NMR (500 MHz, DMSO-d6) δ 8.14 (d, J=8.6 Hz, 1H), 7.97 (t, J=17 Hz, 1H), 7.86 (d, J=6.9 Hz, 1H), 7.74 (s, 1H), 7.73 (d, J=7.0 Hz, 1H), 7.68 (d, J=2 Hz, 1H), 7.60 (dd, J=8.0, 2.2 Hz, 1H), 7.53 (t, J=8.0 Hz, 1H), 7.46-7.44 (m, 1H), 6.97 (d, J=7.5 Hz, 1H), 2.58 (s, 3H).
Reaction SMILES: Cl.[CH2:2]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[C:9]([S:15][C:16]4[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=4)[C:8]=3[NH:7][C:6]=2[CH2:5][CH2:4][NH:3]1.N#N.[BH3-]C#N.[Na+].[OH-].[Na+].[C:31]([OH:38])(=[O:37])/[CH:32]=[CH:33]/[C:34]([OH:36])=[O:35]>C(O)(C(F)(F)F)=O.CO>[C:31]([OH:38])(=[O:37])/[CH:32]=[CH:33]/[C:34]([OH:36])=[O:35].[CH3:22][C:19]1[CH:18]=[CH:17][C:16]([S:15][C:9]2[C:8]3[NH:7][C@@H:6]4[CH2:5][CH2:4][NH:3][CH2:2][C@@H:14]4[C:13]=3[CH:12]=[CH:11][CH:10]=2)=[CH:21][CH:20]=1
Reactant: Cc1ccc(Sc2cccc3c4c([nH]c23)CCNC4)cc1
Agent: Cl
Agent: N#N
Agent: O=C(O)/C=C/C(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: Cc1ccc(Sc2cccc3c2N[C@@H]2CCNC[C@H]32)cc1
Yield: 72.2 %

Procedure:
4-Methylphenyl 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-6-yl sulfide hydrochloride (prepared in Example 1, 331 mg, 1.0 mmol) was suspended in TFA (17 mL) at rt. This mixture was cooled in an ice bath. A stream of N2 was introduced through the solution while solid NaCNBH3 (202 mg, 3.3 mmol) was added in 4 portions over 10 min. maintaining an internal temperature of <7° C. The resultant solution was maintained at ˜0° C. for 5 h at which time it was poured over ice chips. With vigorous stirring, 50% NaOH was added portionwise to pH 12. This mixture was extracted with CHCl3 (3×100 mL). The organic extracts were combined, dried (MgSO4) and concentrated in vacuo. The residue (265 mg, 90%) was treated with Et2O (5 mL) and filtered. The filtrate was treated with a MeOH solution (1 mL) of fumaric acid (116 mg, 1.0 mmol). The resultant solution was concentrated in vacuo. The solid residue was recrystallized from EtOAc-Et2O to afford the title compound (298 mg, 67%) as a crystalline sample. 1H NMR (300 MHz, CDCl3) δ 7.18 (d, J=7.7 Hz, 1H), 7.09 (d, J=7.0 Hz, 1H), 7.29 (s, 4H), 6.72 (t, J=7.3 Hz, 1H), 4.09 (t, J=8.3 Hz, 1H), 3.83 (q, J=5.5 Hz, 1H), 3.2-2.8 (m, 3H), 2.72-2.60 (m, 1H), 2.28 (s, 3H), 1.78-1.63 (m, 2H), 1.57-1.44 (m, 2H) ppm.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([C:13](OC)=O)=[CH:12][C:7]=2[S:6][C:5]2[CH:17]=[CH:18][CH:19]=[CH:20][C:4]=2[NH:3]1.[NH3:21]>CO>[C:13]([C:11]1[CH:10]=[CH:9][C:8]2[C:2](=[O:1])[NH:3][C:4]3[CH:20]=[CH:19][CH:18]=[CH:17][C:5]=3[S:6][C:7]=2[CH:12]=1)#[N:21]
Reactant: COC(=O)c1ccc2c(c1)Sc1ccccc1NC2=O
Reactant: N
Solvent: CO
Product: N#Cc1ccc2c(c1)Sc1ccccc1NC2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Stir 5 gm. of methyl 10,11-dihydro-11-oxodibenzo[b,f][1,4]thiazepin-3-carboxylate in 500 ml. of methanol saturated with ammonia gas for 24 hours at room temperature. Evaporate the reaction mixture to dryness. Reflux the residue in 200 ml. of methylene chloride containing 10 gm. of phosphorous oxychloride for eight hours. Cool the reaction mixture to room temperature and shake several times with water. Separate the organic layer, dry over magnesium sulfate and evaporate to dryness to obtain the title product.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([N:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][N:22]2C(=O)C3=CC=CC=C3C2=O)[CH2:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O.NN>>[NH2:22][CH2:21][CH2:20][N:17]1[CH2:16][CH2:15][N:14]([CH:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:19][CH2:18]1
Reactant: O=C1c2ccccc2C(=O)N1CCN1CCN(C(c2ccccc2)c2ccccn2)CC1
Agent: NN
Solvent: O
Product: NCCN1CCN(C(c2ccccc2)c2ccccn2)CC1
Yield: 52 %

Procedure:
The title compound was prepared in a yield of 52% in a similar manner to that described in Preparation 15' by reacting 4-[α-(2-pyridyl)benzyl]-1-(2-phthalimido-ethyl) piperazine (prepared as described in Preparation 53') and hydrazine hydrate.
Reaction SMILES: [C:1]1([CH:7]2[NH:19][C:17]3[C:18]4[C:9](=[N:10][NH:11][C:12](=[O:20])[C:13]=4[CH:14]=[CH:15][CH:16]=3)[CH:8]2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C=O.[C:29]([BH3-])#N.[Na+]>CO>[CH3:29][N:19]1[C:17]2[C:18]3[C:9](=[N:10][NH:11][C:12](=[O:20])[C:13]=3[CH:14]=[CH:15][CH:16]=2)[CH:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=c1[nH]nc2c3c(cccc13)NC(c1ccccc1)C2c1ccccc1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CN1c2cccc3c(=O)[nH]nc(c23)C(c2ccccc2)C1c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 8,9-diphenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (1.04 mmol) in methanol (20 mL) is treated with formaldehyde (37 wt % in water, 270 μL, 3.61 mmol) at room temperature for overnight. Sodium cyanoborohydride (228 mg, 3.61 mmol) is added and the solution is stirred at room temperature for 3 h. After concentration under reduced pressure, the residue is dissolved in a mixture of trifluoroacetic acid and water and is purified by HPLC giving the 7-methyl-8,9-diphenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one in good yield.
Reaction SMILES: [CH3:1][CH:2]1[CH2:9][C:8]2[C:3]1=[CH:4][CH:5]=[C:6]([Si](C)(C)C)[CH:7]=2.ClN1C(=O)CCC1=O.[Br-:22].[Li+]>CO>[Br:22][C:6]1[CH:7]=[C:8]2[C:3](=[CH:4][CH:5]=1)[CH:2]([CH3:1])[CH2:9]2
Reactant: CC1Cc2cc([Si](C)(C)C)ccc21
Reactant: [Br-]
Agent: O=C1CCC(=O)N1Cl
Agent: [Li+]
Solvent: CO
Product: CC1Cc2cc(Br)ccc21
Reaction time: 2 h

Procedure:
To a solution of 7-methyl-3-trimethylsilylbicyclo[4.2.0]octa-1,3,5-triene (48.1 g, 0.25 mol) in MeOH (1000 ml) at 25° C., was added N-chlorosuccinimide (37.1 g, 0.28 mol), followed by lithium bromide (24.1 g, 0.28 mol) and the reaction mixture was allowed to stir at this temperature for 2 hrs. It was then quenched with H2O (200 ml), and concentrated under reduced pressure. The residue was extracted with hexane (200 ml×4), the combined organic extracts were washed with H2O (3×200 ml), dried over MgSO4 and concentrated under reduce pressure to give a pale yellow oil. The oil was purified by column chromatography (silica, hexane) to give the desired product 3-bromo-7-methyl-bicyclo[4.2.0]octa-1,3,5-triene as a colourless oil (42.6 g, GC-MS: M+=196, M−=198, isolated as a mixture of isomers).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH2:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16]([OH:18])=O)=[N:9][NH:8][C:7]2=[O:22].[CH2:23]([O:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[CH3:24].C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH2:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:15]([C:16]([N:29]3[CH2:30][CH2:31][CH:26]([O:25][CH2:23][CH3:24])[CH2:27][CH2:28]3)=[O:18])[CH:14]=1)=[N:9][NH:8][C:7]2=[O:22]
Reactant: CCOC1CCNCC1
Reactant: O=C(O)c1cccc(Cc2n[nH]c(=O)c3cccc(Cl)c23)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC1CCN(C(=O)c2cccc(Cc3n[nH]c(=O)c4cccc(Cl)c34)c2)CC1
Yield: 41 %

Procedure:
3-((8-chloro-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (118) (200 mg, 0.64 mmol) and 4-ethoxypiperidine were added to DMF (5 mL), to this was added N-ethyl-N-isopropylpropan-2-amine (0.170 mL, 0.95 mmol) and then HBTU (362 mg, 0.95 mmol). The solvent was removed and the crude product dissolved in acetonitrile and purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the desired material as a white solid (111 mg, 41.0% yield); 1H NMR (400.132 MHz, DMSO) δ 1.11 (3H, t), 1.17-1.46 (2H, m), 1.58-1.92 (2H, m), 2.97-3.42 (4H, m), 3.42-3.55 (3H, m), 4.68 (2H, s), 7.13 (1H, s), 7.21 (2H, t), 7.35 (1H, t), 7.81 (1H, t), 7.94-7.99 (1H, m), 8.32-8.36 (1H, m), 12.91 (1H, s); m/z (LC-MS, ESI+), RT=1.96 (M+H 426.7)
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.[CH2:11]([O:13][C:14](=[O:24])[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[CH:18]=1)[CH3:12]>>[CH2:11]([O:13][C:14](=[O:24])[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:8]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([Br:1])[N:7]=2)=[O:10])[CH:18]=1)[CH3:12]
Reactant: O=C(O)c1cccc(Br)n1
Reactant: CCOC(=O)CCc1cccc(N)c1
Product: CCOC(=O)CCc1cccc(NC(=O)c2cccc(Br)n2)c1

Procedure:
6-Bromo-pyridine-2-carboxylic acid (261 mg, 1.29 mmol) was coupled to aniline (124)(250 mg, 1.29 mmol) using Method C to give the title compound.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:21][C:22]([OH:24])=[O:23])[CH:13]=2)=[N:4][NH:3]1.C([O-])([O-])=O.[K+].[K+].[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN(C=O)C>[CH2:31]([N:3]1[C:2](=[O:1])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:21][C:22]([OH:24])=[O:23])[CH:13]=2)=[N:4]1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C(O)Cn1cc(-c2n[nH]c(=O)c3ccccc23)c2ccccc21
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)Cn1cc(-c2nn(Cc3ccccc3)c(=O)c3ccccc23)c2ccccc21
Temperature: 70 °C
Reaction time: 3 h

Procedure:
The product of step c) was dissolved in DMF (4 mL) and treated with K2CO3 (55 mg, 0.4 mmol) and benzyl bromide (0.25 mmol). The reaction was heated to 70° C. for 12 h. Additional K2CO3 (0.2 mmol) and benzyl bromide (0.25 mmol) was added and heating was continued for 3 h. The reaction was cooled and partitioned between EtOAc and water. The organic layer was washed 3 times with water and concentrated. The residue was dissolved in EtOH (2 mL) and treated with NaOH (0.5 mL, 1 M). After heating to 70° C. for 1 h, the reaction was cooled, acidified with HCl, and extracted into DCM. The organic layer was concentrated, dissolved in DMF, and purified by preparative LCMS. 1H NMR (DMSO-d6) δ 8.41 (d, J=6.9 Hz, 1H), 8.16 (d, J=7.2 Hz, 1H), 7.98-7.89 (m, 2H), 7.87 (s, 1H), 7.61 (d, J=8.1 Hz, 1H), 7.44-7.27 (m, 6H), 7.17 (t, J=7.3 Hz, 1H), 7.03 (t, J=7.5 Hz, 1H), 5.43 (s, 2H), 4.80 (s, 2H); MS: ESI (negative): 408 (M−H).
Reaction SMILES: C[O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([C:13]([O:15][CH3:16])=[O:14])=[CH:6]2>Br.C(O)(=O)C>[O:2]=[C:3]1[CH:12]=[CH:11][C:10]2[N:9]=[CH:8][C:7]([C:13]([O:15][CH3:16])=[O:14])=[CH:6][C:5]=2[NH:4]1
Reactant: COC(=O)c1cnc2ccc(OC)nc2c1
Agent: Br
Solvent: CC(=O)O
Product: COC(=O)c1cnc2ccc(=O)[nH]c2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of methyl 6-(methyloxy)-1,5-naphthyridine-3-carboxylate (1.45 g, 6.65 mmol) in 30% HBr in acetic acid (40 ml) was stirred at rt for 18 h before evaporation and drying in vacuo. The solid was washed with Et2O and dried in vacuo to give the desired product as the dihydrobromide salt (2.425 g, 99%).
Reaction SMILES: C(C1C=CC(NC2C=CC=CC=2)=CC=1)CCCCCCCCCCCCC.Br[CH2:29][C:30]([O:32]C)=[O:31].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].[CH2:42]([C:56]1[CH:61]=[CH:60][C:59]([NH:62][CH2:63][C:64]([OH:66])=[O:65])=[CH:58][CH:57]=1)[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55]>CN(C=O)C>[C:64]([CH2:63][N:62]([C:59]1[CH:60]=[CH:61][C:56]([CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])=[CH:57][CH:58]=1)[CH2:29][C:30]([OH:32])=[O:31])([OH:66])=[O:65]
Reactant: CCCCCCCCCCCCCCc1ccc(NCC(=O)O)cc1
Reactant: COC(=O)CBr
Agent: CCCCCCCCCCCCCCc1ccc(Nc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCc1ccc(N(CC(=O)O)CC(=O)O)cc1
Reaction time: 72 h

Procedure:
A mixture of 1.0 g (3.45 mmol) of 4-tetradecylphenyl aniline (Aldrich Chemical Company), 5.0 ml (0.052 mol) of methyl bromoacetate, 0.95 g (6.9 mmol) of potassium carbonate and 0.5 g (3.45 mmol) of sodium iodide in 15 ml of DMF was stirred and heated at 100° for 45 hours. The solvent was removed at reduced pressure and water was added to the residue. The product was extracted with ethyl acetate and the extract was washed with sodium bisulfite solution, dried and concentrated. The residue was purified by chromatography on silica gel using 25% ethyl acetate-hexane togive 0.7 g of N-(2-methoxy-2-oxoethyl)-N-(4-tetradecylphenyl)glycine methylester. This dimethyl ester was hydrolyzed by treatment with 1.5 ml of 6N NaOH in 50 ml of methanol. The mixture was warmed briefly to dissolve the ester and then was kept at room temperature for 3 days. The solvent was removed at reduced pressure and the residue was acidified to pH 2. The product was extracted with ethyl acetate and the dried extract was concentrated at reduced pressure to a solid which was recrystallized from methanol-water to give 0.26 g, mp 160°-165°, of N-carboxymethyl)-N-(4-tetradecylphenyl)glycine.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]([NH:13][NH:14][C:15]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)=O)=[NH:12])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)C>[C:1]1([S:7]([CH2:10][C:11]2[N:12]=[C:15]([C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[NH:14][N:13]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N=C(CS(=O)(=O)c1ccccc1)NNC(=O)c1cccs1
Solvent: CCO
Product: O=S(=O)(Cc1n[nH]c(-c2cccs2)n1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
1.00, (0.003 mol) Thiophene-2-carboxylic acid N′-(2-benzenesulfonyl-1-imino-ethyl)-hydrazide were heated at 200° C. for 20 minutes. The molten mass Bras then cooled, dissolved in 5 ml hot ethanol and stirred for one hour at room temperature. The precipitated crystals were filtered off and dried to yield 0.87 g (93%) 3-benzenesulfonylmethyl-5-thiophen-2-yl-1H-[1,2,4]triazole as yellow crystals with mp. 191-193° C. MS m/e (%): 305 (M+, 100).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:10]=[C:11]([N:14]2[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]2)[S:12][CH:13]=1>C(OCC)(=O)C>[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:10]=[C:11]([N:14]2[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]2)[S:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(-c3ccccc3Cl)cs2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: Clc1ccccc1-c1csc(N2CCNCC2)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 67.9 %

Procedure:
A 4 N solution (100 ml) of hydrogen chloride in ethyl acetate was added to a solution of tert-butyl 4-[4-(2-chlorophenyl)-1,3-thiazol-2-yl]piperazine-1-carboxylate (4.15 g, 10.9 mmol) in ethyl acetate (100 ml), the mixture was stirred at room temperature for 5 hours, and the solvent was distilled off under reduced pressure. The residue was dissolved in water, neutralized with a 1 N sodium hydroxide aqueous solution, and extracted with chloroform. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give 2.07 g (67.6%) of the desired product as a solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:49][N:50]1[CH:54]=[CH:53][CH:52]=[C:51]1[C:55]([NH:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)=[O:56]>CN(C)C=O>[C:58]1([NH:57][C:55]([C:51]2[N:50]([NH:49][C:13]([C@@H:9]3[CH2:10][CH2:11][CH2:12][N:8]3[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:15])[CH:54]=[CH:53][CH:52]=2)=[O:56])[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: Nn1cccc1C(=O)Nc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)Nn1cccc1C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
(S)-1-(tert-Butoxycarbonyl)pyrrolidine-2-carboxylic acid (1.80 g, 8.36 mmol) were dissolved in 20 ml of N,N-dimethylformamide and HATU (3.40 g, 8.95 mmol), DIEA (2.60 ml, 14.89 mmol) and 1-amino-N-phenyl-1H-pyrrole-2-carboxamide were added. The resulting solution was stirred at room temperature overnight and the solvent was removed in vacuum. The residue was taken up in ethyl acetate and the organic solution was washed with water and brine, dried over magnesium sulphate, filtered and evaporated to dryness. The crude product was purified by flash chromatography (0% to 30% hexane/AcOEt) to yield 1.90 g (62%) of the title compound as a white solid.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([C:13]3[C:22](=[O:23])[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[NH:15][CH:14]=3)=[O:12])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.Br[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[N:27]=1>>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([C:13]3[C:22](=[O:23])[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[N:15]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:34])([F:33])[F:35])[N:27]=4)[CH:14]=3)=[O:12])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: O=C(c1ccc2c(c1)OCCO2)c1c[nH]c2ccccc2c1=O
Reactant: FC(F)(F)c1cccc(CBr)n1
Product: O=C(c1ccc2c(c1)OCCO2)c1cn(Cc2cccc(C(F)(F)F)n2)c2ccccc2c1=O
Yield: 18.8 %

Procedure:
Experimental conditions analogous to those described for Step 3 of Example 1, from 3-(2,3-Dihydro-benzo[1,4]dioxine-6-carbonyl)-1H-quinolin-4-one 70 mg (0.228 mmol) and 71.1 mg (0.296 mmol) of 2-Bromomethyl-6-trifluoromethyl-pyridine, to give 20 mg of desired compound. LCMS (M+H)+: 467.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:11]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[CH:13]=1)[C:5](N(OC)C)=[O:6].Br[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([CH3:29])[CH:22]=1>>[Br:1][C:2]1[CH:3]=[C:4]([C:5]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([CH3:29])[CH:22]=2)=[O:6])[CH:11]=[C:12]([O:14][CH2:15][C:16]([F:17])([F:18])[F:19])[CH:13]=1
Reactant: COc1ccc(Br)cc1C
Reactant: CON(C)C(=O)c1cc(Br)cc(OCC(F)(F)F)c1
Product: COc1ccc(C(=O)c2cc(Br)cc(OCC(F)(F)F)c2)cc1C
Yield: 75 %

Procedure:
In analogy to the procedure described for the preparation of the Building Block AU, the reaction of the 3-bromo-N-methoxy-N-methyl-5-(2,2,2-trifluoro-ethoxy)-benzamide and 4-bromo-1-methoxy-2-methyl-benzene, beforehand transformed to the Grignard reagent, yielded the title compound as a white solid (yield: 75% of theory). Mass (calculated) C17H14BrF3O3 [402]; (found) [M]+=403, 405.
Reaction SMILES: [CH2:1]([C:8]1([OH:14])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].Cl[CH2:21][CH2:22][NH:23][C:24]([NH:26][C:27]1[CH:32]=[C:31]([CH3:33])[N:30]=[C:29]([CH3:34])[CH:28]=1)=[O:25]>C1COCC1>[CH2:1]([C:8]1([OH:14])[CH2:13][CH2:12][N:11]([CH2:21][CH2:22][NH:23][C:24]([NH:26][C:27]2[CH:32]=[C:31]([CH3:33])[N:30]=[C:29]([CH3:34])[CH:28]=2)=[O:25])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(NC(=O)NCCCl)cc(C)n1
Reactant: OC1(Cc2ccccc2)CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(NC(=O)NCCN2CCC(O)(Cc3ccccc3)CC2)cc(C)n1

Procedure:
A suspension of commercially available 4-benzyl-piperidin-4-ol (383 mg, 2.0 mmol). NaHCO3 (672 mg, 8.0 mmol) and 1-(2-chloro-ethyl)-3-(2,6-dimethyl-pyridin-4-yl)-urea (Example D1., 227.7 mg 1.0 mmol) in THF (4 mL) is stirred at 50° C. for 4 days. The mixture is quenched with Na2CO3 (10 mL) and extracted with CH2Cl2 (3×10 mL). The organic extracts are washed with sat. aq. Na2CO3 (10 mL), dried (Na2SO4), filtered and evaporated. The residue is purified by HPLC to provide the title compound.
Reaction SMILES: [CH3:1][C:2]([CH2:25][CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][O:18]C2CCCCO2)=[CH:11][CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[OH:18][CH2:17][CH2:16][O:15][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][C:2]([CH3:1])([CH2:25][CH2:26][CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:14][CH:13]=1
Reactant: CCOC(=O)C(C)(CCCc1ccccc1)Cc1ccc(OCCOC2CCCCO2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CCOC(=O)C(C)(CCCc1ccccc1)Cc1ccc(OCCO)cc1
Yield: 71.1 %

Procedure:
In a similar manner to that described in Reference example 3(f), a reaction was carried out using ethyl 2-methyl-2-(3-phenylpropyl)-3-[4-[2-(tetrahydropyran-2-yloxy)ethoxy]phenyl]propionate (1.64 g), which is the product of Reference example 7(e), and p-toluenesulfonic acid monohydrate (0.68 g) and the reaction mixture was treated to afford the desired compound (0.95 g) as a syrup.