Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.O1CCOCC1.[F:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1.C([O-])([O-])=O.[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CC(=O)OCC.O>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([C:23]3[CH:22]=[CH:21][CH:20]=[C:19]([F:18])[CH:24]=3)=[CH:3][N:4]=2)[N:7]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: Clc1ccc2ncc(Br)n2n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Fc1cccc(-c2cnc3ccc(Cl)nn23)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 61.8 %

Procedure:
To a solution of 3-bromo-6-chloroimidazo[1,2-b]pyridazine (500 mg, 2.15 mmol) in a mixed solvent of dioxane (5 mL) and water (0.5 mL) was added (3-fluorophenyl)boronic acid (273 mg, 1.96 mmol), K2CO3 (811 mg, 5.88 mmol) and Pd(dppf)2Cl2 (79 mg, 0.098 mmol). The reaction mixture was stirred at 80° C. overnight under N2. TLC (PE:EA=5:1) showed the starting material was consumed. The mixture was cooled and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether/EtOAc=20:1 to 1:1) to give 6-chloro-3-(3-fluorophenyl)imidazo[1,2-b]pyridazine (300 mg, 56%) as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[CH2:16]([C:23]1[N:27]=[C:26]([NH2:28])[S:25][N:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([C:23]1[N:27]=[C:26]([NH:28][C:2]2[CH:3]=[CH:4][C:5]([N:10]3[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]3)=[C:6]([CH:9]=2)[C:7]#[N:8])[S:25][N:24]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Nc1nc(Cc2ccccc2)ns1
Reactant: Cc1cn(-c2ccc(Br)cc2C#N)cn1
Product: Cc1cn(-c2ccc(Nc3nc(Cc4ccccc4)ns3)cc2C#N)cn1

Procedure:
Prepared in analogy to example 1b) starting with 5-bromo-2-(4-methyl-imidazol-1-yl)-benzonitrile and 3-benzyl-[1,2,4]thiadiazol-5-ylamine. The title compound was obtained as a white solid (Yield=21%). MS ISP (m/e): 373.1 (100) [(M+H)+].
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:5]([OH:6])[CH:4]=1.[CH3:12][C:13]1C=CC(S(OCCC#C)(=O)=O)=[CH:15][CH:14]=1>>[CH2:15]([O:6][C:5]1[CH:4]=[C:3]([CH:11]=[CH:10][C:7]=1[O:8][CH3:9])[CH:2]=[O:1])[CH2:14][C:13]#[CH:12]
Reactant: COc1ccc(C=O)cc1O
Reactant: C#CCCOS(=O)(=O)c1ccc(C)cc1
Product: C#CCCOc1cc(C=O)ccc1OC
Yield: 34.8 %

Procedure:
Isovanillin (0.95 g, 6.2 mmol) was alkylated with but-3-ynyl 4-methylbenzenesulfonate (2.1 g, 9.4 mmol) according to Procedure 4. The crude product was recystallised from EtOAc/petrol to provide 3-(but-3-ynyloxy)-4-methoxybenzaldehyde (0.44 g, 35%) as a colourless crystalline solid; mp 63-65° C.; δH (400 MHz, CDCl3) 2.06 (t, J=2.8 Hz, 1H, C≡CH), 2.76 (td, J=7.2, 2.8 Hz, 2H, CH2C≡CH), 3.96 (s, 3H, OCH3), 4.22 (t, J=7.2 Hz, 2H, OCH2), 6.99 (d, J5,6=8.0 Hz, 1H, H5), 7.43 (d, J2,6=1.4 Hz, 1H, H2), 7.45 (dd, J5,6=8.0, J2,6=1.4 Hz, 1H, H6), 9.85 (s, 1H, CHO); δC (100 MHz, CDCl3) 19.4, 56.2, 67.0, 70.3, 79.8, 110.9, 111.2, 127.1, 130.1, 148.4, 154.9, 190.7; vmax 1015, 1124, 1231, 1586, 1675, 2821, 3305 cm−1.
Reaction SMILES: BrCCBr.C[Si](Cl)(C)C.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([CH:23]=[O:24])[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].Br[C:26]([F:33])([F:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28]>C1COCC1.[Zn]>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([CH:23]([OH:24])[C:26]([F:33])([F:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reactant: CCOC(=O)C(F)(F)Br
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: CCOC(=O)C(F)(F)C(O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 49.8 %

Procedure:
A suspension of 4.38 g (67.0 mmol) of Zn powder in 40 mL of THF was treated with 0.58 mL (6.7 mmol) of 1,2-dibromoethane. The resulting mixture was heated at reflux for 2 min, then cooled to rt. Trimethylsilyl chloride (0.43 mL 3.4 mmol) was then added, the resulting mixture was stirred at ambient temperature for 20 min, the cooled to −5° C. A solution of 2.88 g (13.4 mmol) of 1-(t-butoxycarbonyl)-4-formyl piperidine and 9.52 g (46.9 mmol) of ethyl bromodifluoroacetate in 10 mL of THF was gradually added to the activated Zn. After the resulting exotherm subsided, the cooling bath was removed and the resulting mixture was stirred at rt for 20 h. The reaction was quenched with 50 mL of sat'd NH4Cl and the resulting mixture was partitioned between 300 mL of ether and 100 mL of H2O. The organic layer was separated, washed with 50 mL of sat'd NaHCO3, 50 mL of sat'd NaCl, dried and concentrated. Flash chromatography on 200 g of silica gel using 4:1 v/v, then 2:1 v/v hexanes/EtOAc as the eluants afforded 2.25 g (52%) of the title compound as an oil: 1H NMR (500 MHz, CDCl3) δ 1.31-1.34 (m, 1H), 1.37 (t, J=7.0, 3H), 1.45 (s, 9H), 1.69-1.72 (m, 2H), 1.86-1.92 (m, 2H), 2.40 (d, J=7.0, 1H), 2.68-2.72 (m, 2H), 3.83-3.90 (m, 1H), 4.104.20 (m, 2H), 4.36 (q, J=7.0, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[C:9]([O:16][CH3:17])=[C:8]2[C:4]=1[CH2:5][CH:6]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]1C(=O)C3=CC=CC=C3C1=O)[CH2:7]2.O.NN>C(O)C>[CH3:17][O:16][C:9]1[C:10]([O:14][CH3:15])=[C:11]([O:12][CH3:13])[C:3]([O:2][CH3:1])=[C:4]2[C:8]=1[CH2:7][CH:6]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH2:26])[CH2:5]2
Reactant: COc1c2c(c(OC)c(OC)c1OC)CC(CCCCCCCCN1C(=O)c3ccccc3C1=O)C2
Agent: NN
Solvent: O
Solvent: CCO
Product: COc1c2c(c(OC)c(OC)c1OC)CC(CCCCCCCCN)C2
Temperature: 25 °C
Yield: 91.8 %

Procedure:
The mixture of N-[8-(4,5,6,7-tetramethoxyindan-2-yl)octyl]phthalimide (384 mg), hydrazine monohydrate (194 mg) in ethanol (8 ml) was heated under reflux for 6 hr. The reaction mixture was cooled to room temperature and solid was filtered off and the filtrate was concentrated. The residue was diluted with ethyl acetate, washed with 1M aqueous potassium carbonate, water, and saturated aqueous sodium chloride, and dried. The solvent was removed in vacuo to yield the entitled compound (260 mg) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:13]=[C:12]([C:14]([OH:16])=[O:15])[N:11]=[CH:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].S(=O)(=O)(O)O.[CH3:22]O>>[CH3:22][O:15][C:14]([C:12]1[N:11]=[CH:10][N:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH:13]=1)=[O:16]
Reactant: CO
Reactant: O=C(O)c1cn(-c2ccc(Cl)c(Cl)c2)cn1
Agent: O=S(=O)(O)O
Product: COC(=O)c1cn(-c2ccc(Cl)c(Cl)c2)cn1
Yield: 81 %

Procedure:
A mixture of 1-(3,4-dichloro-phenyl)-1H-imidazole-4-carboxylic acid (7.0 g, 27 mmol), methanol (150 ml) and conc. sulfuric acid (25 ml) was refluxed for 3 h. The solution was then concentrated to 80 ml and a solution of sodium carbonate (60 g) in H2O at 0° C.(500 ml) was added. Extraction with CH2Cl2, drying of the organic phase and evaporation of the solvent gave a brown residue, which upon triturating with ether gave the title compound (6.0 g, 81%) as a light brown solid. MS: m/e=269.9 (M+).
Reaction SMILES: [CH:1]1([CH:4]([OH:26])[C:5]([N:7]2[CH2:11][C:10]([C:12]3[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=3[F:19])=[CH:9][C@H:8]2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:6])[CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]>CN(C=O)C>[CH:1]1([C@H:4]([O:26][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:5]([N:7]2[CH2:11][C:10]([C:12]3[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=3[F:19])=[CH:9][C@H:8]2[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: CCOC(=O)CBr
Reactant: O=C(C(O)C1CC1)N1CC(c2cc(F)ccc2F)=C[C@H]1c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CO[C@H](C(=O)N1CC(c2cc(F)ccc2F)=C[C@H]1c1ccccc1)C1CC1
Temperature: 23 °C
Reaction time: 0.17 h

Procedure:
A solution of (1S)-1-cyclopropyl-2-[(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]-2-oxoethanol (22-9, 150 mg, 0.422 mmol, 1 equiv) in DMP (1 mL) was cooled to 0° C. and treated with a solution of NaH (12 mg, 0.506 mmol, 1.2 eq) in DMF (0.5 ml), then stirred for 10 min. Ethyl bromoacetate (0.078 mL, 0.46 mmol, 1.1 eq) was added to the maroon-colored reaction mixture and the resulting mixture was stirred at 0° C. for 5 min, then warmed to 23° C. and stirred for 30 min. The yellow reaction mixture was partitioned between and water (65 mL) and EtOAc (2×60 mL) and the combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by reverse-phase liquid chromatography (acetonitrile/H2O with 0.1% TEA present) to afford ethyl ({(1S)-1-cyclopropyl-2-[(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]-2-oxoethyl}oxy)acetate (40-1) as a light yellow oil. 1H NMR (300, CDCl3) major rotamer: δ 7.22-7.39 (m, 5H), 6.93-7.12 (m, 3H), 6.42 (br s), 5.87 (d, 1H, J=2.4 Hz), 4.93 (br s, 2H), 4.29 (m, 2H), 3.92 (d, 1H, J=7.6 Hz), 3.66 (d, 1H, J=8.8 Hz), 3.41 (d, 1H, J=8.8 Hz), 1.18 (t, 3H, J=7.3 Hz), 0.61 (m, 4H). LRMS m/z (M+H) 442.4 found, 442.5 required.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][N:6]([C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[CH:7]([CH3:9])[CH3:8])C.[ClH:23].[OH:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[OH:34])[CH2:28][CH2:29][NH2:30].C(O)CCC>O>[ClH:23].[CH2:13]([O:12][C:10]([N:6]([CH2:5][CH:4]1[C:26]2[C:27](=[CH:31][CH:32]=[C:33]([OH:34])[C:25]=2[OH:24])[CH2:28][CH2:29][NH:30]1)[CH:7]([CH3:8])[CH3:9])=[O:11])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: NCCc1ccc(O)c(O)c1
Reactant: CCOC(CN(C(=O)OCc1ccccc1)C(C)C)OCC
Agent: Cl
Solvent: CCCCO
Solvent: O
Product: CC(C)N(CC1NCCc2ccc(O)c(O)c21)C(=O)OCc1ccccc1
Yield: 16.6 %

Procedure:
N-benzyloxycarbonyl-N-isopropylaminoacetaldehyde diethyl acetal (9 g) and 3,4-dihydroxyphenethylamine hydrochloride (4.5 g) were added to a mixture of n-butyl alcohol (100 ml) and water (15 ml) and then the mixture was refluxed for 6 hours. The above-mentioned acetal (2 g) was added thereto and the resultant mixture was refluxed for 1.5 hours. The solvent was distilled off from the reaction mixture. To the residue was added a mixed solvent of isopropyl alcohol, methanol and ether. The crystals obtained were recrystallized from the same mixed solvent to give 1-(N-benzyloxycarbonyl-N-isopropylaminomethyl)-7,8-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (1.6 g), mp 200° to 205° C. (dec). The mother liquor was concentrated and allowed to stand to give 1-(N-benzyloxycarbonyl-N-isopropylaminomethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (4.4 g), colorless crystals, mp 207° to 210° C. (dec).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]=[C:6]([C@H:8]([CH2:17][CH2:18][CH2:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[O:5][N:4]=1.[N:26]1[N:27]=[C:28]([S:31](Cl)(=[O:33])=[O:32])[NH:29][CH:30]=1>>[CH:20]1([CH2:19][CH2:18][CH2:17][C@@H:8]([C:6]2[O:5][N:4]=[C:3]([CH2:2][NH:1][S:31]([C:28]3[NH:29][CH:30]=[N:26][N:27]=3)(=[O:33])=[O:32])[N:7]=2)[CH2:9][C:10]([O:12][C:13]([CH3:15])([CH3:16])[CH3:14])=[O:11])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: O=S(=O)(Cl)c1nnc[nH]1
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(CN)no1
Product: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(CNS(=O)(=O)c2nnc[nH]2)no1

Procedure:
Method as for preparation 10 using tert-butyl(3R)-3-[3-(aminomethyl)-1,2,4-oxadiazol-5-yl]-6-cyclohexylhexanoate (preparation 18) (292 mg, 0.83 mmol) and 4H-1,2,4-triazole-3-sulfonyl chloride (preparation 24) (208 mg, 1.24 mmol) as starting materials.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OC(C)(C)[C:17]#[N:18].C([O-])([O-])=O.[K+].[K+]>C(O)C.C(OCC)C>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([OH:14])([C:17]#[N:18])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(O)C#N
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CCO
Product: N#CC1(O)CCN(Cc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 5 h
Yield: 84.6 %

Procedure:
To a solution of 2 g (10.6 mmoles) of 1-benzyl-piperidin-4-one in 14 ml of ethanol are added 6.8 ml (74.5 mmoles) of 2-hydroxy-2-methyl-propionitrile and 0.41 g (3 mmoles) of K2CO3 at 0° C. The mixture is stirred at 0° C. for 5 hours and diluted with diethyl ether. The organic layer is washed with water, dried over Na2SO4 and concentrated. Chromatography on silica gel (CH2Cl2:MeOH=9:1) gives 1.94 g of desired 1-benzyl-4-hydroxy-piperidine-4-carbonitrile in 85% yield.
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:49]1[CH:54]=[CH:53][C:52]([C:55]2[CH:56]=[C:57]([CH:59]=[CH:60][CH:61]=2)[NH2:58])=[CH:51][CH:50]=1>CN(C=O)C>[N:49]1[CH:54]=[CH:53][C:52]([C:55]2[CH:56]=[C:57]([NH:58][C:22]([C:17]3[C:18](=[O:21])[O:19][C:20]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[OH:10])=[O:24])[CH:59]=[CH:60][CH:61]=2)=[CH:51][CH:50]=1
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Reactant: Nc1cccc(-c2ccncc2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[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: O=C(Nc1cccc(-c2ccncc2)c1)c1cc2cccc(O)c2oc1=O
Temperature: 25 °C
Yield: 42.1 %

Procedure:
DIEA (0.028 mL, 0.160 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.030 g, 0.146 mmol) and HATU (0.061 g, 0.160 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-pyridin-4-ylaniline (0.025 g, 0.146 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.022 g of product in 42% yield: LCMS (ESI) m/z 359 (MH+).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[N:7]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([C:17](OC)=[O:18])[C:11]=2[CH:10]=[CH:9][CH:8]=1.O.[OH-].[Na+]>C1COCC1>[N:7]1[C:16]2[C:11](=[C:12]([CH2:17][OH:18])[CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)c1cccc2ncccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1cccc2ncccc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A suspension of 171 mg (4.49 mmol) of lithium aluminum hydride in 20 ml of THF is cooled to 0° C. A solution of 700 mg (3.74 mmol) of methyl quinoline-5-carboxylate in 5 ml of THF is then added dropwise. The reaction mixture is stirred at 0° C. for 1 hour and then hydrolysed with, in this order, 0.17 ml of H2O, 0.17 ml of NaOH and 3×0.17 ml of H2O. The precipitate formed is filtered off and washed with THF and then with EtOAc. The organic phase is washed with saturated NaCl solution, dried and evaporated. After purification by chromatography on silica gel (eluent: 95/5 DCM/MeOH), 190 mg of quinolin-5-ylmethanol are obtained, corresponding to the following characteristics:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:17]=[CH:18][C:19]([OH:21])=[O:20])[CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH2:14][O:15][CH3:16].[H][H]>CCOC(C)=O.CO.[Pd]>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:17][CH2:18][C:19]([OH:21])=[O:20])[CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH2:14][O:15][CH3:16]
Reactant: [H][H]
Reactant: COCCOc1ccc(C=CC(=O)O)cc1OCCOC
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COCCOc1ccc(CCC(=O)O)cc1OCCOC
Yield: 74.5 %

Procedure:
To a solution of 3-[3,4-Bis-(2-methoxy-ethoxy)-phenyl]-acrylic acid (20 g, 67.5 mmol) in EtOAc (100 ml) and MeOH (100 ml) was added carefully 10% Pd/C (1.5 g), then the mixture was shaken in Parr apparatus for 5 hs under 30-40 psi of hydrogen. The solution was passed through a celite pad, and the filtrate was concentrated to give product (15 g, 78.5%). LC-MS: m/e 297 (M−1)
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:3][CH2:2]1.[CH2:16]=[CH:17][CH:18]=[CH2:19]>C1(C)C=CC=CC=1>[CH:10]1[C:5]2[C:4]3([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:16][CH:17]=[CH:18][CH2:19][CH:3]3[CH2:2][O:1][C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)C1=CCOc2ccccc21
Reactant: C=CC=C
Solvent: Cc1ccccc1
Product: CCOC(=O)C12CC=CCC1COc1ccccc12
Temperature: 150 °C
Yield: 39.3 %

Procedure:
A solution of the product of Example 15 (20.3 g) was dissolved in toluene (100 ml) and to it was added BHT (0.5 g) and butadiene (73 g) the reaction vessal was pressurized with nitrogen (1900 psi) and heated to 150° C. for 6 days. The resulting syrup (40 g) was partitioned between heptane and acetonitrile. The acetonitrile solution was washed with fresh heptane then evaporated in vacuo. The heptane phase was extracted with fresh acetonitrile which was evaporated to give a further recovery of crude product. The resulting oils were chromatographed on silical gel (eluting with ethyl acetate:heptane (1:60)), to give the title compound as a crystalline solid (10.1 g, 38%), mp 88° C. ##STR26##
Reaction SMILES: Cl.Cl[C:3]1[N:8]=[N:7][C:6]([N:9]([CH3:11])[CH3:10])=[C:5]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:4]=1.C([O-])(=O)C.[Na+]>CO.[Pd]>[CH3:10][N:9]([CH3:11])[C:6]1[N:7]=[N:8][CH:3]=[CH:4][C:5]=1[N:12]1[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]1
Reactant: CN(C)c1nnc(Cl)cc1N1CCNCC1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CO
Product: CN(C)c1nnccc1N1CCNCC1

Procedure:
9.4 g (6-chloro-4-piperazin-1-yl-pyridazin-3-yl)-dimethylamine hydrochloride and 7.3 g sodium acetate are suspended in 150 ml of methanol and hydrogenated with 1 g Pd/C 10% at ambient temperature. The catalyst is suction filtered, the filtrate is evaporated to dryness and the product is extracted with chloroform and washed with sodium hydroxide solution. The hydrochloride is precipitated with an ethereal HCl solution. 7 g (V-1) are obtained. M.p.=335° C.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]([O:12]C)=[O:11])[C:4]=2[CH:3]=[CH:2]1.Cl[CH2:15][C:16]1[CH:17]=[C:18]([CH:54]=[CH:55][CH:56]=1)[C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:24][C:23]=1[C:34]1[CH:35]=[C:36]([CH:51]=[CH:52][N:53]=1)[C:37]([NH:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([C:47]([F:50])([F:49])[F:48])[CH:42]=1)=[O:38])=[O:20].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N:28]1([C:25]2[CH:26]=[CH:27][C:22]([NH:21][C:19]([C:18]3[CH:17]=[C:16]([CH:56]=[CH:55][CH:54]=3)[CH2:15][N:1]3[C:9]4[CH:8]=[CH:7][CH:6]=[C:5]([C:10]([OH:12])=[O:11])[C:4]=4[CH:3]=[CH:2]3)=[O:20])=[C:23]([C:34]3[CH:35]=[C:36]([C:37](=[O:38])[NH:39][CH2:40][C:41]4[CH:46]=[CH:45][CH:44]=[C:43]([C:47]([F:48])([F:49])[F:50])[CH:42]=4)[CH:51]=[CH:52][N:53]=3)[CH:24]=2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(N3CCCCC3)ccc2NC(=O)c2cccc(CCl)c2)c1
Reactant: COC(=O)c1cccc2[nH]ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(N3CCCCC3)ccc2NC(=O)c2cccc(Cn3ccc4c(C(=O)O)cccc43)c2)c1
Reaction time: 24 h
Yield: 48.3 %

Procedure:
A mixture of 10.5 mg of methyl 1H-indole-4-carboxylate, 18.2 mg of 2-(2-(3-(chloromethyl)benzamido)-5-(piperidin-1-yl)phenyl)-N-(3-(trifluoromethyl)benzyl)-isonicotinamide 8.1a, and excess potassium carbonate in 300 μL of DMF was stirred for 24 h. The solvent was evaporated and the residue was purified by silica gel chromatography. The product was dissolved in 1 mL of 4:1 THF/water and treated with 10 mg of LiOH.H2O. After stirring 4 days at 70° C. the reaction mixture was acidified with 3.0 N hydrochloric acid and then extracted with ethyl acetate. The aqueous phase was washed with ethyl acetate, and the combined organic extracts washed with brine and dried (NaSO4). The residue was purified by reverse phase HPLC eluting with 0.1% TFA in a water/acetonitrile gradient to give 10.6 mg of product. MS (ES, m/z) 732.4 [M+H]+.
Reaction SMILES: Cl.[CH2:2]([C:4]1[C:5]([NH:14][C@H:15]2[CH2:19][CH2:18][CH2:17][C@@H:16]2[NH2:20])=[N:6][CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[N:9]=1)[CH3:3].[CH3:21][C:22]1[N:26]=[C:25]([C:27]2[CH:35]=[CH:34][CH:33]=[CH:32][C:28]=2[C:29](O)=[O:30])[O:24][N:23]=1.N1C2C(=NC=CC=2)N(O)N=1.C(Cl)CCl.C(N(CC)CC)C>C(Cl)Cl>[CH2:2]([C:4]1[C:5]([NH:14][C@H:15]2[CH2:19][CH2:18][CH2:17][C@@H:16]2[NH:20][C:29](=[O:30])[C:28]2[CH:32]=[CH:33][CH:34]=[CH:35][C:27]=2[C:25]2[O:24][N:23]=[C:22]([CH3:21])[N:26]=2)=[N:6][CH:7]=[C:8]([C:10]([F:13])([F:11])[F:12])[N:9]=1)[CH3:3]
Reactant: Cc1noc(-c2ccccc2C(=O)O)n1
Reactant: CCc1nc(C(F)(F)F)cnc1N[C@H]1CCC[C@@H]1N
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1nc(C(F)(F)F)cnc1N[C@H]1CCC[C@@H]1NC(=O)c1ccccc1-c1nc(C)no1

Procedure:
A solution of (1S,2S)-1-N-[3-ethyl-5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 41; 450 mg, 1.64 mmol), 2-(3-methyl-1,2,4-oxadiazol-5-yl)benzoic acid (CAS number 475105-77-2; 335 mg, 1.64 mmol), 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (335 mg, 2.46 mmol), EDC (472 mg, 2.46 mmol) and triethylamine (0.687 ml, 4.92 mmol) in DCM (5 ml) was stirred at room temperature for 16 hours. The reaction was partitioned between DCM and a saturated solution of sodium bicarbonate, filtered through a hydrophobic frit and loaded directly on to a cation/anion mixed mode cartridge, eluted with DCM and concentrated in vacuo. The resulting residue was purified by reverse phase chromatography (C18 silica, 0-100% water (0.1% ammonia)/acetonitrile) and recrystalised from MTBE/heptane to afford the title compound.
Reaction SMILES: [N:1]1([N:7]2[C:11](=[O:12])[CH2:10][S:9][C:8]2=[O:13])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:14][C:15]1[CH:32]=[CH:31][C:18]([CH2:19][N:20]2[C:28]3[C:23](=[CH:24][C:25]([CH:29]=O)=[CH:26][CH:27]=3)[CH:22]=[N:21]2)=[C:17]([C:33]([F:36])([F:35])[F:34])[CH:16]=1>>[Cl:14][C:15]1[CH:32]=[CH:31][C:18]([CH2:19][N:20]2[C:28]3[C:23](=[CH:24][C:25](/[CH:29]=[C:10]4/[C:11](=[O:12])[N:7]([N:1]5[CH2:6][CH2:5][O:4][CH2:3][CH2:2]5)[C:8](=[O:13])[S:9]/4)=[CH:26][CH:27]=3)[CH:22]=[N:21]2)=[C:17]([C:33]([F:34])([F:36])[F:35])[CH:16]=1
Reactant: O=C1CSC(=O)N1N1CCOCC1
Reactant: O=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1
Product: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1N1CCOCC1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-morpholin-4-yl-1,3-thiazolidine-2,4-dione was prepared from 3-morpholin-4-yl-thiazolidine-2,4-dione and [4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-carbaldehyde (from Example 1) following General Procedure F.
Reaction SMILES: O=C[C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.[C:12](O)(=O)[CH2:13]C(O)=O.N1CCCCC1>C(O)(=O)C>[CH:12]([C:11]1[CH:10]=[C:8]([OH:9])[C:5]([O:6][CH3:7])=[CH:4][CH:3]=1)=[CH2:13]
Reactant: COc1cc(C=O)ccc1O
Reactant: O=C(O)CC(=O)O
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: C=Cc1ccc(OC)c(O)c1
Yield: 51 %

Procedure:
A mixture of vanillin (2.50 g, 0.0164 mol), malonic acid (3.41 g, 0.0328 mol), piperidine (3–5 ml) and acetic acid (10–20 mL) were taken in a 100 ml Erlenmeyer flask fitted with a loose funnel at the top. The flask was shaken well and placed inside the microwave oven and irradiated for 1–7 minutes in parts. The cooled mixture was poured into ice-cold water and extracted with ethyl acetate. The organic layer was washed with dil HCl., saturated sodium chloride and then organic layer dried over sodium sulphate. The solvent was evaporated under reduced pressure to obtain liquid which was purified on silica gel column chromatography using mixture of hexane and ethyl acetate (9:1 to 6:4), provided sweet and pleasant smelling liquid in 51% yield; 1H NMR (CDCl3) δ 6.96 (3H, m, 3,5,6-Ar), 6.70 (1H, dd, J=7.8 Hz, CH═CH2), 5.93 (1H, s, OH), 5.66 (1H, d, J=17.6, cis-CH═CH2), 5.19 (1H, d, J=10.9 Hz, trans-CH═CH2), 3.90 (3H, s, OMe); 13C NMR (CDCl3) δ 147.1 (C-1), 146.07 (C-2), 137.1 (CH═CH2), 130.7 (C-4), 120.4 (C-6), 114.9 (C-5), 111.8 (CH═CH2), 108.5 (C-3), 56.2 (OCH3).