Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5](=[O:13])[N:6]([CH2:8][C:9]([OH:12])([CH3:11])[CH3:10])[CH:7]=1.[OH:14][C:15]([CH3:48])([CH3:47])[CH2:16][C@@:17]1([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[O:22][C:21](=[O:23])[N:20]([C@H:24]([C:26]2[CH:31]=[CH:30][C:29](B3OC(C)(C)C(C)(C)O3)=[CH:28][CH:27]=2)[CH3:25])[CH2:19][CH2:18]1.C([O-])(O)=O.[Na+]>COCCOC.CCO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:14][C:15]([CH3:47])([CH3:48])[CH2:16][C@@:17]1([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[O:22][C:21](=[O:23])[N:20]([C@H:24]([C:26]2[CH:27]=[CH:28][C:29]([C:2]3[CH:3]=[CH:4][C:5](=[O:13])[N:6]([CH2:8][C:9]([OH:12])([CH3:11])[CH3:10])[CH:7]=3)=[CH:30][CH:31]=2)[CH3:25])[CH2:19][CH2:18]1
Reactant: CC(C)(O)Cn1cc(Br)ccc1=O
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: C[C@@H](c1ccc(-c2ccc(=O)n(CC(C)(C)O)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 0 %

Procedure:
To a solution of 5-bromo-1-(2-hydroxy-2-methylpropyl)pyridin-2(1H)-one (20 mg, 81.3 mmol) in DME (6 mL) was added Pd(PPh3)4 (10 mg) under nitrogen. The mixture was stirred for 1 h at rt, and a solution of (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one (38.95 mg, 81.3 mmol) in EtOH (2 mL) and satd aq NaHCO3 (2 mL) were added. The resulting mixture was stirred at 100° C. for 2 h, quenched with water, and extracted with EtOAc. The combined organic layer was dried over anhydrous Na2SO4 and concentrated to give the crude product, which was purified by preparative TLC and preparative HPLC to afford (S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-(2-hydroxy-2-methylpropyl)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (6.5 mg, 15.5%). LC-MS Method 2 tR=0.99 min, m/z=519; 1H NMR (CDCl3): δ 7.60-7.57 (d, 1H), 7.43 (s, 1H), 7.36-7.26 (m, 5H), 7.15 (d, 2H), 7.01 (d, 2H), 6.70 (d, 1H), 2.85 (m, 1H), 5.69-5.66 (m, 1H), 4.13-4.09 (s, 2H), 4.05-3.98 (s, 1H), 2.89-2.86 (m, 1H), 2.44-2.36 (m, 1H), 2.28-2.16 (m, 5H), 1.58-1.53 (d, 3H), 1.33-1.30 (s, 6H), 1.19 (s, 3H), 1.12 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)[N:11]=[C:10]([CH2:23]O)[CH:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[CH3:37][O:38][C:39]1[CH:40]=[C:41]([SH:45])[CH:42]=[CH:43][CH:44]=1.[H-].[Na+].S([O-])(=O)(=O)C.Cl>C1COCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)[N:11]=[C:10]([CH2:23][S:45][C:41]3[CH:42]=[CH:43][CH:44]=[C:39]([O:38][CH3:37])[CH:40]=3)[CH:9]=2)=[CH:6][CH:7]=1
Reactant: NS(=O)(=O)c1ccc(-n2nc(CO)cc2-c2ccc(Cl)cc2)cc1
Reactant: COc1cccc(S)c1
Agent: CS(=O)(=O)Cl
Agent: CS(=O)(=O)[O-]
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1cccc(SCc2cc(-c3ccc(Cl)cc3)n(-c3ccc(S(N)(=O)=O)cc3)n2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.9 %

Procedure:
4-[5-(4-Chlorophenyl)-3-hydroxymethyl)-1H-pyrazol-1-yl]benzenesulfonamide from Step 3 (500 mg, 1.374 mmol) was dissolved in anhydrous THF (30 mL). Triethylamine (0.385 mL, 2.749 mmol) and methanesulfonyl chloride (0.16 mL, 2.062 mmol) were added sequentially, and the cloudy suspension was stirred at room temperature for 0.5 hour. The reaction was diluted with ethyl acetate (35 mL) and washed with aqueous HCl (1N, 50 mL). The organic solution was dried over anhydrous MgSO4 and filtered, then the solvent was evaporated under reduced pressure to yield a crude oil. The oil was dissolved in anhydrous THF (10 mL). 3-Methoxythiophenol (0.205 mL, 1.649 mmol) was dissolved in anhydrous THF. Sodium hydride (95%, 42 mg, 1.649 mmol) was added, and the resulting frothy suspension was stirred at room temperature for 20 minutes, forming a clear, colorless solution. The solution of the mesylate prepared above was added, then the reaction was warmed to 40° C. and held for 16 hours. The reaction was cooled to room temperature then 1N HCl (30 mL) was added. After stirring an additional 0.5 hour, the system was extracted with ethyl acetate (2×40 mL). The combined organic solution was sequentially washed with 1 N HCl (40 mL), saturated aqueous NaHCO3 (2×40 mL), 50% saturated NaCl (2×40 mL), and brine (40 mL), then dried over anhydrous MgSO4 and filtered. The solvents were evaporated under reduced pressure to yield an oil. The oil was purified by flash chromatography over silica gel eluting with 40% ethyl acetate in hexane to yield 4-[5-(4-chlorophenyl)-3-(3-methoxyphenyl)thiomethyl-1H-pyrazol-1-yl]benzenesulfonamide (273 mg, 41%) as a foam: Mass Spectrum: 486 (MH+). High resolution mass spectrum Calc'd. for C23H20N3O3ClS2: 486.0713. Found: 486.0757. Anal. Calc'd. for C23H20N3O3ClS2: C, 56.84; H, 4.15; N, 8.65; Cl, 7.29; S, 13.19. Found: C, 56.56; H, 4.22; N, 8.61; Cl, 7.41; S, 13.00.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[S:8][CH:9]=[C:10]([C:12]3[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=3)[N:11]=2)[CH2:3][CH2:2]1.[CH2:21]=O>C(O)(=O)C.CO.O1CCCC1>[CH3:21][N:1]1[CH2:6][CH2:5][CH:4]([C:7]2[S:8][CH:9]=[C:10]([C:12]3[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=3)[N:11]=2)[CH2:3][CH2:2]1
Reactant: C=O
Reactant: O=C(O)c1ccc(-c2csc(C3CCNCC3)n2)cc1
Solvent: C1CCOC1
Solvent: CO
Solvent: CC(=O)O
Product: CN1CCC(c2nc(-c3ccc(C(=O)O)cc3)cs2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-(2-Piperidin-4-yl-thiazol-4-yl)-benzoic acid (1 mmol) in acetic acid (0.5 mL), methanol (3 mL) and tetrahydrofurane (4.5 mL) was added formaldehyde (aq. 37%, 300 mL) and polystyrene bound cyanoborohydride (2.36 mmol/g, 900 mg). The slurry was then agitated for 16 hours at room temperature. The slurry was then filtered and the resin washed with methanol (2 mL). The solution was concentrated to dryness in vacuo. m/z=303.1 in MS ES+, which was characterized by hplc and MS and used in the next step without any further purification.
Reaction SMILES: [CH2:1]([N:5]([CH2:9][CH2:10][CH2:11][CH3:12])[CH2:6][CH2:7][NH2:8])[CH2:2][CH2:3][CH3:4].[C:13]([C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([CH2:24][CH2:25][NH:26][C:27](=[O:41])[C:28]3[CH:33]=[CH:32][C:31]([C:34]4[CH:39]=[CH:38][N:37]=[C:36](Cl)[N:35]=4)=[CH:30][CH:29]=3)[CH:22]=2)[NH:17][CH:16]=1)#[N:14]>>[C:13]([C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([CH2:24][CH2:25][NH:26][C:27](=[O:41])[C:28]3[CH:33]=[CH:32][C:31]([C:34]4[CH:39]=[CH:38][N:37]=[C:36]([NH:8][CH2:7][CH2:6][N:5]([CH2:9][CH2:10][CH2:11][CH3:12])[CH2:1][CH2:2][CH2:3][CH3:4])[N:35]=4)=[CH:30][CH:29]=3)[CH:22]=2)[NH:17][CH:16]=1)#[N:14]
Reactant: CCCCN(CCN)CCCC
Reactant: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(Cl)n4)cc3)cc12
Product: CCCCN(CCCC)CCNc1nccc(-c2ccc(C(=O)NCCc3ccc4[nH]cc(C#N)c4c3)cc2)n1

Procedure:
Using 2-(dibutylamino)-ethylamine and N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide (reference example 1az) as substrates.
Reaction SMILES: [F:1][C:2]1([F:16])[O:6][C:5]2[CH:7]=[CH:8][C:9]([CH:11]=[CH:12][C:13](O)=[O:14])=[CH:10][C:4]=2[O:3]1.C(Cl)(=O)C(Cl)=O.[NH3:23]>O1CCCC1.CN(C)C=O>[F:1][C:2]1([F:16])[O:6][C:5]2[CH:7]=[CH:8][C:9]([CH:11]=[CH:12][C:13]([NH2:23])=[O:14])=[CH:10][C:4]=2[O:3]1
Reactant: O=C(O)C=Cc1ccc2c(c1)OC(F)(F)O2
Reactant: N
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: NC(=O)C=Cc1ccc2c(c1)OC(F)(F)O2
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
To a suspension of 8.00 g (35.1 mmol) 3-(2,2-difluoro-benzo[1,3]dioxol-5-yl)-acrylic acid in 40 ml tetrahydrofuran and 0.4 ml N,N-dimethyl formamide, 3.86 ml (45.0 mmol) oxalyl chloride was added dropwise at 0° C. within 10 min. Stirring was continued at 0-5° C. for 30 min. and 2 h at room temperature thereafter. The resulting solution was cooled to 0-5° C. again and then added within 15 min. to 34 ml of an 25% aqueous solution of ammonia. After stirring for 30 min. the precipitated amide was collected, washed with water and dried at 40° C. in vacuo. 7.20 g (90%) 3-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-acrylamide were obtained.
Reaction SMILES: [OH:1][C@:2]([C:32]1[CH:36]=[C:35]([CH3:37])[O:34][N:33]=1)([CH3:31])[C:3]#[C:4][C:5]1[CH:6]=[CH:7][C:8]2[O:14][CH2:13][CH2:12][N:11]3[C:15]([C:21]([NH:23][CH:24]4[CH2:29][CH2:28]O[CH2:26][CH2:25]4)=[O:22])=[C:16]([C:18]([NH2:20])=[O:19])[N:17]=[C:10]3[C:9]=2[CH:30]=1.Cl.NC1CC[C:43]([F:47])([F:46])CC1>>[F:46][C:43]1([F:47])[CH2:28][CH2:29][CH:24]([NH:23][C:21]([C:15]2[N:11]3[CH2:12][CH2:13][O:14][C:8]4[CH:7]=[CH:6][C:5]([C:4]#[C:3][C@@:2]([OH:1])([C:32]5[CH:36]=[C:35]([CH3:37])[O:34][N:33]=5)[CH3:31])=[CH:30][C:9]=4[C:10]3=[N:17][C:16]=2[C:18]([NH2:20])=[O:19])=[O:22])[CH2:25][CH2:26]1
Reactant: NC1CCC(F)(F)CC1
Reactant: Cc1cc([C@](C)(O)C#Cc2ccc3c(c2)-c2nc(C(N)=O)c(C(=O)NC4CCOCC4)n2CCO3)no1
Agent: Cl
Product: Cc1cc([C@](C)(O)C#Cc2ccc3c(c2)-c2nc(C(N)=O)c(C(=O)NC4CCC(F)(F)CC4)n2CCO3)no1

Procedure:
Prepared as described for (R)-10-(3-hydroxy-3-(5-methylisoxazol-3-yl)but-1-yn-1-yl)-N3-(tetrahydro-2H-pyran-4-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2,3-dicarboxamide replacing 4-aminotetrahydropyran with 4-amino-1,1-difluorocyclohexane hydrochloride. Off-white solid 40.2 mg, 12%).
Reaction SMILES: C([NH:5][C:6]1[CH:11]=[C:10]([CH:12]([F:14])[F:13])[CH:9]=[CH:8][N:7]=1)(C)(C)C.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>>[F:13][CH:12]([F:14])[C:10]1[CH:9]=[CH:8][N:7]=[C:6]([NH2:5])[CH:11]=1
Reactant: CC(C)(C)Nc1cc(C(F)F)ccn1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: Nc1cc(C(F)F)ccn1
Temperature: 90 °C
Reaction time: 21 h
Yield: 99.2 %

Procedure:
A flask containing N-tert-butyl-4-(difluoromethyl)pyridin-2-amine (4.43 g, 22.1 mmol), triethylsilane (7.28 mL, 44.2 mmol) and trifluoroacetic acid (22.1 mL, 1 M) was fitted with a reflux condenser. The reaction mixture was stirred at 90° C. for 21 hr and then, after cooling to rt, concentrated to dryness and partitioned between CH2Cl2 and sat. aq. NaHCO3. After separation of the phases, the aqueous layer was re-extracted with CH2Cl2 and the combined organics were dried over MgSO4. Concentration afforded 4-(difluoromethyl)pyridin-2-amine as a light brown solid (3.16 g, >99%); 1H NMR (400 MHz, CDCl3) δ 8.16 (d, J=5.3 Hz, 1H), 6.74 (d, J=5.3 Hz, 1H), 6.66-6.33 (m, 2H), 4.62 (br s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH2:8][C:7](=[O:11])[CH2:6]1)=[O:4].[BH4-].[Na+].O.CCOC(C)=O>CO>[OH:11][CH:7]1[CH2:8][CH2:9][CH2:10][CH:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:6]1
Reactant: COC(=O)C1CCCC(=O)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)C1CCCC(O)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
3-oxo-1-cyclohexanecarboxylic acid methyl ester (1.1 g, 7.04 mmol) was dissolved in methanol (25 ml) and cooled to 0° C. under N2. Sodium borohydride (0.550 g, 14.54 mmol) was added in portions and the resulting solution stirred at 0° C. for 2 h. The solution was then diluted by the dropwise addition of water, followed by EtOAc (100 mL). The aqueous phase was separated and extracted with EtOAc (2×50 ml). The combined organic layers were washed with brine, dried over sodium sulphate, and concentrated in vacuo to give the title compound. TLC: 40% EtOAc/hexanes, high Rf: 0.4, low Rf: 0.3.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][N:22]3[CH2:27][CH2:26][N:25]([C:28]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[O:29])[CH2:24][CH2:23]3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.N1(CCCOC2C=CC(CN3CCCNCC3)=CC=2)CCCCC1>>[C:30]1([C:28]([N:25]2[CH2:24][CH2:23][N:22]([CH2:21][C:18]3[CH:19]=[CH:20][C:15]([O:14][CH:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)=[CH:16][CH:17]=3)[CH2:27][CH2:26]2)=[O:29])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(CN3CCN(C(=O)c4ccccc4)CC3)cc2)CC1
Agent: c1cc(OCCCN2CCCCC2)ccc1CN1CCCNCC1
Product: O=C(c1ccccc1)N1CCN(Cc2ccc(OC3CCNCC3)cc2)CC1

Procedure:
The title compound (E32) was prepared from 4-{4-[4-(1-phenyl-methanoyl)-piperazin-1-ylmethyl]-phenoxy}-piperidine-1-carboxylic acid tert-butyl ester (D7) using the method described in Description 4 (D4). MS(ES+) m/e 380 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]([C:13]1[CH:26]=[CH:25][C:16]([O:17][CH2:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[C:15]([CH3:27])[CH:14]=1)([C:6]1[CH:11]=[CH:10][C:9](I)=[CH:8][CH:7]=1)[CH2:4][CH3:5])[CH3:2].[CH3:28][N:29](C=O)C>CCOCC.[C-]#N.[C-]#N.[Zn+2].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].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.[Fe+2]>[CH3:21][C:20]([CH3:23])([CH3:22])[C:19](=[O:24])[CH2:18][O:17][C:16]1[CH:25]=[CH:26][C:13]([C:3]([C:6]2[CH:11]=[CH:10][C:9]([C:28]#[N:29])=[CH:8][CH:7]=2)([CH2:4][CH3:5])[CH2:1][CH3:2])=[CH:14][C:15]=1[CH3:27]
Reactant: CCC(CC)(c1ccc(I)cc1)c1ccc(OCC(=O)C(C)(C)C)c(C)c1
Reactant: CN(C)C=O
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOCC
Product: CCC(CC)(c1ccc(C#N)cc1)c1ccc(OCC(=O)C(C)(C)C)c(C)c1
Temperature: 100 °C
Yield: 46 %

Procedure:
To a mixture of 1-{4-[1-ethyl-1-(4-iodo-phenyl)-propyl]-2-methyl-phenoxy}-3,3-dimethyl-butan-2-one (3.0 g 6.27 mmol) and DMF (30 mL) is added Zn(CN)2 (0.44 g, 3.76 mmol), Pd2(dba)3 (0.29 g, 0.31 mmol), and DPPF (0.42 g, 0.75 mmol). The solution is heated at 100° C. overnight, diluted with Et2O (200 mL), washed with 4:1:4 sat NH4Cl:Conc. NH4OH:water (100 mL), water (100 mL), brine (100 mL), dried MgSO4, filtered and concentrated. The residue is purified by ISCO (10%-2-% EtOAc gradient) to furnish the title compound (1.1 g, 2.91 mmol, 46%).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:18]=[CH:19][CH:20]=2)[O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:22]1[S:23][C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=1>C(OCC)(=O)C>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:18]=[CH:19][CH:20]=2)[O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:22]2[S:23][C:24]3[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=3[N:26]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Clc1nc2ccccc2s1
Reactant: NCCCCCOc1cccc(CN2CCCCC2)c1
Solvent: CCOC(C)=O
Product: c1cc(CN2CCCCC2)cc(OCCCCCNc2nc3ccccc3s2)c1

Procedure:
5-(3-(Piperidinomethyl)phenoxy]pentylamine (0.8 g) and 2-chlorobenzthiazole (0.53 g) were fused at 140° C. for 3 hours. The cooled residue was subjected to medium pressure column chromatography on silica using ethyl acetate as eluant to give the title compound as an oil. This was converted to 2-[5-[3-piperidinomethyl)phenoxy]pentylamino]benzthiazole dihydrochloride (0.18 g), m.p. 140°-145° C. (recrystallised from ethanol/ether).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1([C:23]#[N:24])[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.N>[Ni].CO>[NH2:24][CH2:23][C:10]1([CH2:9][O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(COCc2ccccc2)CC1
Agent: [Ni]
Agent: N
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(CN)(COCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.9 %

Procedure:
To a slurry of Raney nickel (1 g, 10% w/w) in methanol are added tert-butyl 4-[(benzyloxy)methyl]-4-cyanopiperidine-1-carboxylate (10 g, 30.3 mmol) and methanol/NH3 (1 mL). The reaction mixture is stirred at room temperature under 60 psi of H2 for 16 h. Then the reaction mixture is filtered through a pad of Celite and the filtrate is concentrated to afford the title compound (8 g, 79%) as a colorless liquid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:8]([C:10]1[CH:11]=[C:12](B(O)O)[CH:13]=[CH:14][CH:15]=1)=[O:9].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO.CCOC(C)=O.[Cl-].[Na+].O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[C:2]1([C:14]2[CH:15]=[C:10]([CH:11]=[CH:12][CH:13]=2)[CH:8]=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccccc1
Reactant: O=Cc1cccc(B(O)O)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=Cc1cccc(-c2ccccc2)c1
Yield: 115.8 %

Procedure:
In a microwave tube, to a solution of bromo-benzene (0.5 g, 3.18 mmol) dissolved in a 1:1 mixture toluene/EtOH (14 mL), 3-formylphenyl boronic acid (0.573 g, 3.82), palladium-tetrakis(triphenylphosphine) (0.184 g, 0.159 mmol) and 10% Na2CO3 solution (7 mL) were sequentially added. The reaction was run at 100° C. for 30 min under microwave irradiation. The crude product was diluted with AcOEt and brine, and extracted. The organic phase was separated, dried over Na2SO4 and filtered over a pad of celite to give an organic fraction, which was concentrated to dryness to afford the title compound (0.671 g, quant.). 1H NMR (CDCl3): δ 8.23-7.36 (m, 9H), 10.13 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:7](=[O:18])[CH:6]=[N:5]2.[OH:19]O>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:7](=[O:18])[C:6](=[O:19])[NH:5]2
Reactant: CCOC(=O)Cn1c(=O)cnc2cc(Br)ccc21
Reactant: OO
Solvent: CC(=O)O
Product: CCOC(=O)Cn1c(=O)c(=O)[nH]c2cc(Br)ccc21
Yield: 77 %

Procedure:
The above ester (1.25 g; 4 mmol) was reacted with 30% H2O2 (6 ml) in glacial acetic acid (16 ml) at 55° C. for 2 h. The mixture was cooled, the precipitate filtered off and recrystallized from dilute acetic acid to afford 1.0 g (77%) of the title compound. M.p. 282°-83° C. 1H-NMR (DMSO-d6):δ1.22 (t, 3H), 4.17 (q, 2H), 4.92 (s, 1H), 7.33 (m, 3H), 12.24 (br.s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:36])[CH:5]=[CH:6][CH:7]([N:18]([CH3:35])[C:19](=[O:34])[C:20]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]([F:33])([F:32])[F:31])[CH:21]=1)[CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1)[CH3:2].ClC1C=CC=CC=1Cl>O1CCCC1.[Pd]>[CH2:1]([O:3][C:4](=[O:36])[CH2:5][CH2:6][CH:7]([N:18]([CH3:35])[C:19](=[O:34])[C:20]1[CH:25]=[C:24]([C:26]([F:28])([F:27])[F:29])[CH:23]=[C:22]([C:30]([F:31])([F:32])[F:33])[CH:21]=1)[CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)C=CC(Cc1c[nH]c2ccccc12)N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: Clc1ccccc1Cl
Product: CCOC(=O)CCC(Cc1c[nH]c2ccccc12)N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
A solution of 34.3 g of 4-[N-methyl-N-(3,5-bistrifluoromethyl-benzoyl)-amino]-5-(1H-indol-3-yl)-pent-2-enoic acid ethyl ester in 340 ml of tetrahydrofuran is hydrogenated at 20° C. for 80 minutes in the presence of 3.4 g of palladium/activated carbon (10%) and 0.4 g of 1,2-dichlorobenzene. The reaction mixture is then filtered and concentrated by evaporation. In this way the title compound is obtained in the form of a brownish resin.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[CH:10][C:11](=O)[NH:12][N:13]=1.P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:11]1[N:12]=[N:13][C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[C:9]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)n[nH]1
Product: Clc1ccc(-c2cc(Cl)nnc2-c2ccccc2Cl)cc1
Temperature: 95 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
A suspension of 6-(2-chlorophenyl)-5-(4-chlorophenyl)pyridazin-3(2H)-one (4.1 g, 12.9 mmol) in phosphorus oxychloride (15 mL) was stirred at 95° C. for 1 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was partitioned between EtOAc and saturated aqueous NaHCO3. The separated aqueous layer was extracted with EtOAc (40 mL×2). The combined organic was washed with saturated aqueous NaHCO3, saturated aqueous NaCl, dried (Na2SO4) and concentrated under reduced pressure to afford 4.2 g (97%) of the title compound as a pink foam. HPLC/MS (method A): retention time=3.50 min, (M+H)+=335.0.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][C:9]=2[CH2:17][CH:18]([CH3:20])[CH3:19])=[CH:4][CH:3]=1.[C:23]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)(=[O:27])[CH:24]([CH3:26])[CH3:25]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([N:31]3[CH2:32][CH2:33][N:28]([C:23](=[O:27])[CH:24]([CH3:25])[CH3:26])[CH2:29][CH2:30]3)=[O:14])=[CH:10][C:9]=2[CH2:17][CH:18]([CH3:20])[CH3:19])=[CH:21][CH:22]=1
Reactant: CC(C)Cc1cc(C(=O)O)ccc1OCc1ccc(F)cc1
Reactant: CC(C)C(=O)N1CCNCC1
Product: CC(C)Cc1cc(C(=O)N2CCN(C(=O)C(C)C)CC2)ccc1OCc1ccc(F)cc1
Yield: 90 %

Procedure:
As in the case of Example 16, 4-(4-fluorobenzyloxy)-3-isobutylbenzoic acid (1.51 g) was subjected to a condensation reaction with 1-isobutyrylpiperazine (0.78 g). Thus obtained solid was recrystallized (from ether) to yield 1.98 g of the aimed compound.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)=[CH:4][C:3]=1OC.[F:32]C1C=CC(C=CCBr)=CC=1>>[F:32][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1
Reactant: COc1cc(/C=C/CN2CCC(c3ccc(Oc4ccccc4)cc3)CC2)ccc1O
Reactant: Fc1ccc(C=CCBr)cc1
Product: Fc1ccc(/C=C/CN2CCC(c3ccc(Oc4ccccc4)cc3)CC2)cc1

Procedure:
The same procedure was followed as in Example 11 using the compound (9) synthesized in Example 2 and 4-fluorocinnamyl bromide to produce the above.
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([OH:17])(=O)[C:6]1[CH:15]=[CH:14][C:11]([O:12][CH3:13])=[C:8]([O:9][CH3:10])[CH:7]=1>C1C=CC=CC=1.N1C=CC=CC=1>[C:5]([Cl:3])(=[O:17])[C:6]1[CH:15]=[CH:14][C:11]([O:12][CH3:13])=[C:8]([O:9][CH3:10])[CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(C(=O)O)cc1OC
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: COc1ccc(C(=O)Cl)cc1OC
Temperature: 25 °C
Reaction time: 0.05 h
Yield: 99.9 %

Procedure:
In a 2-neck 100 ml-round bottom flask, 10.0 g (54.9 m mol) of veratric acid was dissolved in 50 ml of benzene, and after adding 2 to 3 drops of pyridine to the solution, 13 g (109 m mol) of thionyl chloride was dropped into the solution while stirring the solution at room temperature within 3 min. Then the content was heated to 70° to 80° C. on a water bath, and maintained at the temperature for 2 hours under a reflux condenser and agitation. Then, the solvent and excess thionyl chloride were evaporated off under a reduced pressure to obtain 11.0 g of veratroyl chloride as colourless powder in a yield of 100%.