Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]([CH3:17])[C:5]1[S:6][C:7]2[CH:13]=[C:12]([N+:14]([O-])=O)[CH:11]=[CH:10][C:8]=2[N:9]=1)([CH3:3])[CH3:2].[H][H]>[Pd].CCO.C1COCC1>[CH:1]([N:4]([CH3:17])[C:5]1[S:6][C:7]2[CH:13]=[C:12]([NH2:14])[CH:11]=[CH:10][C:8]=2[N:9]=1)([CH3:3])[CH3:2]
Reactant: CC(C)N(C)c1nc2ccc([N+](=O)[O-])cc2s1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)N(C)c1nc2ccc(N)cc2s1
Yield: 89.5 %

Procedure:
Combine isopropyl-methyl-(6-nitro-benzothiazol-2-yl)-amine (1.32 g, 5.25 mmol) and 5% palladium on carbon (3.00 g) in EtOH (50 mL) and THF (25 mL). Shake on a Parr shaker at 60 psi hydrogen at room temperature for 7 h. Filter with filter paper, washing with EtOH (20 mL), and concentrate in vacuo to afford the title compound (1.04 g, 90%). 1H NMR (400 MHz, CDCl3): δ 7.36 (d, 1H, J=8.4 Hz), 6.93 (d, 1H, J=2.2 Hz), 6.67 (dd, 1H, J=8.6, 2.4 Hz), 4.31 (m, 1H), 3.62 (s, 2H), 2.99 (s, 3H), 1.25 (d, 6H, J=6.6 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[CH3:9])[CH:5]=[CH:4][N:3]=1.[OH:12]O>C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:10])([F:11])[CH3:9])[CH:5]=[CH:4][N+:3]=1[O-:12]
Reactant: OO
Reactant: CC(F)(F)c1ccnc(Cl)c1
Solvent: O=C(O)C(F)(F)F
Product: CC(F)(F)c1cc[n+]([O-])c(Cl)c1

Procedure:
To a solution of 1.27 g (7 mmol) 2-chloro-4-(1,1-difluoro)ethylpyridine (Preparation 4) in TFA was added 30% hydrogen peroxide (6 mL) and the solution was heated at reflux for 2.5 h. The TFA was removed in vacuo and the residue poured into ice-cold H2O. The mixture was neutralized with Na2CO3 and extracted with EtOAc and CH2Cl2. The pooled organic layers were dried (Na2SO4), filtered and concentrated in vacuo to give 2-chloro-4-(1,1-difluoroethyl)-pyridine 1-oxide (1.00 g) as a brown oil: 1H NMR (CDCl3): δ 8.39 (d, J=6.6 Hz, 1H), 7.63 (d, J=2.4 Hz, 1H), 7.33 (dd, J=6.6, 2.4 Hz, 1H), 1.94 (t, J=18 Hz, 3H); EIMS m/z 193 ([M]).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:6]([CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[C:5]2[C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1.[CH3:32][S:33](Cl)(=[O:35])=[O:34].C(N(CC)CC)C.O>O1CCCC1>[CH2:12]([C:7]1[C:6]([CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[C:5]([C:25]2[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=2)[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([NH:1][S:33]([CH3:32])(=[O:35])=[O:34])[CH:3]=2)[N:8]=1)[CH:13]([CH3:15])[CH3:14]
Reactant: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)c(CC(C)C)nc3ccc(N)cc23)cc1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)c(CC(C)C)nc3ccc(NS(C)(=O)=O)cc23)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.4 %

Procedure:
To a solution of tert-butyl [6-amino-2-isobutyl-4-(4-methylphenyl)-3-quinolinyl]methylcarbamate (0.21 g, 0.5 mmol) in tetrahydrofuran (10 ml) were added dropwise methanesulfonyl chloride (0.05 ml, 0.6 mmol) and triethylamine (0.08 ml, 0.6 mmol) and the mixture was stirred at room temperature for 2 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give tert-butyl [2-isobutyl-4-(4-methylphenyl)-6-[(methylsulfonyl)amino]-3-quinolinyl]methylcarbamate (0.21 g, yield 84%) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:9]=[N:10]/[CH3:11].[Cl:12][C:13]1[CH:18]=[CH:17][C:16](/[C:19](=[CH:22]/[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])/[C:20]#[N:21])=[C:15]([F:28])[CH:14]=1.[OH-].[K+]>CS(C)=O>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2([C:20]#[N:21])[CH:22]([CH2:23][C:24]([CH3:25])([CH3:26])[CH3:27])[CH2:11][NH:10][CH:9]2[C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=2[Cl:1])=[C:15]([F:28])[CH:14]=1
Reactant: C/N=C/c1cccc(Cl)c1Cl
Reactant: CC(C)(C)C/C=C(\C#N)c1ccc(Cl)cc1F
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(C)(C)CC1CNC(c2cccc(Cl)c2Cl)C1(C#N)c1ccc(Cl)cc1F
Yield: 21 %

Procedure:
In a manner similar to the method described in Example 3a, [1-(2,3-dichloro-phenyl)-meth-(E)-ylidene]-methyl-amine (3.76 g, 20.00 mmol) reacted with (Z)-2-(4-chloro-2-fluoro-phenyl)-5,5-dimethyl-hex-2-enenitrile (5.03 g, 20.00 mmol) in DMSO (30 mL) in the presence of KOH powder (5.72 g, 56.11 mmol) to give rac-(2S,3S,4S)-3-(4-chloro-2-fluoro-phenyl)-2-(2,3-dichloro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (1.85 g 21.0%). LC-MS (ES+) m/z Calcd for C22H22Cl3FN2+H [(M+H)+]: 441, found: 441.
Reaction SMILES: [CH3:1][C:2]([O:27]C1CCCCO1)([CH3:26])[C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)[N:12]=2)[NH:7][CH:6]=1)=[O:4].C(O)(=O)C.C1COCC1>O>[OH:27][C:2]([CH3:26])([CH3:1])[C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([C:14]3[CH:15]=[C:16]([O:24][CH3:25])[C:17]([O:22][CH3:23])=[C:18]([O:20][CH3:21])[CH:19]=3)[N:12]=2)[NH:7][CH:6]=1)=[O:4]
Reactant: COc1cc(-c2cnc3[nH]cc(C(=O)C(C)(C)OC4CCCCO4)c3n2)cc(OC)c1OC
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1cc(-c2cnc3[nH]cc(C(=O)C(C)(C)O)c3n2)cc(OC)c1OC
Temperature: 50 °C

Procedure:
2-Methyl-2-(tetrahydro-pyran-2-yloxy)-1-[2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-propan-1-one, 0.012 gm, was mixed with 0.8 ml acetic acid, 0.4 ml THF and 0.2 ml water and heated for 90 minutes in a 50° C. oil bath. The mixture was concentrated, saturated aqueous sodium bicarbonate was added and the mixture extracted twice with ethyl acetate, dried over magnesium sulfate, filtered and stripped and the solid dried overnight at 2 torr in an 80° C. vacuum oven to give 2-Hydroxy-2-methyl-1-[2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-propan-1-one. (M+H)+=372.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:24]([O-])=O)=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][CH:9]([NH:12][C:13](=[O:23])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][CH2:21][CH3:22])[CH2:8][CH2:7]2.C([O-])=O.[NH4+]>[Pd]>[Cl:1][C:2]1[C:3]([NH2:24])=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][CH:9]([NH:12][C:13](=[O:23])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][CH2:21][CH3:22])[CH2:8][CH2:7]2
Reactant: CCCc1ccccc1C(=O)NC1CCc2ccc([N+](=O)[O-])c(Cl)c2C1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Product: CCCc1ccccc1C(=O)NC1CCc2ccc(N)c(Cl)c2C1
Yield: 70.9 %

Procedure:
A mixture of 12 g (32 mmol) 8-chloro-7-nitro-2-(n-propylbenzoyl)amino-1,2,3,4-tetrahydronaphthalene, 25 g ammonium formate and 1.0 g Pd/C (added cautiously under inert atmosphere) was stirred over night. After filtering (Celite) and evaporation the material was brought to suspension in ethyl acetate. Filtering and evaporation yielded 7.8 g (22.7 mmol) of 8-chloro-7-amino-2-(n-propylbenzoyl)amino-1,2,3,4-tetrahydronaphthalene, which was recharged with 50 g ammonium formate, 2 g Pd/C (added cautiously under inert atmosphere) and 200 ml ethanol. The mixture was stirred at room temperature for 4 days. The reaction ceased at about 1/1 ratio (GLC) of product and starting material. The mixture was worked-up as below and recharged with ammonium formate and Pd/C. After stirring for two days the reaction was almost completed. The mixture was filtered (Celite) and evaporated. Ethyl acetate and water where added, the mixture shaken and separated. The organic phase was washed (10% sodium carbonate), dried (magnesium sulfate), filtered and evaporated to yield 5.3 g (54%) crude product which was purified on silica column (dichloromethane/methanol, 19:1) giving 3.9 g product.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([NH:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]([OH:25])=O)=[N:21][CH:22]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH2:47][CH2:48][C:49]([N:51]1[CH2:56][CH2:55][N:54]([C:57](=[O:68])[C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=2[C:64]([F:67])([F:66])[F:65])[CH2:53][CH2:52]1)=[O:50].Cl>CN(C=O)C.O>[F:67][C:64]([F:65])([F:66])[C:59]1[CH:60]=[CH:61][CH:62]=[CH:63][C:58]=1[C:57]([N:54]1[CH2:55][CH2:56][N:51]([C:49](=[O:50])[CH2:48][NH:47][C:23]([C:20]2[CH:19]=[CH:18][C:17]([NH:16][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)=[CH:22][N:21]=2)=[O:25])[CH2:52][CH2:53]1)=[O:68]
Reactant: O=C(O)c1ccc(Nc2ccccc2)cn1
Reactant: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1ccc(Nc2ccccc2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42 %

Procedure:
DIPEA (90 mg, 0.12 mL, 0.7 mmol) was added drop wise to 5-(phenyl-amino)-pyridine-2-carboxylic acid (50 mg, 0.23 mmol) in DMF (5 mL). EDCI (111 mg, 0.58 mmol) and HOBT (37 mg, 0.28 mmol) were added consecutively and, after 10 minutes, 2-amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone in its HCl salt form (98 mg, 0.28 mmol) was added. The resulting mixture was stirred at room temperature overnight. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to get the residue. The obtained residue was purified by column chromatography (using silica gel of 60-120 mesh and 50% EtOAc in Hexane as eluent) to afford 50 mg (42% yield) of 5-phenylamino-pyridine-2-carboxylic acid {2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-amide. LC-MS purity: 93.93%. 1H-NMR (DMSO-d6): δ 8.9 (s, 1H), 8.5 (t, 1H), 8.3 (d, 1H), 7.8 (m, 5H), 7.6 (d, 2H), 7.4 (t, 2H), 7.2 (d, 2H), 7.0 (t, 1H), 4.2 (dd, 2H), 3.6 (m, 4H), 3.4 (m, 2H), 3.2 (m, 2H).
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][N:7]([C:9]3[CH:14]=[CH:13][N:12]=[C:11]([C:15]([NH:17][C:18]4[CH:22]=[C:21]([C:23]([NH:25][NH2:26])=O)[S:20][CH:19]=4)=[O:16])[CH:10]=3)[CH:8]=2)[CH2:3][CH2:2]1.[CH3:27][CH:28]([CH3:32])[C@@H:29]([NH2:31])[CH3:30].[C:33](O)(=O)C>C1(C)C=CC=CC=1>[CH:1]1([C:4]2[N:5]=[CH:6][N:7]([C:9]3[CH:14]=[CH:13][N:12]=[C:11]([C:15]([NH:17][C:18]4[CH:22]=[C:21]([C:23]5[N:31]([C@H:29]([CH:28]([CH3:32])[CH3:27])[CH3:30])[CH:33]=[N:26][N:25]=5)[S:20][CH:19]=4)=[O:16])[CH:10]=3)[CH:8]=2)[CH2:3][CH2:2]1
Reactant: NNC(=O)c1cc(NC(=O)c2cc(-n3cnc(C4CC4)c3)ccn2)cs1
Reactant: CC(C)[C@H](C)N
Reactant: CC(=O)O
Solvent: Cc1ccccc1
Product: CC(C)[C@H](C)n1cnnc1-c1cc(NC(=O)c2cc(-n3cnc(C4CC4)c3)ccn2)cs1
Temperature: 150 °C
Reaction time: 0.08 h
Yield: 41.5 %

Procedure:
A mixture of 4-(4-cyclopropyl-1H-imidazol-1-yl)-N-(5-(hydrazinecarbonyl)thiophen-3-yl)picolinamide (130 mg, 0.35 mmol) and toluene (2 mL) were added to a sealable vial. N,N-dimethylformamide/N,N-dimethylacetamide complex (120 μL, 0.88 mmol) was added and the reaction was stirred for 5 minutes. (S)-3-methylbutan-2-amine (170 μL, 1.4 mmol), and acetic acid (20 μL, 0.35 mmol) were added, and the reaction was heated in a microwave reactor at 150° C. for 30 minutes. The reaction was concentrated and purified by RP-HPLC to provide 65 mg (42%) of (S)-4-(4-cyclopropyl-1H-imidazol-1-yl)-N-(5-(4-(3-methylbutan-2-yl)-4H-1,2,4-triazol-3-yl)thiophen-3-yl)picolinamide as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9](Cl)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH:19]1([NH2:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.[OH-].[Na+]>C(O)CCC>[NH2:1][C:2]1[N:10]=[C:9]([NH:25][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NC1CCCCC1
Reactant: Nc1nc(Cl)nc2c1ncn2Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCO
Product: Nc1nc(NC2CCCCC2)nc2c1ncn2Cc1ccccc1
Yield: 46.3 %

Procedure:
6-Amino-9-benzyl-2-chloropurine (200 mg, 0.77 mmol) and cyclohexylamine (764 mg, 7.70 mmol) in 1-butanol (10 ml) were refluxed on heating for 60 hours. The reaction mixture was condensed in vacuo. To the residue was added 5N aqueous sodium hydroxide and the solution was extracted with chloroform. The organic layer was dried on sodium sulfate, filtered and the solvent in the filtrate was evaporated in vacuo. The residue was purified with silica gel chromatography (2% methanol/chloroform) to give the subject compound (115 mg, yield 46%).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[C:14]([F:24])=[C:15]4[C:20](=[CH:21][C:22]=3[F:23])[N:19]=[CH:18][CH:17]=[CH:16]4)[CH3:12])=[N:9][N:10]=2)[N:7]=1.C([Sn](CCCC)(CCCC)[C:30]([O:32][CH2:33][CH3:34])=[CH2:31])CCC>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:33]([O:32][C:30]([C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[C:14]([F:24])=[C:15]4[C:20](=[CH:21][C:22]=3[F:23])[N:19]=[CH:18][CH:17]=[CH:16]4)[CH3:12])=[N:9][N:10]=2)[N:7]=1)=[CH2:31])[CH3:34]
Reactant: CC(c1c(F)cc2ncccc2c1F)c1nnc2ccc(Cl)nn12
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: C=C(OCC)c1ccc2nnc(C(C)c3c(F)cc4ncccc4c3F)n2n1
Temperature: 82.5 °C
Reaction time: 6 h

Procedure:
A solution of 6-[1-(6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)-ethyl]-5,7-difluoro-quinoline (1.500 g, 4.34 mmol) in dioxane (60 mL) was purged with argon for 3 min, followed by addition of tributyl-(1-ethoxy-vinyl)-stannane (2.2 mL, 6.51 mmol) and PdCl2(PPh3)2 (150 mg, 0.21 mmol) sequentially. The mixture was purged with argon for another half min. The reaction mixture was stirred at 80-85° C. for 6 h under argon. LC/MS showed the reaction was complete. The reaction mixture was diluted with EtOAc, washed successively with aqueous KF solution (2×25 mL), water, and brine. The organic phase was dried over anhydrous Na2SO4, concentrated to give the crude title compound, which was used without further purification. LCMS (method A): [MH]+=382, tR=5.05 min.
Reaction SMILES: C(N(CC)[CH2:4][C:5]#[C:6][CH2:7][N:8]1[CH2:12][CH2:11][C@H:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C:9]1=[O:21])C.N#C[Br:26]>C(OCC)C>[Br:26][CH2:4][C:5]#[C:6][CH2:7][N:8]1[CH2:12][CH2:11][C@H:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C:9]1=[O:21]
Reactant: CCN(CC)CC#CCN1CC[C@H](O[Si](C)(C)C(C)(C)C)C1=O
Reactant: N#CBr
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)O[C@H]1CCN(CC#CCBr)C1=O
Yield: 81.5 %

Procedure:
A solution of 2.4 g of (S)-1-[4-diethylamino-2-butynyl]-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-2-pyrrolidinone and 0.8 g of cyanogen bromide in 40 ml of diethyl ether is stirred at room temperature for 18 hours. The solution is washed with 30 ml of 1N hydrochloric acid and saturated sodium bicarbonate, dried and concentrated in vacuo. The residue is purified by chromatography (silica gel, methylene chloride) to give 2.0 g of the desired product as a colorless oil.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]#[C:28][C:29]1[C:30]([O:39][CH3:40])=[CH:31][C:32]([O:37][CH3:38])=[C:33]([CH:36]=1)[CH:34]=O.C[O-].[Li+]>CN(C=O)C.CO>[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]#[C:28][C:29]1[C:30]([O:39][CH3:40])=[CH:31][C:32]([O:37][CH3:38])=[C:33](/[CH:34]=[CH:2]/[C:1]([C:4]2[CH:5]=[CH:6][C:7]([S:10]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)(=[O:12])=[O:11])=[CH:8][CH:9]=2)=[O:3])[CH:36]=1
Reactant: COc1cc(OC)c(C=O)cc1C#Cc1ccccc1N
Reactant: CC(=O)c1ccc(S(=O)(=O)Nc2ccccn2)cc1
Agent: C[O-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CO
Product: COc1cc(OC)c(/C=C/C(=O)c2ccc(S(=O)(=O)Nc3ccccn3)cc2)cc1C#Cc1ccccc1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.6 %

Procedure:
Ex-57A: A solution of 4-acetyl-N-pyridin-2-ylbenzenesulfonamide (Ex-5A, 451 mg, 1.63 mmol) and 5-(2-aminophenylethynyl)-2,4-dimethoxybenzaldehyde (Ex-35C, 459 mg, 1.63 mmol) in DMF (10.0 mL) and MeOH (5.0 mL) was treated with lithium methoxide (248 mg, 6.52 mmol). The reaction mixture was stirred at room temperature for 3 h under nitrogen, quenched with water (50 mL), and extracted with (3:1) ethyl acetate/THF (4×30 mL). The combined organic phase was brined, dried over sodium sulfate, and concentrated to a yellow oil. The crude material was purified by column chromatography (2–5% MeOH in dichloromethane) to give 735 mg (65%) of 4-{3E-[5-(2-amino-phenylethynyl)-2,4-dimethoxyphenyl]acryloyl}-N-pyridin-2-yl-benzenesulfonamide as a yellow oil. 1H-NMR (300 MHz, DMSO-d6) 8.21 (d, 2H, J=7.5), 8.18 (s, 1H), 8.00 (m, 4H), 7.81 (d, 1H, J=15.0 Hz), 7.74 (t, 2H, J=7.5 Hz), 7.17 (m, 2H), 7.05 (t, 2H, J=7.2 Hz), 6.80 (m, 3H), 6.52 (t, 1H), J=7.5 Hz), 5.43 (d, 1H, J=6.9 Hz), 3.96 (s, 3H), 3.95 (s, 3H).
Reaction SMILES: [CH:1]1[C:6]2[NH:7][C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[CH2:10][CH2:11][CH2:12][C:5]=2[CH:4]=[CH:3][CH:2]=1.[O:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]1[O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28]Cl.[NH2-].[Na+].O>C1(C)C=CC=CC=1>[O:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]1[O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][N:7]1[C:6]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[CH2:12][CH2:11][CH2:10][C:9]2[CH:13]=[CH:14][CH:15]=[CH:16][C:8]1=2
Reactant: ClCCOCCOC1CCCCO1
Reactant: c1ccc2c(c1)CCCc1ccccc1N2
Agent: [NH2-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: c1ccc2c(c1)CCCc1ccccc1N2CCOCCOC1CCCCO1
Temperature: 25 °C

Procedure:
To a solution of 5,6,7,12-tetrahydrodibenz[b,g]azocine (2.5 g, 12 mmol, prepared in a similar way as described in Chem. Pharm. Bull. 1978, 26, 942-950) and 2-(2-((tetrahydro-2-pyranyl)oxy)ethoxy)ethylchloride (3.0 g, 14 mmol) in toluene (50 ml) was added a suspension of sodium amide (1.50 g, 19 mmol, 50% wt suspension in toluene). The reaction mixture was heated at reflux temperature for 10 h. The mixture was allowed to cool to room temperature and water (52.5 ml) was carefully added. The phases were separated and the aqueous phase was extracted with toluene (50 ml). The combined organic phases were washed with water (2×5 ml), brine (15 ml) and dried over magnesium sulphate. The solvent was evaporated in vacuo. The oily residue was submitted to column chromatography on silica gel (150 g) using a mixture of ethyl acetate and n-heptane (1:4) as eluent. Collecting the proper fractions afforded 3.0 g of crude 12-(2-(2 -((tetrahydro-2-pyranyl)oxy)ethoxy)ethyl)-5,6,7,12-tetrahydrodibenz[b,g]azocine. TLC: rf=0.11 (SiO2 ; ethyl acetate/n-heptane=1:4).
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C@H:9]1[CH2:14][CH2:13][C@H:12]([O:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH2:11][CH2:10]1)C1C=CC=CC=1.[H][H]>[OH-].[OH-].[Pd+2].CO>[N:18]1([CH2:17][CH2:16][O:15][C@H:12]2[CH2:11][CH2:10][C@H:9]([NH2:8])[CH2:14][CH2:13]2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: [H][H]
Reactant: c1ccc(CN(Cc2ccccc2)[C@H]2CC[C@H](OCCN3CCCCC3)CC2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: N[C@H]1CC[C@H](OCCN2CCCCC2)CC1

Procedure:
Trans-N,N-dibenzyl-4-(2-(piperidin-1-yl)ethoxy)cyclohexanamine (4.7 g, 11.6 mmol), 20% Pd(OH)2/C (0.94 g) and methanol (40 mL) were charged into a septum-sealed flask. The reaction mixture was placed under balloon pressure of hydrogen for 18 h at ambient temperature, at which time LCMS indicated complete debenzylation to form the free amine. The catalyst was filtered off and the filtrate evaporated under reduced pressure to give 2.42 g of a crystalline material (93%). In some cases an additional portion of catalyst (ca. 50% of the initial charge) was needed in order to attain complete reaction. LRMS (ES) m/e 227.2 [MH]+; 1H NMR (300 MHz, CD3OD) δ 3.51 (t, 2H), 3.12 (m, 1H), 2.61 (m, 1H), 2.42 (t, 2H), 2.18 (m, 4H), 1.93 (m, 2H), 1.80 (m, 2H), 1.50 (m, 4H), 1.33 (m, 2H), 1.12 (m, 4H).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][N:23]([C:26]4[CH2:27][CH2:28][C:29]5[N:30]([C:32]([C:35]([F:38])([F:37])[F:36])=[N:33][N:34]=5)[N:31]=4)[CH2:22][CH2:21]3)=[CH:16][CH:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[C:39](O)(=O)[CH2:40][CH2:41]CC>>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]([N:20]3[CH2:25][CH2:24][N:23]([C:26]4[CH2:27][CH2:28][C:29]5[N:30]([C:32]([C:35]([F:37])([F:36])[F:38])=[N:33][N:34]=5)[N:31]=4)[CH2:22][CH2:21]3)=[CH:18][CH:19]=2)[CH2:6][CH2:5]1)(=[O:3])[CH2:2][CH2:39][CH2:40][CH3:41]
Reactant: CCCCC(=O)O
Reactant: CC(=O)N1CCN(CCCOc2ccc(N3CCN(C4=Nn5c(nnc5C(F)(F)F)CC4)CC3)cc2)CC1
Product: CCCCC(=O)N1CCN(CCCOc2ccc(N3CCN(C4=Nn5c(nnc5C(F)(F)F)CC4)CC3)cc2)CC1
Yield: 70 %

Procedure:
Obtained in 70% yield by an analogous method to Example 4.1, starting from 6-{4-[4-(3-piperazin-1-ylpropoxy)phenyl]piperazin-1-yl}-3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazine (obtained as described in Example 29, preparation of starting materials) and pentanoic acid.
Reaction SMILES: C1(C(C2C=CC=CC=2)([C@H]2CCCN2)O)C=CC=CC=1.B(OC)(OC)OC.B.C(N(CC)C1C=CC=CC=1)C.[Cl:39][C:40]1[CH:45]=[CH:44][C:43]([C:46](=[O:61])[CH2:47][CH2:48][C:49]([C:51]2[CH:56]=[CH:55][C:54]([Cl:57])=[C:53]([N+:58]([O-:60])=[O:59])[CH:52]=2)=[O:50])=[CH:42][C:41]=1[N+:62]([O-:64])=[O:63]>C1COCC1>[Cl:39][C:40]1[CH:45]=[CH:44][C:43]([C@@H:46]([OH:61])[CH2:47][CH2:48][C@@H:49]([C:51]2[CH:56]=[CH:55][C:54]([Cl:57])=[C:53]([N+:58]([O-:60])=[O:59])[CH:52]=2)[OH:50])=[CH:42][C:41]=1[N+:62]([O-:64])=[O:63]
Reactant: O=C(CCC(=O)c1ccc(Cl)c([N+](=O)[O-])c1)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: B
Agent: COB(OC)OC
Agent: OC(c1ccccc1)(c1ccccc1)[C@H]1CCCN1
Solvent: CCN(CC)c1ccccc1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc([C@@H](O)CC[C@H](O)c2ccc(Cl)c([N+](=O)[O-])c2)ccc1Cl
Temperature: 10 °C
Reaction time: 1 h
Yield: 97.9 %

Procedure:
(R)-(+)-alpha,alpha-diphenyl-2-pyrrolidinemethanol (1.08 g, 4.28 mmol) was dissolved in 70 mL of THF at ambient temperature in a dry flask under nitrogen and the trimethyl borate (650 uL, 5.54 mmol) was added dropwise. The resulting solution was stirred for 1 hr. The solution was cooled in a cold bath to ˜10° C. and the N,N-diethylaniline borane (9.18 mL, 51.6 mmol) was added dropwise with some bubbling. After 15 min, this solution was transferred to an addition funnel and added dropwise to 1,4-bis(4-chloro-3-nitrophenyl)butane-1,4-dione (Example 109B) (10.0 g, 25.2 mmol) suspended in 200 mL of THF and cooled to ˜10° C. Bubbling was observed. After the addition, mixture was stirred at ambient temperature for 4 hours. The mixture was cooled in an ice bath and 30 mL MeOH was added dropwise till bubbling stopped, then the mixture was let stir at ambient temperature for 30 min. The mixture was filtered to get rid of a trace of insoluble unreacted SM. The filtrate was concentrated, poured into 1 M HCl and extracted into ethyl acetate, dried over sodium sulfate; concentrated to give the title compound (9.9 g, 99%) as a yellow waxy solid. Chiral HPLC e.e. >99.9% (RR diol was undetectable). 1H NMR (400 MHz, DMSO-d6) δ 7.94 (d, J=1.9 Hz, 2H), 7.69 (d, J=8.4 Hz, 2H), 7.60 (dd, J=8.4, 1.9 Hz, 2H), 4.65 (m, 2H), 1.62 (m, 4H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[CH:7]=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:9]2)=[CH:4][CH:3]=1.Cl>[Pd].CCO>[CH2:15]([O:14][C:12]([CH:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][C:2]([OH:1])=[CH:3][CH:4]=2)[O:9]1)=[O:13])[CH3:16]
Reactant: CCOC(=O)c1cc(=O)c2ccc(O)cc2o1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C1CCc2ccc(O)cc2O1

Procedure:
To a large hydrogenation vessel were added ethyl 7-hydroxychromone-2-carboxylate (=ethyl 7-hydroxy-4-oxo-4H-chromene-2-carboxylate) (675.4 g, 2.88 mol), EtOH 4 liters, conc. hydrochloric acid 40 ml. The resulting suspension was combined with 5% Pd/C 68 g, and subjected to hydrogenation condition (H2, 40 psi, rt) overnight. The reaction mixture was filtered through a pad of celite to remove the catalyst. The filtrate was concentrated to give thick oily material, which solidified upon standing. Tan solid 630.1 g (98%).