Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH2:14][CH2:15][CH:16]=[C:17]([CH3:34])[CH2:18][CH2:19][CH:20]=[C:21]([CH3:33])[CH2:22][CH2:23][CH:24]=[C:25]([CH3:32])[CH2:26][CH2:27][CH:28]=[C:29]([CH3:31])[CH3:30])=[CH:3][CH2:4][S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:7])=[O:6].C(=O)=O.CO.[Li]CCCC.Br[CH2:46][C:47]([CH3:70])=[CH:48][CH2:49][CH2:50][C:51]([CH3:69])=[CH:52][CH2:53][C:54]1[C:63]([CH3:64])=[C:62]([O:65][CH3:66])[C:61]2[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=2)[C:55]=1[O:67][CH3:68]>C1COCC1>[C:8]1([S:5]([CH:4]([CH:3]=[C:2]([CH3:1])[CH2:14][CH2:15][CH:16]=[C:17]([CH3:34])[CH2:18][CH2:19][CH:20]=[C:21]([CH3:33])[CH2:22][CH2:23][CH:24]=[C:25]([CH3:32])[CH2:26][CH2:27][CH:28]=[C:29]([CH3:31])[CH3:30])[CH2:46][C:47]([CH3:70])=[CH:48][CH2:49][CH2:50][C:51]([CH3:69])=[CH:52][CH2:53][C:54]2[C:63]([CH3:64])=[C:62]([O:65][CH3:66])[C:61]3[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=3)[C:55]=2[O:67][CH3:68])(=[O:6])=[O:7])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COc1c(C)c(CC=C(C)CCC=C(C)CBr)c(OC)c2ccccc12
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCS(=O)(=O)c1ccccc1
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CO
Product: COc1c(C)c(CC=C(C)CCC=C(C)CC(C=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C)S(=O)(=O)c2ccccc2)c(OC)c2ccccc12
Temperature: -78 °C
Reaction time: 2.5 h
Yield: 135.9 %

Procedure:
9.06 g (18.76 mmol) (3,7,11,15,19-pentamethyl-eicosa-2,6,10,14,18-pentaene-1-sulfonyl)-benzene were dissolved in 80 ml of dry THF and the solution was cooled to −78° C. with CO2/MeOH. At −78° C., 11.80 ml (18.88 mmol) BuLi (1.6 M solution in hexane) was added drop wise via septum and syringe over 10 min. The orange solution was stirred for 2.5 h at −78° C. 6.07 g (14.56 mmol) 2-(8-bromo-3,7-dimethyl-octa-2,6-dienyl)-1,4-dimethoxy-3-methyl-naphtalene dissolved in 30 ml of dry THF was added via dropping funnel over 10 min. The brown reaction mixture was stirred at −78° C. for 1.5 h. At −78° C., the reaction was quenched by addition of 50 ml of a Et2O/MeOH mixture (1:1 v/v). The mixture was allowed to reach room temperature and after that 100 ml of saturated NH4Cl solution was added. The layers were separated and the aqueous layer was extracted with Et2O. The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo by rotary evaporation at 30° C. to give 16.21 g of 2-(9-benzenesulfonyl-3,7,11,15,19,23,27-heptamethyl-octacosa-2,6,10,14,18,22,26-heptaenyl)-1,4-dimethoxy-3-methyl-naphtalene as a brownish yellow oil, which was used in the next step without further purification.
Reaction SMILES: C([N:3]1[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)C>[O-]S(C(F)(F)F)(=O)=O.[Cu+2].[O-]S(C(F)(F)F)(=O)=O>[CH:5]1[C:4]2[NH:3][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: CCn1c2ccccc2c2ccccc21
Agent: [Cu+2]
Agent: O=S(=O)([O-])C(F)(F)F
Product: c1ccc2c(c1)[nH]c1ccccc12

Procedure:
Copper (II) triflate (ex. Aldrich, 0.72 g) was then dissolved in the above N-ethyl carbazole/NC solution (9.38 g).
Reaction SMILES: S([N:11]=[N+:12]=[N-])(C1C=CC(C)=CC=1)(=O)=O.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23](=[O:30])[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:18][CH:17]=1.C(N(CC)CC)C>ClCCl>[N+:11](=[C:24]([C:23](=[O:30])[CH2:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][CH3:14])=[CH:21][CH:20]=1)[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[N-:12]
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: CCOC(=O)CC(=O)Cc1ccc(OC)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=[N+]=[N-])C(=O)Cc1ccc(OC)cc1
Temperature: 25 °C
Yield: 65 %

Procedure:
Synthesis of B can be performed in analogy to the protocol in J. Org. Chem. 2001, 66, 2509-2511. At 0° C. a solution of sodium azide (2.287 g, 35.2 mmol) in a minimum amount of water was added to a solution of tosylchloride (6.71 g, 35.2 mmol) in acetone (40 ml). The reaction mixture was stirred at 0° C. for 2 h. Acetone was evaporated and the remaining aqueous residue was extracted three times with Et2O, dried over MgSO4, filtrated and evaporated to provide the tosyl azide as a clear oil. The freshly prepared tosyl azide was dissolved in DCM (40.0 ml), a mixture of commercially available ethyl 4-(4-methoxyphenyl)-3-oxobutanoate (5.54 g, 23.45 mmol) and triethylamine (4.90 ml, 35.2 mmol) in DCM (dichloromethane) was added, and stirred at room temperature over night. The product as evaporated and purified by flash chromatography on 80 g SiO2 using 20% EtOAc in cyclohexane to obtain 4.03 g of the desired product (15.36 mM; yield: 65%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[S:21]1[CH2:25][CH2:24][NH:23][CH2:22]1>CN(C=O)C>[Cl:8][C:6]1[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:3]=[C:2]([N:23]2[CH2:24][CH2:25][S:21][CH2:22]2)[N:7]=1
Reactant: C1CSCN1
Reactant: Clc1nc(Cl)nc(N2CCOCC2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1nc(N2CCOCC2)nc(N2CCSC2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.6 %

Procedure:
The obtained 2,4-dichloro-6-morpholino-1,3,5-triazine (237 mg, 1.00 mmol) was dissolved in DMF (3 ml), added with anhydrous potassium carbonate (138 mg, 1.00 mmol) and cooled to -5° C.-0° C. This mixture was gradually added dropwise with thiazolidine (103 mg, 1.15 mmol) dissolved in DMF (1 ml). The reaction mixture was stirred at room temperature overnight and was evaporated under reduced pressure. The residue was added with ethyl acetate and water, and then shaken for mixing. The organic layer was separated from the mixture, washed with water, dried over anhydrous magnesium sulfate and evaporated. The residue obtained was purified by silica gel column chromatography, using n-hexane and ethyl acetate (7:3) as eluant, to obtain 282 mg (yield: 97.2%) of 2-chloro-4-morpholino-6-(3-thiazolidinyl)-1,3,5-triazine having melting point of 137° C.-139.5° C. (3) The obtained 2-chloro-4-morpholino-6-(3-thiazolidinyl)-1,3,5-triazine (85.2 mg, 0.296 mmol) was dissolved in DMF (2 ml), added with sodium hydroxide (23.7 mg, 0.593 mmol) and imidazole (43.4 mg, 0.637 mmol) and stirred at 110° C.-120° C. for 30 minutes. The reaction mixture was evaporated under reduced pressure. The obtained residue was added with ethyl acetate and water, and then shaken for mixing. The organic layer was separated from the mixture, washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography, using dichloromethane and methanol (98: 2) as eluant, to obtain 83.7 mg (yield: 88.6%) of the titled compound.
Reaction SMILES: [CH2:1]([C:9]#[N:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH:11][CH2:12][CH2:13]N>C([O-])(=O)C.[Zn+2].C([O-])(=O)C.C(O)CCC>[CH2:1]([C:9]1[O:11][CH2:12][CH2:13][N:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCC#N
Reactant: NCCO
Agent: CC(=O)[O-]
Agent: [Zn+2]
Solvent: CCCCO
Product: CCCCCCCCC1=NCCO1
Temperature: 120 °C
Yield: 46.6 %

Procedure:
A mixture of octyl cyanide (75.0 g, 0.539 mol), anhydrous zinc acetate (2.47 g, 0.0134 mol) and 1-butanol (270 ml) was stirred at 120° C. under nitrogen. To this mixture was dropwisely added 2-hydroxyethyl amine (39.5 g, 0.647 mol) in 20 min., and the resulting mixture was stirred at 120° C. for 40 h. The resulting admixture was distilled under reduced pressure three times. The fraction at 75°-80° C./0.2 mmHg was collected to give 2-octyl-2-oxazoline as a colorless liquid (46 g, 47% yield). The product was again distilled under reduced pressure from calcium hydride: 1H NMR (CDCl3) delta 0.88 (5, J=6.6 Hz, 3H, CH3), 1.29 (m, 10H, CH2×8), 1.63 (t of t, J=6.6 and 6.9 Hz, 2H, CH2), 2.26 (t, J=7.2 Hz, 2H, CH2), 3.82 (t, J=9.6 Hz, 2H, CH2O), and 4.22 (t, J=9.6, 2H, CH2N).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[Cl:24])[O:5][C:6]1[N:11]=[C:10]2[S:12][C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])=[N:14][C:9]2=[CH:8][CH:7]=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]=[C:33]=[O:34])=[CH:28][C:27]=1[C:35]([F:38])([F:37])[F:36]>CN(C)C=O.C(OCC)(=O)C>[Cl:24][C:23]1[CH:22]=[CH:21][C:4]([O:5][C:6]2[N:11]=[C:10]3[S:12][C:13]([NH:15][C:16]([CH:18]4[CH2:20][CH2:19]4)=[O:17])=[N:14][C:9]3=[CH:8][CH:7]=2)=[CH:3][C:2]=1[NH:1][C:33](=[O:34])[NH:32][C:29]1[CH:30]=[CH:31][C:26]([Cl:25])=[C:27]([C:35]([F:36])([F:37])[F:38])[CH:28]=1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)ccc1Cl
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)ccc1Cl
Temperature: 25 °C
Reaction time: 10 h
Yield: 32.8 %

Procedure:
N-[5-(3-Amino-4-chlorophenoxy)[1,3]thiazolo[5,4-b]pyridin-2-yl]cyclopropanecarboxamide (120 mg, 0.33 mmol) was dissolved in N,N-dimethylformamide (2.0 ml), 1-chloro-4-isocyanato-2-(trifluoromethyl)benzene (89 mg, 0.40 mmol) was added, and the mixture was stirred at room temperature for 10 hr. The reaction mixture was diluted with ethyl acetate (10 mL), and washed with saturated brine (10 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/hexane=50/50→100/0), and the obtained solution was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give the title compound (63 mg, 33%) as a colorless powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH2:16][CH:17]=[CH2:18])([CH2:14][OH:15])[CH2:11][CH:12]=[CH2:13])=[CH:6][CH:5]=1.[CH3:20][C:21]1[CH:26]=[C:25](O)[CH:24]=[C:23]([CH3:28])[C:22]=1[C:29]1[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.CO>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH2:16][CH:17]=[CH2:18])([CH2:14][O:15][C:25]2[CH:26]=[C:21]([CH3:20])[C:22]([C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:36])([F:38])[F:37])=[CH:31][CH:30]=3)=[C:23]([CH3:28])[CH:24]=2)[CH2:11][CH:12]=[CH2:13])=[CH:6][CH:5]=1
Reactant: C=CCC(CO)(CC=C)c1ccc(C(=O)OC)cc1
Reactant: Cc1cc(O)cc(C)c1-c1ccc(C(F)(F)F)cc1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: Cc1ccccc1
Product: C=CCC(CC=C)(COc1cc(C)c(-c2ccc(C(F)(F)F)cc2)c(C)c1)c1ccc(C(=O)OC)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 64.3 %

Procedure:
A solution of 4-(1-allyl-1-hydroxymethyl-but-3-enyl)-benzoic acid methyl ester (0.768 g, 2.95 mmol), 2,6-dimethyl-4′-trifluoromethyl-biphenyl-4-ol (0.861 g, 3.23 mmol), and triphenylphosphine (1.180 g, 4.50 mmol) in toluene (30 mL) is treated with 1,1′-(azodicarbonyl)-dipiperidine (1.182 g, 4.68 mmol) and stirred overnight at 80° C. The reaction mixture is then cooled to room temperature, diluted with MeOH, and concentrated. The residue is loaded onto silica gel and eluted with hexanes using a gradient of 0% EtOAc to 40% EtOAc to provide 0.964 g (64%) of the title compound as a clear syrup. 1H NMR (CDCl3): δ 8.02-8.00 (m, 2H), 7.67 (d, J=8.0 Hz, 2H), 7.46-7.44 (m, 2H), 7.26 (d, J=7.8 Hz, 2H), 6.68 (s, 2H), 5.60-5.54 (m, 2H), 5.08-5.00 (m, 4H), 4.15 (s, 2H), 3.91 (s, 3H), 2.66 (d, J=7.6 Hz, 4H), 1.99 (s, 6H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH:3]1[C:8]1[S:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:12]=1.[F:19][C:20]([F:36])([F:35])[C:21]1[O:25][N:24]=[C:23]([C:26]2[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=2)[C:29](O)=[O:30])[N:22]=1>>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:29]([C:28]2[CH:32]=[CH:33][CH:34]=[C:26]([C:23]3[N:22]=[C:21]([C:20]([F:35])([F:19])[F:36])[O:25][N:24]=3)[CH:27]=2)=[O:30])[CH2:4][CH:3]1[C:8]1[S:9][CH:10]=[C:11]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:12]=1
Reactant: CN1CCNCC1c1nc(-c2ccccc2)cs1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Product: CN1CCN(C(=O)c2cccc(-c3noc(C(F)(F)F)n3)c2)CC1c1nc(-c2ccccc2)cs1
Yield: 32 %

Procedure:
This compound was synthesized from 2-(1-methylpiperazin-2-yl)-4-phenylthiazole and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described for example 37 step 3 (30 mg, yield 32%) as colorless viscous liquid. 1H NMR (400 MHz, CDCl3) δ 8.17-8.16 (m, 2H), 7.93-7.79 (m, 2H), 7.64-7.62 (m, 2H), 7.48-7.32 (m, 4H), 4.78-4.53 (m, 1H), 3.85-3.69 (m, 2H), 3.49-3.30 (m, 2H), 3.17-2.98 (m, 1H), 2.53-2.40 (m, 1H), 2.32 (s, 3H). MS (ESI) m/z: Calculated for C24H20F3N5O2S: 499.12. found: 500.2 (M+H)+
Reaction SMILES: [OH-].[K+].[C:3]([C:7]1[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:10]=[CH:9][C:8]=1[O:17][C@H:18]([CH3:23])[C:19]([O:21]C)=[O:20])([CH3:6])([CH3:5])[CH3:4].Cl>O.O1CCCC1>[C:3]([C:7]1[CH:12]=[C:11]([C:13]([CH3:14])([CH3:15])[CH3:16])[CH:10]=[CH:9][C:8]=1[O:17][C@H:18]([CH3:23])[C:19]([OH:21])=[O:20])([CH3:4])([CH3:5])[CH3:6]
Reactant: COC(=O)[C@@H](C)Oc1ccc(C(C)(C)C)cc1C(C)(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](Oc1ccc(C(C)(C)C)cc1C(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.2 %

Procedure:
To a solution of 5.98 mg (11 mmol) of potassium hydroxide in water (75 mL) and tetrahydrofuran (75 mL) was added 3.34 mg (10 mmol) of methyl (2R)-2-(2,4-di-t-butylphenyloxy)propanate (17). The reaction mixture was allowed to stir overnight at room temperature. The reaction mixture was acidified to pH 2 with concentrated hydrochloric acid and the resulting solution was extracted with diethyl ether (3×200 mL). The combined extracts were washed with an aqueous saturated sodium chloride solution (1×300 mL) and dried (MgSO4). Filtration and concentration afforded a thick crude oil. Purification by precipitation from hexane at -78° C. afforded 2.65 g (83%) of (2R)-2-(2,4-di-t-butylphenyloxy)propanoic acid (18) as a white crystalline material: 1H NMR (CDCl3) δ1.29 (s, 9 H), 1.42 (s, 9 H), 1.68-1.70 (d, 3 H), 4.77-4.85 9q, 1 H), 6.58-6.61 (d, 1 H), 7.11-7.15 (d, 1 H), 7.34 (s, 1 H); 13C NMR (CDCl3) δ177.2, 153.5, 143.3, 137.3, 124.4, 123.3, 110.7, 71.4, 35.0, 34.3, 31.6, 30.0, 18.5.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:14][C:6]2[C:7]([CH3:13])=[N:8][CH:9]=[C:10]([CH:11]=O)[C:5]=2[CH2:4][O:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl[C:36]([F:41])([F:40])C([O-])=O.[Na+]>COCCOCCOC>[F:40][C:36]([F:41])=[CH:11][C:10]1[CH:9]=[N:8][C:7]([CH3:13])=[C:6]2[O:14][C:2]([CH3:15])([CH3:1])[O:3][CH2:4][C:5]=12
Reactant: O=C([O-])C(F)(F)Cl
Reactant: Cc1ncc(C=O)c2c1OC(C)(C)OC2
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOCCOC
Product: Cc1ncc(C=C(F)F)c2c1OC(C)(C)OC2

Procedure:
A mixture of 0.1 mole of 2,2,8-trimethyl-4H-1,3-dioxino[4,5-c]pyridine-5-carboxaldehyde, 0.11 mole of triphenylphosphine and 0.11 mole of sodium chlorodifluoroacetate in 100 ml. of diglyme is heated under nitrogen at 90° for 24hours. The reaction mixture is then filtered and concentrated in vacuo. Chromatography of the residue on silica gel and elution with etherpetroleum ether (10-50%) gives 5-(2,2-difluorovinyl)-2,2,8-trimethyl-4H-1,3-dioxino[4,5-c]pyridine.
Reaction SMILES: [Cl:1][CH2:2][C:3](=O)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].OS(O)(=O)=O.[CH3:16][C:17]1[C:22]([OH:23])=[CH:21][CH:20]=CC=1O>O>[Cl:1][CH2:2][C:3]1[C:9]2[C:8](=[C:17]([CH3:16])[C:22]([OH:23])=[CH:21][CH:20]=2)[O:7][C:5](=[O:6])[CH:4]=1
Reactant: Cc1c(O)cccc1O
Reactant: CCOC(=O)CC(=O)CCl
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1c(O)ccc2c(CCl)cc(=O)oc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To ethyl 4-chloro-3-oxobutanoate (5.77 mL) was added conc.H2SO4 (15.03 mL) at 0° C. Then to the mixture was added 2-methylbenzene-1,3-diol (5.0 g) in several portions at 0° C. The mixture was stirred at 0° C. for 30 min. The mixture was warmed to room temperature for 1.5 h. The reaction mixture was poured into water under stirring at 0° C. The precipitate was collected by filtration and washed with water to give the title compound (8.58 g).
Reaction SMILES: [C:1]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([CH3:11])[CH2:8][CH2:9]O.[CH:18]([NH2:21])([CH3:20])[CH3:19]>[Ni]>[CH:18]([NH:21][CH2:9][CH2:8][CH:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:11])([CH3:20])[CH3:19]
Reactant: CC(CCO)c1ccccc1-c1ccccc1
Reactant: CC(C)N
Agent: [Ni]
Product: CC(C)NCCC(C)c1ccccc1-c1ccccc1
Reaction time: 15 h

Procedure:
2.26 g of 3-p-biphenylylbutan-1-ol are dissolved in 10 ml of isopropylamine and, after adding 0.5 g of Raney nickel, the solution is shaken for 15 hours at 160° in a tube. After cooling, filtering off the catalyst and evaporating, 1-isopropylamino-3-p-biphenylyl-butane is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][N:10]([CH3:12])[CH2:9][C:8](=[O:13])[NH:7][C:6]=2[CH:14]=1.[CH3:15][NH:16][C:17]([C:19]1[S:20][CH:21]=[C:22]([CH3:33])[C:23]=1[NH:24][C:25]1[C:30]([Cl:31])=[CH:29][N:28]=[C:27](Cl)[N:26]=1)=[O:18].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>CC(O)C>[CH3:15][NH:16][C:17]([C:19]1[S:20][CH:21]=[C:22]([CH3:33])[C:23]=1[NH:24][C:25]1[C:30]([Cl:31])=[CH:29][N:28]=[C:27]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[CH2:11][N:10]([CH3:12])[CH2:9][C:8](=[O:13])[NH:7][C:6]=3[CH:14]=2)[N:26]=1)=[O:18]
Reactant: CN1CC(=O)Nc2cc(N)ccc2C1
Reactant: CNC(=O)c1scc(C)c1Nc1nc(Cl)ncc1Cl
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)O
Product: CNC(=O)c1scc(C)c1Nc1nc(Nc2ccc3c(c2)NC(=O)CN(C)C3)ncc1Cl
Yield: 3.4 %

Procedure:
A mixture of 8-amino-4-methyl-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (25 mg, 0.13 mmol), 3-(2,5-dichloro-pyrimidin-4-ylamino)-4-methyl-thiophene-2-carboxylic acid methylamide (49.6 mg, 0.16 mmol), and camphorsulfonic acid (33 mg, 0.13 mmol) were heated in IPA (3 mL) at 120° C. for 16 hours. Concentration and chromatography on preparative TLC with methylene chloride and methanol (100:8) gave 2.1 mg of 3-[5-chloro-2-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-ylamino)-pyrimidin-4-ylamino]-4-methyl-thiophene-2-carboxylic acid methylamide (3.4%): 1H NMR (300 MHz, CD3OD) δ 8.1 (d, 1H), 7.98 (s, 1H), 7.7 (m, 1H), 7.35 (m, 2H), 7.15 (s, 1H), 3.65 (s, 1H), 3.61 (s, 1H), 3.2 (s, 2H), 2.85 (s, 3H), 2.52 (s, 3H), 2.1 (s, 3H); MS (m/e): 472.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[C:5]([NH:7][C:8]1[C:9](Cl)=[N:10][CH:11]=[C:12]([Cl:14])[CH:13]=1)=[O:6].[NH:19]1[CH2:25][CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[C:5]([NH:7][C:8]1[C:9]([N:19]2[CH2:25][CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[N:10][CH:11]=[C:12]([Cl:14])[CH:13]=1)=[O:6]
Reactant: C1CNCCNC1
Reactant: O=C(Nc1cc(Cl)cnc1Cl)c1cccc(Cl)c1
Solvent: CC#N
Product: O=C(Nc1cc(Cl)cnc1N1CCCNCC1)c1cccc(Cl)c1
Temperature: 175 °C
Yield: 64.3 %

Procedure:
A mixture of 0.500 g (1.66 mmol) of 3-chloro-N-(2,5-dichloro-pyridin-3-yl)-benzamide and 0.498 g (4.97 mmol) of homopiperazine in acetonitrile (5 mL) is heated at 175° C. in a microwave reactor for 90 minutes. The mixture is cooled to room temperature and concentrated under reduced pressure. The residue is purified by flash silica gel chromatography to give 0.390 g (66.8%) of 3-chloro-N-(5-chloro-2-[1,4]diazepan-1-yl-pyridin-3-yl)-benzamide as a red oil.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[C@@H:6]3[C@@H:11]([CH2:12][CH2:13][C:4]=2[CH:3]=1)[NH:10][C:9](=[O:14])[CH2:8][CH2:7]3.[CH2:17](I)[CH2:18][CH3:19]>C1COCC1.[OH-].[Na+]>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[C@@H:6]3[C@@H:11]([CH2:12][CH2:13][C:4]=2[CH:3]=1)[N:10]([CH2:17][CH2:18][CH3:19])[C:9](=[O:14])[CH2:8][CH2:7]3
Reactant: CCCI
Reactant: O=C1CC[C@@H]2c3ccc(Cl)cc3CC[C@H]2N1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCN1C(=O)CC[C@@H]2c3ccc(Cl)cc3CC[C@H]21
Reaction time: 22 h

Procedure:
A 2.35 g portion of (4aR)-(10bR)-8-chloro-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one was slurried in 40 mL of THF and 5 mL of 50% aqueous sodium hydroxide, and 3.4 g of propyl iodide was added. The mixture was heated to about 60°, and the mixture was stirred at that temperature for about 22 hours. Workup was carried out by separating the organic layer and evaporating it to dryness, and adding water and ethyl acetate. The organic layer was separated, washed twice with water, dried, filtered and evaporated under vacuum to obtain 710 mg of white crystalline product, found to be of about 90% purity. It was then purified by silica gel flash chromatography, eluting with ethyl acetate, to obtain 510 mg of purified product, m.p. 110°-11°, of 98.98% purity, by HPLC, eluting with 1:1 acetonitrile:aqueous buffer (5% ammonium acetate) and monitoring at 220 nanometers.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[S:12][C:11]([NH:13][C:14]3[CH:19]=[N:18][CH:17]=[CH:16][N:15]=3)=[N:10][C:9]=2[CH3:20])[CH:5]=[CH:4][N:3]=1.[NH2:21][CH2:22][CH2:23][CH2:24][OH:25]>>[CH3:20][C:9]1[N:10]=[C:11]([NH:13][C:14]2[CH:19]=[N:18][CH:17]=[CH:16][N:15]=2)[S:12][C:8]=1[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:21][CH2:22][CH2:23][CH2:24][OH:25])[CH:7]=1
Reactant: Cc1nc(Nc2cnccn2)sc1-c1ccnc(Cl)c1
Reactant: NCCCO
Product: Cc1nc(Nc2cnccn2)sc1-c1ccnc(NCCCO)c1
Temperature: 150 °C
Reaction time: 1 h

Procedure:
[5-(2-Chloro-pyridin-4-yl)-4-methyl-thiazol-2-yl]-pyrazin-2-yl-amine (Example 2b, 0.077 g, 0.254 mmol) is suspended in 3-amino-propanol (3 ml) and heated to 150° C. using microwave heating (Prolabo Synthewave™ s402 microwave oven). After 1 hour, the reaction mixture is concentrated in vacuo and diluted with water (50 ml). The aqueous is extracted with ethyl acetate (2×100 ml). The combined organic extract is dried (MgSO4) and concentrated to afford the titled compound which is purified by filtration and recrystallised from dichloromethane.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[NH2:11][CH2:12][C@H:13]([NH:21][C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C=O)C>[C:17]([O:16][C:14](=[O:15])[C@@H:13]([NH:21][C:22]([O:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:23])[CH2:12][NH:11][C:6](=[O:8])[C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:10][CH:9]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)[C@H](CN)NC(=O)OCc1ccccc1
Reactant: O=C(O)c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)[C@H](CNC(=O)c1ccc(O)cc1)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1.41 g (10.2 mmol) of 4-hydroxybenzoic acid and 3 g (10.2 mmol) of (1.1) were suspended in 25 ml of DMF. 1.38 g (10.2 mmol) of 1-hydroxy-benzotriazole (HOBt) and, at 0° C., dicyclohexylcarbodiimide (DCCI) were added. The mixture was stirred at 0° C. for 1 h and allowed to stand at room temperature overnight. After filtration, the solvent was removed in vacuo and the residue was chromatographed on silica gel by means of MPLC using heptanelethyl acetate (1/1). (1.2) was obtained as a colorless solid; melting point 69° C.
Reaction SMILES: C[O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1[NH2:13].[OH-].[Na+:16].CCO>O>[Na+:16].[NH2:13][C:5]1[C:6]([N+:10]([O-:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:4]=1[C:3]([O-:14])=[O:2]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1N
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1c(C(=O)[O-])cccc1[N+](=O)[O-]
Temperature: 80 °C

Procedure:
A suspension of 2-amino-3-nitro-benzoic acid methyl ester (785 mg, 4 mmol) and sodium hydroxide (194 mg, 4.4 mmol) in mixed solvent of EtOH (2 mL) and water (2 mL) was heated at 80° C. for 5 h. After it was cooled to the room temperature, the red colored precipitate was formed and dried at 40° C. under reduced pressure to afford the crude product.