Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][N:20]=4)[CH2:15][CH2:14]3)[CH:10]=[N:11][C:5]=2[N:4]2[CH2:28][CH2:29][CH2:30][C@@H:3]12.[CH:31]1([NH2:34])[CH2:33][CH2:32]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:31]1([NH:34][C:23](=[O:24])[C:22]2[CH:26]=[CH:27][C:19]([N:16]3[CH2:17][CH2:18][N:13]([CH2:12][C:9]4[CH:10]=[N:11][C:5]5[N:4]6[CH2:28][CH2:29][CH2:30][C@H:3]6[C:2](=[O:1])[NH:7][C:6]=5[CH:8]=4)[CH2:14][CH2:15]3)=[N:20][CH:21]=2)[CH2:33][CH2:32]1
Reactant: NC1CC1
Reactant: O=C(O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)nc1
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(NC1CC1)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.7 %

Procedure:
(S)-6-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)nicotinic acid (87 mg, 0.213 mmol) and cyclopropanamine (18.24 mg, 0.319 mmol) were suspended in DMF (1 ml) and treated with DIPEA (0.186 ml, 1.065 mmol) and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (162 mg, 0.426 mmol). The reaction mixture was stirred at room temperature for 3 h and purified using HPLC (10-95% acetonitrile in water, NH4HCO3 buffered) to afford (S)—N-cyclopropyl-6-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)nicotinamide (70.3 mg, 0.157 mmol, 73.7% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 0.49-0.56 (m, 2 H) 0.62-0.70 (m, 2H) 1.82-2.02 (m, 3 H) 2.11-2.22 (m, 1 H) 2.40 (t, J=4.93 Hz, 4 H) 2.78 (tq, J=7.34, 3.86 Hz, 1H) 3.34 (br. s., 2 H) 3.36-3.44 (m, 1 H) 3.49-3.64 (m, 5 H) 3.94-4.03 (m, 1 H) 6.81 (d, J=8.59 Hz, 1 H) 6.98 (d, J=1.77 Hz, 1 H) 7.61 (d, J=1.77 Hz, 1 H) 7.90 (dd, J=9.09, 2.53 Hz, 1H) 8.20 (d, J=4.04 Hz, 1 H) 8.54 (d, J=1.77 Hz, 1 H) 10.44 (s, 1 H); [M+H] calc'd for C24H29N7O2, 448; found, 448.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:19][CH3:20])=[C:7]([CH:18]=1)[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)=[O:9])#[N:2].OO.C(=O)([O-])[O-:24].[K+].[K+].O>CS(C)=O>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([NH:10][C:8](=[O:9])[C:7]2[CH:18]=[C:3]([CH:4]=[CH:5][C:6]=2[O:19][CH3:20])[C:1]([NH2:2])=[O:24])=[CH:12][CH:13]=1
Reactant: COc1ccc(C#N)cc1C(=O)Nc1ccc(Cl)cc1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(C(N)=O)cc1C(=O)Nc1ccc(Cl)cc1
Reaction time: 1 h
Yield: 98.9 %

Procedure:
5-Cyano-N-(4-chlorophenyl)-2-methoxybenzamide (9.8 g) obtained in step D was dissolved in 80 mL of dimethyl sulfoxide, and the solution was cooled in a water bath. A solution prepared from 17.4 mL of a 30% aqueous solution of hydrogen peroxide and 9.5 g of potassium carbonate was added dropwise to the solution. After stirring for 1 hour, the mixture was poured into 800 mL of cold water. The precipitate formed was separated by filtration, washed with cold water, and then dried over diphosphorus pentoxide under reduced pressure to obtain 10.3 g (99%) of 3-N-(4-chlorophenyl)-4-methoxyisophthalamide.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:19])[C:10]2[CH:15]=[C:14]([NH2:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[CH:4][CH:3]=1.[C:20]([O:24][C:25]([NH:27][CH2:28][C:29]1[CH:30]=[CH:31][C:32]([Cl:38])=[C:33]([CH:37]=1)[C:34](O)=[O:35])=[O:26])([CH3:23])([CH3:22])[CH3:21].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl.CCO>[CH3:18][O:17][C:11]1[CH:12]=[CH:13][C:14]([NH:16][C:34](=[O:35])[C:33]2[CH:37]=[C:29]([CH2:28][NH:27][C:25]([O:24][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:26])[CH:30]=[CH:31][C:32]=2[Cl:38])=[CH:15][C:10]=1[C:9]([NH:8][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)=[O:19]
Reactant: COc1ccc(N)cc1C(=O)Nc1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)c(C(=O)O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCO
Solvent: ClCCl
Product: COc1ccc(NC(=O)c2cc(CNC(=O)OC(C)(C)C)ccc2Cl)cc1C(=O)Nc1ccc(Br)cc1

Procedure:
Prepared analogously to Example 4c from N-(4-bromophenyl)-2-methoxy-5-amino-benzoic acid amide and 5-(tert.butoxycarbonylamino)methyl-2-chloro benzoic acid with TBTU and TEA. Yield: (85%). MS [m+H]+=588 (Br/Cl-isotope pattern); TLC: Rf=0.60 (silica gel, DCM:EtOH 9:1).
Reaction SMILES: [C:1]([N:4]1[C@H:8]([CH2:9]O)[C@@H:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[O:6][C:5]1([CH3:22])[CH3:21])(=[O:3])[CH3:2].C(N(CC)C(F)(F)C(F)C(F)(F)[F:29])C>C(Cl)Cl>[C:1]([N:4]1[C@H:8]([CH2:9][F:29])[C@@H:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[O:6][C:5]1([CH3:22])[CH3:21])(=[O:3])[CH3:2]
Reactant: CC(=O)N1[C@H](CO)[C@@H](c2ccc(S(C)(=O)=O)cc2)OC1(C)C
Reactant: CCN(CC)C(F)(F)C(F)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)N1[C@H](CF)[C@@H](c2ccc(S(C)(=O)=O)cc2)OC1(C)C
Temperature: 22.5 °C

Procedure:
(4R,5R)-3-acetyl-2,2-dimethyl-4-hydroxymethyl-5-[4-(methylsulfonyl)phenyl]-1,3-oxazolidine (Compound II) (75 g, 0.2291 moles) in methylene chloride (525 ml) reacts with N,N-diethyl-1,1,2,3,3,3-hexafluoro-1-propanamine (Ishikawa Reagent) (76.7 g, 0.3437 moles) at 95-105° C. for about 4 hours. Cooling to 20-25° C., addition to sodium hydroxide (6 g) in water (2500 mL), separation of the methylene chloride layer, distillation and replacement of methylene chloride by isopropanol (750 mL), precipitates the desired product. Filtration, washing with water (100 mL) and isopropanol (75 mL), then drying yields (4S,5R)-3-acetyl-2,2-dimethyl-4-fluoromethyl-5-[4-(methylsulfonyl)phenyl]-1,3-oxazolidine (Compound IX: R1 is methylsulfonyl; R2, R3 and R4 are methyl).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](=[O:12])[CH3:11])=[CH:4][CH:3]=1.Br[CH2:14][C:15]([O:17][CH3:18])=[O:16].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[C:15]([CH2:14][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10](=[O:12])[CH3:11])=[CH:6][CH:7]=1)([O:17][CH3:18])=[O:16]
Reactant: COC(=O)CBr
Reactant: CC(=O)CCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc(CCC(C)=O)cc1
Yield: 82.6 %

Procedure:
A solution of 4-(4-hydroxyphenyl) butan-2-one (16.4 g), methyl bromoacetate (15.3 g, 8.5 ml), potassium carbonate (13.8 g) and a trace of potassium iodide in acetone (200 ml) was heated under reflux for 16 hours. The solution was filtered, evaporated and the residue dissolved in ether. The ether solution was shaken successively with 2 N sodium hydroxide solution, water, dried (MgSO4) and evaporated to give the title compound as an oil (19.5 g).
Reaction SMILES: CS(C)=O.[H-].[Na+].[I-].[CH3:8][S+](C)C.[C:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:14])[CH3:13]>C1COCC1>[CH3:13][C:12]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:8][O:14]1
Reactant: C[S+](C)C
Reactant: CC(=O)c1ccccc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CC1(c2ccccc2)CO1
Temperature: 65 °C
Reaction time: 0.17 h

Procedure:
The title compound was prepared by following general procedure 3. DMSO was added to NaH (1 equiv.) and heated to 65° C. for 1 h. THF was added at the same temperature and heated for another 10 min. After 10 min., the reaction mixture was cooled to 0° C. Trimethylsulfonium iodide (1 equiv.) was added and stirred for 10 min. after which the solution of acetophenone (1 equiv.) in THF was added dropwise. After complete addition, the reaction mixture was stirred at RT for 2 h. The product was detected by LCMS and the reaction mixture was poured into ice water, extracted in diethyl ether (4×50 mL), dried over Na2SO4 and concentrated at 25° C. to obtain the product.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:7](Cl)(=[O:9])[CH3:8]>[O-]S(C(F)(F)F)(=O)=O.[Ga+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O>[C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])[CH3:8]
Reactant: c1ccccc1
Reactant: CC(=O)Cl
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Ga+3]
Product: CC(=O)c1ccccc1

Procedure:
Benzene (1 equivalent) was reacted with acetyl chloride (0.5 equivalents) in the presence of 0.25 equivalents of gallium triflate catalyst at 50°-60° C. for 1 hour giving 0.35 equivalents of acetophenone.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:26][C:12]3[N:13]=[CH:14][N:15]=[C:16]([NH:17][C@@H:18]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH3:19])[C:11]=3[CH:10]=2)=[CH:5][CH:4]=1.[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[NH:26][C:12]4[N:13]=[CH:14][N:15]=[C:16]([NH:17][C@@H:18]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[CH3:19])[C:11]=4[CH:10]=3)=[CH:5][CH:4]=2)[CH2:30][CH2:29]1
Reactant: C[C@@H](Nc1ncnc2[nH]c(-c3ccc(CCl)cc3)cc12)c1ccccc1
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[C@@H](Nc1ncnc2[nH]c(-c3ccc(CN4CCN(C)CC4)cc3)cc12)c1ccccc1
Temperature: 65 °C

Procedure:
A mixture of 10.8 g (30 mmol) [6-(4-chloromethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-((R)-1-phenyl-ethyl)-amine in 450 ml DMF is treated with 6.8 ml (63 mmol) N-methylpiperazine and 20.7 g (150 mmol) anhydrous potassium carbonate and the mixture heated to 65° C. for 1 hour. The reaction mixture is cooled and the inorganic salts removed by filtration (Hyflo Super Cel®; Fluka, Buchs, Switzerland). The DMF is evaporated under reduced pressure and the residue purified through flash chromatography using first dichloromethane/ethanol 9:1 and then dichloromethane/ethanol 9:1 plus 1% conc. ammonia. Crystallization of the pure fractions from THF (20 ml) and hexanes (80 ml) gives the title compound; m.p. 248-250° C.; MS-ES+: (M+H)+=427.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([Cl:15])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:18])=O>>[Cl:1][C:2]1[C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([Cl:15])[CH:8]=[CH:7][C:3]=1[C:4]([Cl:18])=[O:5]
Reactant: COC(=O)c1c(Cl)ccc(C(=O)O)c1Cl
Reactant: O=S(Cl)Cl
Product: COC(=O)c1c(Cl)ccc(C(=O)Cl)c1Cl
Reaction time: 3 h

Procedure:
2,4-Dichloro-3-methoxycarbonylbenzoic acid (32.37 g) and thionyl chloride (100 ml) was heated under reflux with stirring for 3 hours. The mixture was cooled and evaporated in vacuo, then re-evaporated after addition of toluene to give 2,4-dichloro-3-methoxycarbonylbenzoyl chloride (34.76 g) as a dark brown oil. This was used in the next stage without purification.
Reaction SMILES: O[CH2:2][CH2:3][O:4][CH2:5][C:6]([CH3:12])([CH3:11])[C:7]([O:9][CH3:10])=[O:8].N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:37]I>C(Cl)Cl>[I:37][CH2:2][CH2:3][O:4][CH2:5][C:6]([CH3:12])([CH3:11])[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)C(C)(C)COCCO
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)C(C)(C)COCCI
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
To a mixture of methyl 3-(2-hydroxyethoxy)-2,2-dimethylpropanoate (2.30 g, 1 eq.), 1H-imidazole (1.07 g, 1.2 eq.) and DCM (100 ml) was slowly added resin-bound triphenylphosphine (1.2 eq.) and iodine (3.98 g, 1.2 eq.). The reaction mixture was stirred at room temperature overnight and filtered. The filtrate was concentrated and subject to silica gel chromatography using 0-25% ether-heptane to yield the title compound as a colorless oil (3.73 g, 62%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.ClC1C=CC=CC=1.[C:16]([CH:19]1[CH2:24][CH2:23][O:22][C:20]1=[O:21])(=O)[CH3:17]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[OH:8][C:7]1[C:2]2=[N:1][C:16]([CH3:17])=[C:19]([CH2:24][CH2:23][OH:22])[C:20](=[O:21])[N:3]2[CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ncccc1O
Reactant: CC(=O)C1CCOC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Clc1ccccc1
Solvent: O
Product: Cc1nc2c(O)cccn2c(=O)c1CCO
Temperature: 125 °C
Reaction time: 18 h
Yield: 74.6 %

Procedure:
In a reaction vessel equipped with a dropping funnel and a reverse water-separator, 2-amino-3-hydroxypyridine (110.12 g; 1 mol) was added to chlorobenzene (1500 ml) at room temperature. 2-Acetylbutyrolactone (134.53 g; 1.05 mol) was added dropwise to this mixture from the dropping funnel while stirring. The dropping funnel was rinsed with chlorobenzene (250 ml) and the resulting solution was added dropwise to the previously obtained mixture. Next, p-toluenesulfonic acid monohydrate (5.7 g; 0.03 mol) was added, and the resulting mixture was heated to reflux temperature (refluxing starting at 125° C.). The reaction mixture was refluxed for 19 hours, while the water liberated during the course of the reaction was collected in the reverse water-separator. The mixture was allowed to cool to about 80° C. and then there were added 2-propanol (250 ml), activated carbon (Norit A™ supra, 25 g) and filter agent (dicalite speed plus; 2.5 g). The mixture was heated to reflux (100° C.) during 30 minutes. The reaction mixture was filtered at a temperature of 90 to 95° C. and the filter cake was washed with chlorobenzene (100 ml; 80° C.). The combined filtrate was allowed to cool to room temperature. Crystallization of the reaction product started at about 40-45° C. and was left to continue for 18 hours at room temperature. The crystals were collected and washed with chlorobenzene (100 ml) and dried in vacuo at 50-60° C. for 24 hours, yielding 164.2 g (73.6%) 9-hydroxy-3-(2-hydroxyethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one; mp 150° C.; purity >97% (LC % w/w); residual 2-amino-3-hydropyridine: 0.85%; sum of other impurities <0.52%; residual 2-acetylbutyrolactone was 0% (GC % w/w).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:15]=[C:14]([NH:16][CH3:17])[N:13]=[C:12](Cl)[N:11]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1.C(Cl)Cl.[K+].[Br-]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:15]=[C:14]([NH:16][CH3:17])[N:13]=[C:12]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=3)[N:11]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Nc1ccc(O)cc1
Reactant: CNc1nc(Cl)nc(Nc2cc(Cl)cc(Cl)c2)n1
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Product: CNc1nc(Nc2ccc(O)cc2)nc(Nc2cc(Cl)cc(Cl)c2)n1
Yield: 74 %

Procedure:
The title compound was synthesized from 2-(3,5-dichlorophenylamino)-4-methylamino-6-chloro-1,3,5-triazine and 4-aminophenol using a similar procedure to the one used in 8. Yield: 74%; Tg 83° C., Tc 155° C., Tm 187° C.; FTIR (CH2Cl2/KBr) 3401, 3282, 3180, 3112, 2952, 2918, 2850, 1572, 1514, 1503, 1421, 1400, 1366, 1258, 1227, 1168, 1114, 1080, 1011, 993, 937, 833, 807, 737, 703, 668, 632 cm−1; 1H NMR (300 MHz, DMSO-d6, 298 K): δ 9.43 (br s, 0.5H), 9.29 (br s, 0.5H), 9.00 (br s, 0.5H), 8.83 (br s, 0.5H), 7.90 (br d, 2H), 7.43 (br s, 2H), 7.06 (s, 1H), 7.00 (br s, 1H), 6.70 (d, 3J=8.8 Hz, 2H), 2.81 (d, 3J=4.1 Hz, 3H) ppm; 13C NMR (75 MHz, DMSO-d6): δ 165.9, 164.0, 163.6, 152.7, 143.0, 133.6, 131.1, 122.6, 120.0, 117.1, 114.9, 27.2 ppm; HRMS (EI) calcd. for C16H14Cl2N6O (m/e): 376.0606.found: 376.0601.
Reaction SMILES: [C:1]1([CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16](#[N:19])[CH:17]=[CH2:18].N12CCCN=C1CCCCC2>C(O)(C)C>[C:10]1([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([CH:8]=[O:9])[CH2:18][CH2:17][C:16]#[N:19])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: C=CC#N
Reactant: O=CC(c1ccccc1)c1ccccc1
Solvent: CC(C)O
Solvent: C1CCC2=NCCCN2CC1
Product: N#CCCC(C=O)(c1ccccc1)c1ccccc1
Temperature: 70 °C

Procedure:
Diphenylacetaldehyde (25.6 g), acrylonitrile (12.5 ml), and 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU:2.5 g) were stirred in isopropyl alcohol (250 ml) with warming at 70° C. for 6 hours. The reaction mixture was concentrated to dryness and the group was purified by silica gel column chromatography. The crude crystal crop obtained was washed with isopropyl ether to provide the title compound (19.8 g) as colorless crystals.
Reaction SMILES: C(=O)(OC)[O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6](Br)=[CH:5][C:4]=1[CH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.CC1(C)C(C)(C)OB([C:29]2[CH2:30][CH2:31][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:33][CH:34]=2)O1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O.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>[CH:13]1([C:4]2[C:3]([OH:2])=[CH:8][C:7]([N+:9]([O-:11])=[O:10])=[C:6]([C:29]3[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH:30]=3)[CH:5]=2)[CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: COC(=O)Oc1cc([N+](=O)[O-])c(Br)cc1C1CCCC1
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: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CC=C(c2cc(C3CCCC3)c(O)cc2[N+](=O)[O-])CC1
Temperature: 90 °C
Yield: 75.6 %

Procedure:
4-Bromo-2-cyclopentyl-5-nitrophenyl methyl carbonate (700 mg, 2.03 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (629 mg, 2.03 mmol), Pd(PPh3)4 (235 mg, 0.20 mmol), and Cs2CO3 (1325 mg, 4.07 mmol) were combined in DMF (10 mL) and heated at 90° C. for 4 h under N2 atmosphere. The reaction was diluted with water and extracted with dichloromethane (3×10 mL). The organic fractions were combined, dried over MgSO4, filtered and concentrated. Purification by silica gel chromatography (0-100% ethyl acetate/hexanes) yielded tert-butyl 4-(5-cyclopentyl-4-hydroxy-2-nitrophenyl)-5,6-dihydropyridine-1(2H)-carboxylate (596 mg, 77% yield). LC/MS m/z 389.4 [M+H]+.
Reaction SMILES: [Na].[CH3:2][O:3][C:4]1[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[CH:9]=[CH:8][C:5]=1[CH:6]=[O:7].[N+:16]([CH:19]([CH3:21])[CH3:20])([O-:18])=[O:17]>CO.C(O)(=O)C>[CH3:2][O:3][C:4]1[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[CH:9]=[CH:8][C:5]=1[CH:6]([OH:7])[C:19]([CH3:21])([N+:16]([O-:18])=[O:17])[CH3:20]
Reactant: CC(C)[N+](=O)[O-]
Reactant: COc1ccc(C=O)c(OC)c1OC
Agent: [Na]
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc(C(O)C(C)(C)[N+](=O)[O-])c(OC)c1OC
Temperature: 15 °C
Reaction time: 0.67 h
Yield: 86.7 %

Procedure:
6.4 g of sodium are added to 250 ml of anhydrous methanol, and 50 g of 2,3,4-trimethoxybenzaldehyde and 54.4 g of 2-nitropropane are added dropwise thereto at 15° C. for 40 minutes under stirring. The mixture is stirred at 25° C. for 24 hours, and 17 ml of acetic acid and 20 ml of methanol are added to said mixture under ice-cooling. The mixture is evaporated to remove solvent, and the residue is extracted with benzene. The extract is washed with water, an aqueous sodium bisulfite solution, water and a saturated sodium chloride solution, successively. The washed extract is dried and then evaporated to remove solvent. 63 g of 1-(2,3,4-trimethoxyphenyl)-2-methyl-2-nitropropanol are thereby obtained as a pale yellow oil.
Reaction SMILES: [CH2:1]([N:8]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:9]1[C:10]([F:29])=[C:11]([C:16](=O)[C:17](=[C:24]2[S:27]CS2)[C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[C:12]([F:15])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:38][NH2:39]>C(O)C>[CH2:30]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]1[C:10]([F:29])=[C:11]([C:16]2[C:17]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)=[C:24]([SH:27])[NH:38][N:39]=2)[C:12]([F:15])=[CH:13][CH:14]=1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: NN
Reactant: O=C(C(=C1SCS1)c1ccncc1)c1c(F)ccc(N(Cc2ccccc2)Cc2ccccc2)c1F
Solvent: O
Solvent: CCO
Product: Fc1ccc(N(Cc2ccccc2)Cc2ccccc2)c(F)c1-c1n[nH]c(S)c1-c1ccncc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
1-(3-Dibenzylamino-2,6-difluoro-phenyl)-2-[1,3]dithietan-2-ylidene-2-pyridin-4-yl-ethanone (1.26 g, 2.44 mmol) was suspended in absolute ethanol (10 mL). Hydrazine monohydrate (0.473 mL, 9.755 mmol, 4 eq) was added dropwise and the mixture was stirred at 60° C. for 2 hours. The suspension was concentrated under reduced pressure, taken up with toluene (2×20 mL) and evaporated to dryness. The crude product (1.35 g) was used in the following step without further purification.
Reaction SMILES: [CH3:1][C:2]1[O:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.F[C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13]>>[CH3:1][C:2]1[O:8][C:5]([CH2:6][NH:7][C:15]2[CH:16]=[N:17][CH:18]=[CH:10][C:11]=2[C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccncc1F
Reactant: Cc1ccc(CN)o1
Product: Cc1ccc(CNc2cnccc2C(=O)O)o1
Yield: 34 %

Procedure:
The title compound was prepared in 34% yield from 5-methylfurfurylamine and 3-fluoroisonicotinic acid according to the procedure for the preparation of Example 3. 1H NMR (400 MHz, DMSO-d6): δ 13.45 (br s, 1H), 8.35 (s, 1H), 7.86 (d, 1H, J=5.0 Hz), 7.77 (br s, 1H), 7.57 (d, 1H, J=5.0 Hz), 6.24 (d, 1H, J=2.9 Hz), 6.00 (d, 1H, J=2.0 Hz), 4.50 (s, 2H), 2.23 (s, 3H). [M+H] calc'd for C12H12N2O3, 233. found 233.
Reaction SMILES: [CH:1]1([N:7]([CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:8](=[O:20])[NH:9][C:10]2[S:11][C:12]([S:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:13][N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(CCN)CCCCC=1.C1(=O)CCCCC1>C(OC(=O)C)C>[C:23]1([CH2:22][CH2:21][N:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:8](=[O:20])[NH:9][C:10]2[S:11][C:12]([S:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:13][N:14]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]=1
Reactant: O=C(O)CSc1cnc(NC(=O)N(CCc2ccccc2)C2CCCCC2)s1
Agent: NCCC1=CCCCC1
Solvent: CCOC(C)=O
Solvent: O=C1CCCCC1
Product: O=C(O)CSc1cnc(NC(=O)N(CCC2=CCCCC2)C2CCCCC2)s1

Procedure:
Prepared as described for the synthesis of [2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid, from 2-(1-cyclohexenyl)-ethylamine, cyclohexanone and 2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.
Reaction SMILES: [Br-].[Li+].[CH3:3][C:4]1([O:7][CH2:6]1)[CH3:5].[CH2:8]([NH:15][CH2:16][C:17]([CH3:19])=[CH2:18])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(Cl)Cl>[CH2:8]([N:15]([CH2:16][C:17]([CH3:19])=[CH2:18])[CH2:6][C:4]([CH3:5])([OH:7])[CH3:3])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC1(C)CO1
Reactant: C=C(C)CNCc1ccccc1
Agent: [Br-]
Agent: [Li+]
Solvent: ClCCl
Product: C=C(C)CN(Cc1ccccc1)CC(C)(C)O
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 98.1 %

Procedure:
Add lithium bromide (955 mg, 11.0 mmol) to a mixture of isobutylene oxide (6.20 mL, 68.8 mmol) and benzyl-(2-methyl-allyl)-amine (9.51 g, 59.0 mmol). Stir the mixture for 3.5 h at room temperature then treat with additional epoxide (1.5 mL, 16.6 mmol) and heat at 60° C. for 1.7 h. Dilute the mixture with CH2Cl2 (200 mL) and wash with water (200 mL). Dry, filter and concentrate the organic solution. Dry the residue at 80° C. under vacuum to give the title compound (13.5 g, 98%) as a colorless oil. 1H NMR (400 MHz, DMSO-d6): δ 7.2-7.4 (5H, m), 4.90 (1H, s), 4.83 (1H, s), 4.18 (1H, s), 3.59 (2H, s), 2.98 (2H, s), 2.27 (2H, s), 1.71 (3H, s), 1.05 (6H, s).