Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[O:12])[CH:8]=[C:7]([CH3:20])[C:3]=1[C:4]([OH:6])=[O:5].[CH2:21]([O:23][C:24]1[CH:25]=[C:26]([CH:29]=[C:30]([O:33][CH2:34][CH3:35])[C:31]=1[F:32])[CH:27]=O)[CH3:22].C([BH3-])#N.[Na+].C(N(C(C)C)C(C)C)C>C(O)C.C(O)(=O)C>[CH2:21]([O:23][C:24]1[CH:25]=[C:26]([CH:29]=[C:30]([O:33][CH2:34][CH3:35])[C:31]=1[F:32])[CH2:27][N:17]1[CH2:16][CH2:15][CH:14]([NH:13][C:11](=[O:12])[C:9]2[CH:10]=[C:2]([CH3:1])[C:3]([C:4]([OH:6])=[O:5])=[C:7]([CH3:20])[CH:8]=2)[CH2:19][CH2:18]1)[CH3:22]
Reactant: CCOc1cc(C=O)cc(OCC)c1F
Reactant: Cc1cc(C(=O)NC2CCNCC2)cc(C)c1C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Product: CCOc1cc(CN2CCC(NC(=O)c3cc(C)c(C(=O)O)c(C)c3)CC2)cc(OCC)c1F

Procedure:
In analogy to the procedure described in example 50k), 2,6-dimethyl-N-piperidin-4-yl-terephthalamic acid (example 126b) was reacted with 3,5-diethoxy-4-fluoro-benzaldehyde (example 50 g), sodium cyanoborohydride, N-ethyl-diisopropylamine and acetic acid in ethanol at 50° C. to yield the title compound as colorless solid. MS: 472.9 (MH+).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:47])[C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[CH2:16][C@@H:17]([NH:39]C(OC(C)(C)C)=O)[CH2:18][S:19]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(C(O)=O)(F)(F)F.C([SiH](CC)CC)C>C(Cl)Cl>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:47])[C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[CH2:16][C@@H:17]([NH2:39])[CH2:18][SH:19]
Reactant: Cc1cccc(NC(=O)[C@@H]2CCCN2C[C@H](CSC(c2ccccc2)(c2ccccc2)c2ccccc2)NC(=O)OC(C)(C)C)c1C
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cccc(NC(=O)[C@@H]2CCCN2C[C@@H](N)CS)c1C
Reaction time: 2 h

Procedure:
N-[2(R)-t-butoxycarbonylamino-3-triphenylmethylmercapto-propyl]-L-proline-2,3-dimethylphenyl amide (0.124 g, 0.19 mmol) was dissolved in CH2Cl2 (3 mL) and CF3CO2H (1 mL) at ambient temperature, treated with triethylsilane (0.121 mL, 0.76 mmol) and stirred for 2 h. Thereaction mixture was concentrated, triturated with 0.1% aq TFA soln, the solid precipitate filtered off, and the filtrate lyophilized to provide the title compound. 1H NMR (CD3OD) δ 7.10 (s, 3H), 3.55-3.68 (m, 1H), 3.32-3.45 (m, 2H), 2.75-3.19 (m, 5H), 2.5-2.65 (m, 1H),2.31 (s, 3H), 2.15 (s, 3H), 1.9-2.15 (m, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[CH:5]=[N:6][CH:7]=1.[S:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[Sn](CCCC)(CCCC)CCCC>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.O1CCOCC1>[CH3:14][N:11]1[CH2:12][CH2:13][N:8]([C:4]2[CH:5]=[N:6][CH:7]=[C:2]([C:16]3[S:15][CH:19]=[CH:18][CH:17]=3)[CH:3]=2)[CH2:9][CH2:10]1
Reactant: CN1CCN(c2cncc(Br)c2)CC1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CN1CCN(c2cncc(-c3cccs3)c2)CC1
Temperature: 100 °C

Procedure:
To a vial was added 1-(5-bromo-pyridin-3-yl)-4-methyl-piperazine (47 mg, 0.13 mmol), Pd(PPh3)4 (34 mg), 2-thienyltributylstannane (67 mg, 0.15 mmol) and dioxane (1 mL). The resulting mixture was heated at 100° C. for 24 hrs. The resulting mixture was extracted with EtOAc. The organic layer was dried and concentrated, and the residue was purified by preparative TLC (hexanes/EtOAc) to yield the title compound as a solid.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[C:7]3[CH:13]=[C:12]([CH3:14])[NH:11][C:8]=3[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[H-].[Na+].Br[CH2:18][C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=1.[NH4+].[Cl-]>CN(C=O)C>[CH3:1][C:2]1[N:6]2[C:7]3[CH:13]=[C:12]([CH3:14])[N:11]([CH2:18][C:19]4[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=4)[C:8]=3[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1
Reactant: Cc1cc2c(ccc3nnc(C)n32)[nH]1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cn2c(C)cc3c2ccc2nnc(C)n23)cc1
Reaction time: 0.17 h

Procedure:
To a solution of 1,7-dimethyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine (0.15 g, 0.80 mmol, prepared as in Example 2, Step 5) in DMF (20 mL) was added sodium hydride (42 mg, 1.0 mmol, 60% in mineral oil). This was stirred for 10 minutes, followed by the addition of methyl 4-bromomethylbenzoate (0.18 g, 0.80 mmol, Aldrich). After 45 minutes, the reaction mixture was poured into saturated NH4Cl solution and extracted with six portions of EtOAc. The combined extracts were washed twice with water, once with brine, dried over sodium sulfate, filtered and concentrated afford product as a light yellow solid, which was used without further purification in the next Step.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[C:2]1[C:9]1[S:10][CH:11]=[CH:12][C:13]=1[C:14]([OH:16])=[O:15]>C(OC(=O)C)(=O)C>[S:10]1[CH:11]=[CH:12][C:13]2[C:14]([O:16][C:6]([C:3]3[CH:4]=[CH:5][S:1][C:2]=3[C:9]1=2)=[O:8])=[O:15]
Reactant: O=C(O)c1ccsc1-c1sccc1C(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=c1oc(=O)c2ccsc2c2sccc12
Temperature: 0 °C
Yield: 97.7 %

Procedure:
Diacid (3) (12.6 g, 49.4 mmol) was stirred in 100 mL of acetic anhydride at reflux for 6 h. Upon cooling to 0° C., the solid was collected by filtration, washed with 20 mL of cold acetic anhydride, and dried in vacuo at 120° C. overnight. The resulting light yellow crystals (11.4 g, 98% yield) were used without further purification. Anal. Calcd. for C10H4O3S2: C, 50.84; H, 1.71. Found: C, 50.78; H, 1.66; 1H NMR (CDCl3): 7.68 (d, J=4.0 Hz, 2H), 7.40 (d, J=5.0 Hz, 2H); m.p. 260-263° C.; MS (EI): m/z (%) 235.96 (100) [M+].
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[CH:12]=[C:13]([N+:27]([O-:29])=[O:28])[CH:14]=[C:15]([C:17]([C:19]3[CH:24]=[CH:23][C:22]([O:25]C)=[CH:21][CH:20]=3)=[O:18])[CH:16]=2)=[O:10])=[CH:5][CH:4]=1.Cl.N1C=CC=CC=1.[K+].[Br-]>O>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([C:11]2[CH:12]=[C:13]([N+:27]([O-:29])=[O:28])[CH:14]=[C:15]([C:17](=[O:18])[C:19]3[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=3)[CH:16]=2)=[O:10])=[CH:7][CH:8]=1
Reactant: COc1ccc(C(=O)c2cc(C(=O)c3ccc(OC)cc3)cc([N+](=O)[O-])c2)cc1
Agent: Cl
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: c1ccncc1
Product: O=C(c1ccc(O)cc1)c1cc(C(=O)c2ccc(O)cc2)cc([N+](=O)[O-])c1
Temperature: 120 °C
Reaction time: 4 h
Yield: 96 %

Procedure:
Into a 250 mL three-necked, round-bottomed flask equipped with a magnetic stirrer, a condenser, and nitrogen inlet, 3,5-bis(4-methoxyphenylcarbonyl)nitrobenzene (6.2 g, 15.8 mmol) and freshly prepared pyridine hydrochloride (100 g) were placed. The mixture was heated under reflux until the solution became homogeneous. It took about 4 h. After cooled down 120° C., the mixture was poured into water. The resulting precipitate was collected and dried. The yellow solid was slurred in boiling toluene and collected by suction filtration to give 5.5 g (96% yield), m.p. 230-231.8° C. Anal. Calcd. for C20H13NO6: C, 66.12%; H, 3.61%; N, 3.86%; O, 26.42%. Found: C, 66.07%; H, 3.64%; N, 3.67%; O, 17.01%. FT-IR (KBr, cm−1): 1321, 1538 (Ar—NO2), 1602, 1648 (carbonyl), 3420 (Ar—OH). Mass spectrum (m/e): 363 (M+, 100% relative abundance). 1H-NMR (DMSO-d6, δ in ppm): 6.93-6.96 (d, 4H, Ar), 7.76-7.79 (d, 4H, Ar), 8.23 (s, 1H, Ar), 8.58 (s, 2H, Ar), 10.66 (s, 2H, OH). 13C-NMR (DMSO-d6, δ in ppm) 115.48, 126.02, 126.65, 132.84, 134.83, 139.44, 147.61, 156.80, 162.70, 191.36.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]([C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=3)[C:17]([CH3:20])=[CH:18][CH:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]C.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]([C:21]3[CH:22]=[CH:23][C:24]([O:27][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[CH:25][CH:26]=3)[C:17]([CH3:20])=[CH:18][CH:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2ccc(OCc3ccccc3)cc2)n1-c1ccc(O)cc1
Reactant: CCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCCCOc1ccc(-n2c(C)ccc2-c2ccc(OCc3ccccc3)cc2)cc1
Yield: 85.2 %

Procedure:
A solution of 4-[2-(4-benzyloxyphenyl)-5-methyl-1H-pyrrol-1-yl]phenol (1.50 g, 4.22 mmol), 1-bromoundecane (1.31 ml, 6.33 mmol) and potassium carbonate (874 mg, 6.33 mmol) in DMF (15 ml) was stirred at 80° C. for 4 hours. The reaction solution was poured into water and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate anhydride and solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=30:1) to give the object compound as an oily substance. 1.78 g (yield: 85.2%)
Reaction SMILES: [F:1][C:2]([F:29])([C:25]([F:28])([F:27])[F:26])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23]Br)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[N:30]1([C:36]2[CH:45]=[CH:44][C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[N:37]=2)[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[F:1][C:2]([F:29])([C:25]([F:28])([F:27])[F:26])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:33]2[CH2:34][CH2:35][N:30]([C:36]3[CH:45]=[CH:44][C:43]4[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=4)[N:37]=3)[CH2:31][CH2:32]2)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: O=C(NCC(F)(F)C(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: c1ccc2nc(N3CCNCC3)ccc2c1
Product: O=C(NCC(F)(F)C(F)(F)F)C1(CCCCN2CCN(c3ccc4ccccc4n3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 1 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,3,3,3-pentafluoro-propyl)-amide and 2-piperazin-1-yl-quinoline.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[CH3:8].[O:12]=[C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15]>>[CH2:17]([O:16][C:14]([C:13]([OH:12])([CH2:10][C:9]([C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([F:1])[CH:3]=1)=[O:11])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:15])[CH3:18]
Reactant: CC(=O)c1ccc(C)c(F)c1
Reactant: CCOC(=O)C(=O)C(=O)OCC
Product: CCOC(=O)C(O)(CC(=O)c1ccc(C)c(F)c1)C(=O)OCC
Temperature: 120 °C
Reaction time: 48 h
Yield: 79.3 %

Procedure:
A mixture of 3′-fluoro-4′-methylacetophenone (4.92 g, 32.3 mmol) and diethyl ketomalonate (6.19 g, 35.6 mmol) was stirred at 120° C. for 48 hours. The temperature of the reaction mixture was allowed to drop back to room temperature, and the mixture was purified by column chromatography on silica gel [silica gel 100 g, chloroform/ethyl acetate (10/1)] to yield the title compound as yellow crystals (8.41 9, 79.3%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:13]([CH3:20])[CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[NH2:54][CH2:55][C:56]1[C:57](=[O:64])[NH:58][C:59]([CH3:63])=[CH:60][C:61]=1[CH3:62]>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([N:13]([CH3:20])[CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([NH:54][CH2:55][C:56]1[C:57](=[O:64])[NH:58][C:59]([CH3:63])=[CH:60][C:61]=1[CH3:62])=[O:9]
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Reactant: COc1c(C(=O)O)cc(Cl)cc1N(C)C1CCOCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1c(C(=O)NCc2c(C)cc(C)[nH]c2=O)cc(Cl)cc1N(C)C1CCOCC1
Yield: 62.6 %

Procedure:
To a solution of 5-chloro-2-methoxy-3-[methyl(oxan-4-yl)amino]benzoic acid (200 mg, 0.67 mmol) in DMF (2 ml) at room temperature under nitrogen was added HBTU (304 mg, 0.80 mmol) followed by N-ethyl-N-(propan-2-yl)propan-2-amine (174 μl, 1.0 mmol) and 3-(aminomethyl)-4,6-dimethyl-1,2-dihydropyridin-2-one (89%, 125 mg, 0.73 mmol). After stirring for 2 hours at room temperature EtOAc (30 ml) was added to the reaction mixture and this was then washed with deionized water (5 ml) followed by saturated NaHCO3(aq) (3×5 ml). The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by FCC (10 g silica, Isolute cartridge, gradient of eluents; 100% DCM to 96:4 DCM:MeOH) to give 182 mg (63%) of the title compound as an off-white solid. LC-MS 98%, m/z=434.1/436.1, 1H NMR (500 MHz, Chloroform-d) δ ppm 12.52 (br s, 1H), 8.76 (t, J=5.8 Hz, 1H), 7.69 (d, J=2.6 Hz, 1H), 7.01 (d, J=2.6 Hz, 1H), 5.94 (s, 1H), 4.56 (d, J=6.0 Hz, 2H), 3.99 (dd, J=11.2, 3.9 Hz, 2H), 3.72 (s, 3H), 3.49 (tt, J=11.5, 3.7 Hz, 1H), 3.36 (t, J=11.2 Hz, 2H), 2.67 (s, 3H), 2.42 (s, 3H), 2.31 (s, 3H), 1.93-1.73 (m, 2H), 1.64-1.52 (m, 2H).
Reaction SMILES: [H][H].[C:3]1([C:9]#[C:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C1COCC1>[C:3]1([CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: [H][H]
Reactant: C(#Cc1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: c1ccc(CCc2ccccc2)cc1
Reaction time: 0.08 h
Yield: 100 %

Procedure:
In Example 5, hydrogenation reaction was conducted under the same condition as Example 1 for THF diluted solution concentration of the substance to be reduced, its flow rate, and hydrogen 9 flow rate, using 1,2-diphenylacetylene as the substance to be reduced. The reaction time was within five minutes. The analytical result of the reaction product by 1H-NMR showed almost complete hydrogenation of 1,2-diphenylacetylene, and 1,2-diphenylethane was obtained at about 100% yield (See FIG. 6.).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11])([CH3:3])[CH3:2].[CH3:12][N:13]([S:17][S:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:21][CH:20]=1)[C:14](F)=[O:15].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][C:14](=[O:15])[N:13]([CH3:12])[S:17][S:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([CH3:26])([CH3:28])[CH3:27])=[CH:21][CH:20]=1)([CH3:3])[CH3:2]
Reactant: CN(SSc1ccc(C(C)(C)C)cc1)C(=O)F
Reactant: CC(C)Oc1ccccc1O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)Oc1ccccc1OC(=O)N(C)SSc1ccc(C(C)(C)C)cc1
Reaction time: 48 h
Yield: 23.7 %

Procedure:
To a solution of 4.0 g (0.026 m) of 2-isopropoxyphenol and 7.11 g (0.026 m) of N-methyl-N-(p-tert-butylphenylthiosulfenyl)carbamoyl fluoride in 75 ml of toluene was added 2.63 g (0.026 m) of triethylamine. After stirring for 48 hours the reaction mixture was washed with water and dried over anhydrous MgSO4. The product was purified by dry column chromatography to give 2.5g of a white solid. m.p. 84°-85° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][C:10]2=O)=[CH:5][CH:4]=1.[C:14]([CH2:16]C(O)=O)#[N:15].C(O)(=O)CCCCCC.NC1C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]=[C:10]2[CH2:16][C:14]#[N:15])=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)C(=O)CCC2
Reactant: N#CCC(=O)O
Agent: CCCCCCC(=O)O
Solvent: Cc1ccccc1
Solvent: Nc1ccccc1
Product: COc1ccc2c(c1)C(CC#N)=CCC2
Yield: 87 %

Procedure:
There are introduced into a 670 litre reactor 85.0 kg of 7-methoxy-1-tetralone, 60.3 kg of cyanoacetic acid and 15.6 kg of heptanoic acid in toluene in the presence of 11.0 kg of aniline. The mixture is heated at reflux. When all the starting substrate has disappeared, the solution is cooled and filtered. The precipitate obtained is washed with toluene and then the filtrate obtained is washed with a 2N sodium hydroxide solution and subsequently with water until neutral. After removal of the solvent by evaporation, the resulting solid is recrystallised from an ethanol/water (80/20) mixture to give the title product in a yield of 87% and with a chemical purity exceeding 99%.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[C:9]#[N:10])[CH:5]=[CH:4][N:3]=[CH:2]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:25][C:26]([CH3:28])=[O:27].C(=O)(O)[O-].[Na+]>C1COCC1.O>[OH:27][C:26]([CH3:28])([CH3:25])[CH:6]([C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[C:9]#[N:10])[N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: N#Cc1ccccc1Cn1ccnc1
Reactant: CC(C)=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])O
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(O)C(c1ccccc1C#N)n1ccnc1
Temperature: -75 °C

Procedure:
2-Imidazol-1-ylmethyl-benzonitrile (1.0 g, 5.49 mmol) is dissolved in THF (10 mL) and cooled to −75° C. LHMDS (1M in THF, 8.24 mL, 8.24 mmol) is added dropwise. Ten min after the end of addition, acetone (0.48 g, 8.24 mmol) is added. Thirty min after the end of addition, saturated aqueous sodium bicarbonate (10 mL) is added and the mixture is allowed to warm to r.t., then poured into water. After extraction with ethyl acetate the organic phase is dried over Na2SO4 and concentrated in vacuo. The residue is used in the next step without further purification; MS (ESI) m/z 242.1 (M+H).
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([CH2:15][N:16]3[N:20]=[C:19]([N+:21]([O-])=O)[CH:18]=[N:17]3)[CH:10]=2)[O:8][CH2:7][CH2:6][O:5]1.[NH4+].[Cl-]>CCO.O.[Fe]>[CH3:3][C:4]1([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([CH2:15][N:16]3[N:20]=[C:19]([NH2:21])[CH:18]=[N:17]3)[CH:10]=2)[O:8][CH2:7][CH2:6][O:5]1
Reactant: CC1(c2ccnc(Cn3ncc([N+](=O)[O-])n3)c2)OCCO1
Agent: [Fe]
Agent: N#N
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: CC1(c2ccnc(Cn3ncc(N)n3)c2)OCCO1
Temperature: 75 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a mixture of 4-(2-methyl-[1,3]dioxolan-2-yl)-2-(4-nitro-[1,2,3]triazol-2-ylmethyl)-pyridine (210 mg, 0.71 mmol), iron powder (120 mg, 2.12 mmol) and NH4Cl (191 mg, 3.53 mmol) in a mixture of EtOH (2.0 mL) and water (1.0 mL) was stirred at 75° C. for 1 h. The reaction mixture was filtered while hot and the filter cake rinsed with EtOH. The filtrate was concentrated under reduced pressure and the residue partitioned between CH2Cl2 (10 mL) and aq. 1M NaOH (10 mL). The aq. layer was extracted with CH2Cl2 (2×10 mL). The combined org. extracts were dried over MgSO4, filtered, and the solvent removed under reduced pressure. Purification of the residue by FC (99:1 to 19:1 CH2Cl2-MeOH) gave the title compound as a brown oil: TLC:rf (19:1 CH2Cl2-MeOH)=0.33. LC-MS: tR=0.64 min, [M+H]+=262.29.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[C:6]2[CH:16]=[C:15]([N+:17]([O-])=O)[CH:14]=[CH:13][C:7]=2[S:8][C:9]=1[C:10]([NH2:12])=[O:11])[CH3:3]>C(O)(=O)C.[Pd]>[NH2:17][C:15]1[CH:14]=[CH:13][C:7]2[S:8][C:9]([C:10]([NH2:12])=[O:11])=[C:5]([O:4][CH:2]([CH3:1])[CH3:3])[C:6]=2[CH:16]=1
Reactant: CC(C)Oc1c(C(N)=O)sc2ccc([N+](=O)[O-])cc12
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(C)Oc1c(C(N)=O)sc2ccc(N)cc12
Reaction time: 1.5 h
Yield: 66.9 %

Procedure:
A mixture of 3-(1-methylethoxy) -5-nitrobenzo[b]-thiophene-2-carboxamide (104 mg, 0.37 mmol) and 5% Pd on carbon (10 mg) in 20 mL of acetic acid is hydrogenated for 1.5 hours. The catalyst is removed by filtration and the filtrate concentrated in vacuo. The crude product is chromatograhed, eluting with 1:2 hexane:ethyl acetate, providing 62 mg of 5-amino-3-(1-methylethoxy)benzo[b]thiophene-2-carboxamide (67%); mp 150°-151° C.
Reaction SMILES: [C:1]1([CH2:11][C:12]([OH:14])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.CN(C)C=O.[NH2:26][C:27]1[CH:28]=[C:29]([N:33]2[C:38](=[O:39])[C:37]([CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[N:36][C:35]3[CH:47]=[CH:48][CH:49]=[N:50][C:34]2=3)[CH:30]=[CH:31][CH:32]=1>ClCCl.O.C(OCC)(=O)C.C(N(CC)CC)C>[CH2:40]([C:37]1[C:38](=[O:39])[N:33]([C:29]2[CH:30]=[CH:31][CH:32]=[C:27]([NH:26][C:12](=[O:14])[CH2:11][C:1]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:4]=[CH:3][CH:2]=3)[CH:28]=2)[C:34]2[N:50]=[CH:49][CH:48]=[CH:47][C:35]=2[N:36]=1)[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: O=C(O)Cc1cccc2ccccc12
Reactant: Nc1cccc(-n2c(=O)c(Cc3ccccc3)nc3cccnc32)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(Cc1cccc2ccccc12)Nc1cccc(-n2c(=O)c(Cc3ccccc3)nc3cccnc32)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.1 %

Procedure:
A mixture of 1-naphthylacetic acid (82 mg), oxalyl chloride (0.02 ml) and catalytic amount of N,N-dimethylformamide in dichloromethane (2 ml) was stirred at room temperature for 30 minutes. The above solution was added to a mixture of 4-(3-aminophenyl)-3-oxo-2-benzyl-3,4-dihydropyrido[2,3-b]pyrazine (131 mg) and triethylamine (0.085 ml) in dichloromethane (2 ml). The mixture was stirred at room temperature for 30 minutes, then poured into a mixture of ethyl acetate add water. The organic phase was washed with aqueous sodium bicarbonate solution and brine, dried over magnesium sulfate and concentrated. The residue was crystallized with ethanol to give 2-benzyl-3-oxo-4-[3-[(1-naphthyl)acetylamino]phenyl]-3,4-dihydropyrido[2,3-b]pyrazine (123 mg).
Reaction SMILES: O.[F:2][C:3]1[CH:29]=[CH:28][C:6]([O:7][C:8]2[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:9]=2[C:10]([NH:12][C:13]2[CH:18]=[CH:17][NH:16][C:15](=[O:19])[CH:14]=2)=[O:11])=[C:5]([CH3:30])[CH:4]=1.CN(C)C=O.[Cl:36][C:37](OCCl)=O>ClCCl.C(OCC)(=O)C>[Cl:36][CH2:37][N:16]1[CH:17]=[CH:18][C:13]([NH:12][C:10](=[O:11])[C:9]2[CH:20]=[CH:21][C:22]([C:24]([F:27])([F:25])[F:26])=[CH:23][C:8]=2[O:7][C:6]2[CH:28]=[CH:29][C:3]([F:2])=[CH:4][C:5]=2[CH3:30])=[CH:14][C:15]1=[O:19]
Reactant: O=C(Cl)OCCl
Reactant: Cc1cc(F)ccc1Oc1cc(C(F)(F)F)ccc1C(=O)Nc1cc[nH]c(=O)c1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(F)ccc1Oc1cc(C(F)(F)F)ccc1C(=O)Nc1ccn(CCl)c(=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.8 %

Procedure:
A sample of 2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide monohydrate (9a) (6.0 g, 14.7 mmol) was dehydrated under vacuum at 65° C. A solution of anhydrous 2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide (9a) (5.0 g, 12.31 mmol) and N,N-dimethylformamide (10.0 mL) in dichloromethane (50.0 mL) was stirred at room temp., chloromethyl chloroformate (1.64 ml, 18.46 mmol) was added and the solution was stirred at room temperature for one hour. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate, brine, dried with anhydrous sodium sulfate, filtered and evaporated to dryness. The resulting oil was purified by column chromatography (40 g silica, 20-100% EtOAc in Hexanes), product fractions were pooled and evaporated to give N-[1-(chloromethyl)-2-oxo-4-pyridyl]-2-(4-fluoro-2-methyl-phenoxy)-4-(trifluoromethyl)benzamide (3.26 g, 7.168 mmol) that was used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6) δ 10.83 (s, 1H), 7.86 (d, J=7.8 Hz, 1H), 7.76 (d, J=7.6 Hz, 1H), 7.66-7.58 (m, 1H), 7.28-7.19 (m, 1H), 7.10 (dd, J=7.7, 2.0 Hz, 2H), 6.98 (s, 1H), 6.92 (d, J=2.1 Hz, 1H), 6.50 (dd, J=7.6, 2.3 Hz, 1H), 5.79 (s, 2H), 2.16 (s, 3H) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][S:9]([CH2:12][CH2:13][OH:14])(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.Cl[C:16]1[N:21]=[C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:28][CH3:29])[CH:19]=[CH:18][N:17]=1>CN(C=O)C>[CH3:29][O:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:20]1[CH:19]=[CH:18][N:17]=[C:16]([NH:1][C:2]2[CH:3]=[C:4]([CH2:8][S:9]([CH2:12][CH2:13][OH:14])(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=2)[N:21]=1
Reactant: COc1ccccc1-c1ccnc(Cl)n1
Reactant: Nc1cccc(CS(=O)(=O)CCO)c1
Solvent: CN(C)C=O
Product: COc1ccccc1-c1ccnc(Nc2cccc(CS(=O)(=O)CCO)c2)n1
Yield: 75.1 %

Procedure:
A solution of 2-(3-amino-phenylmethanesulfonyl)-ethanol (0.215 g, 1 mmol) and 2-chloro-4-(2-methoxy-phenyl)-pyrimidine (0.22 g, 1 mmol) in DMF (3 mL) was stirred for 2 hours at 80° C. (TLC control). The solvent was removed under reduced pressure to afford an oily residue which was crystallized from isopropanol yielding 2-{3-[4-(2-methoxy-phenyl)-pyrimidin-2-ylamino]-phenylmethanesulfonyl}-ethanol (0.3 g, 75%).