Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([C@H:13]2[CH2:18][CH2:17][C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:15][CH2:14]2)=[CH:9][CH:8]=1)(=O)=O>CO.[Pd]>[C:10]1([C@H:13]2[CH2:14][CH2:15][C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][CH2:18]2)[CH:11]=[CH:12][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)C[C@H]1CC[C@H](c2ccc(OS(=O)(=O)C(F)(F)F)cc2)CC1
Agent: [Pd]
Solvent: CO
Product: COC(=O)C[C@H]1CC[C@H](c2ccccc2)CC1
Reaction time: 16 h

Procedure:
10% Pd/C (4520 mg) was added to a solution of methyl [trans-4-(4-{[(trifluoromethyl)sulfonyl]oxy}phenyl)cyclohexyl]acetate (prepared as described in Patent Application WO2004/047755) (8100 mg) in MeOH (150 mL). The resulting suspension was stirred for 16 h under an atmosphere of Hydrogen. The suspension was filtered through diatomaceous earth and concentrated in vacuo to give a slurry. This was extracted into EtOAc (300 mL). The organic extract was washed with saturated aqueous sodium hydrogen carbonate solution (75 mL) and then brine (75 mL). The organic layer was dried and concentrated in vacuo to give the title compound (4720 mg) as an oil; 1H NMR δ 7.28-7.11 (5H, m), 3.58 (3H, s), 2.43 (1H+DMSO, m), 2.22 (2H, d), 1.83-1.67 (5H, m), 1.44 (2H, m), 1.13 (2H, m); MS m/e MH+ 233.
Reaction SMILES: [C:1]1([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:13][C:12](=[N:14][O:15][CH3:16])[CH2:11][C@H:10]2[C:17]2[O:21][N:20]=[C:19]([CH:22]3[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]3)[N:18]=2)=[O:8])=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O.C(Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+]>>[CH3:16][O:15][N:14]=[C:12]1[CH2:11][C@@H:10]([C:17]2[O:21][N:20]=[C:19]([CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:18]=2)[N:9]([C:7]([C:4]2[CH:3]=[CH:2][C:1]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:6][CH:5]=2)=[O:8])[CH2:13]1
Reactant: CON=C1C[C@@H](c2nc(C3CCN(C(=O)OC(C)(C)C)CC3)no2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CON=C1C[C@@H](c2nc(C3CCNCC3)no2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Yield: 80 %

Procedure:
tert-butyl 4-{5-[(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyrrolidinyl]-1,2,4-oxadiazol-3-yl}-1-piperidinecarboxylate) (100 mg, 1.80 mmol) was treated with a 25% TFA/DCM solution at 0° C. for 1 hour. The reaction was then made basic with a sodium carbonate solution (10%) and extracted with DCM. The organic phases were combined and dried over magnesium sulfate and solvent removal afforded a residue which was purified by flash-chromatography using cyclohexane/ethylacetate (2/8) as eluent to give (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[3-(4-piperidinyl)-1,2,4-oxadiazol-5-yl]-3-pyrrolidinone O-methyloxime as a mixture of E-/Z-isomers in 80% yield (96.1% purity by HPLC).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].O=[C:8]1[CH:17]=[N:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9]1.C(OC(=O)C)C>C1COCC1>[NH:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:16][CH2:17][CH2:8]1
Reactant: O=c1cnc2ccccc2[nH]1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: c1ccc2c(c1)NCCN2
Temperature: 0 °C
Yield: 66 %

Procedure:
Basically, a 500 ml, three-necked flask was charged with lithium aluminum hydride (300 Ml, 1M in THF, 300 mmol) under an inert atmosphere. To the lithium aluminum hydride was added 2-keto-1,2-dihydroquinoxaline (22 g, 0.15 mol) in dry THF (100 ml) in small portions to prevent a sharp rise of temperature. After the addition was complete, the mixture was heated at the refluxing temperature of THF for 4 hours. The excess lithium aluminum hydride was decomposed by a slow addition of ethylacetate (10 ml) at room temperature. The resulting mixture was dropped slowly into ice water and extracted with diethyl ether. The diethyl ether solution was dried over anhydrous MgSO4, filtered and the solvent evaporated to give a yellow solid. The solid was recrystallized in hexane to give 1,2,3,4-tetrahydroquinoxaline in 66% yield.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[CH2:9][CH2:10][CH2:11][CH3:12])=[CH:4][CH:3]=1.[CH2:14](O)[CH2:15][OH:16]>C1C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH2:9][CH2:10][CH2:11][CH3:12])[O:16][CH2:15][CH2:14][O:13]2)=[CH:6][CH:7]=1
Reactant: CCCCC(=O)c1ccc(Br)cc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CCCCC1(c2ccc(Br)cc2)OCCO1
Yield: 91.5 %

Procedure:
To a solution of 4′-bromovalerophenone (2.41 g, 10 mmol) in benzene (60 ml) was added ethylene glycol (2.0 ml, 36 mmol), p-toluenesulfonic acid monohydrate (100 mg, 0.53 mmol) and the mixture refluxed under nitrogen in a Dean-Stark apparatus for 16 h. The reaction mixture was washed with sodium bicarbonate solution (5%, 50 ml), brine (1×50 ml), dried (Na2SO4) and evaporated to give 2-(4-bromophenyl)-2-butyl-1,3-dioxolane (11) as a clear oil (2.61 g, 92%). 1H nmr (CDCl3, 300 MHz) 0.88, t (6.9 Hz), H4″; 1.2-1.4, m, H2″,3″; 1.88, m, H1″; 3.7-3.8, m, CH2O; 4.0-4.1, m, CH2O; 7.34, d (8.4 Hz), H2′,6′; 7.49, d (8.4 Hz), H3′,5′. ESI (+ve) MS m/z 285/287 (M+H, 8%).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[CH:6]=1)=[O:4].[S-:13][C:14]#[N:15].[K+].O>C(O)C>[CH3:12][O:11][C:7]1[CH:6]=[C:5]([C:3](=[O:4])[CH2:2][S:13][C:14]#[N:15])[CH:10]=[CH:9][CH:8]=1
Reactant: N#C[S-]
Reactant: COc1cccc(C(=O)CBr)c1
Agent: [K+]
Solvent: O
Solvent: CCO
Product: COc1cccc(C(=O)CSC#N)c1
Temperature: 25 °C
Yield: 97.2 %

Procedure:
A solution of 2-bromo-1-(3-methoxyphenyl)ethanone (7.63 g, 33.3 mmol) and potassium thiocyanate (3.24 g, 33.3 mmol) in ethanol (70 ml) was stirred at 80° C. for 2 hours. After cooling to room temperature, water (70 ml) was added to the reaction mixture, and the mixture was extracted with chloroform. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give 6.71 g (97.2%) of the desired product as a solid.
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:58][N:59]([CH3:67])[CH:60]1[CH2:65][CH2:64][CH:63]([NH2:66])[CH2:62][CH2:61]1>>[CH:1]1([N:7]2[CH2:13][C:12]([F:14])([F:15])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:66][CH:63]5[CH2:64][CH2:65][CH:60]([N:59]([CH3:67])[CH3:58])[CH2:61][CH2:62]5)=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Reactant: CN(C)C1CCC(N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)NC2CCC(N(C)C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and N1,N1-dimethylcyclohexane 1,4-diamine. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.11-1.96 (m, 18H) 2.17 (s, 6H) 3.31 (s, 3H) 3.73 (m, 1H) 3.92 9m, 1H) 3.94 (s, 3H) 4.06 (t, J=13.52 Hz, 2H) 4.46 (m, 1H) 7.42-7.59 (m, 2H) 7.89 (s, 1H) 8.11 (m, 1H) 8.21 (s, 1H) 8.26 (d, J=8.34 Hz, 1H). Melting point: 208-214° C. [M+H] calculated for C30H41F2N7O3, 586. found 586.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C([Li])(C)(C)C.[S:19](Cl)([Cl:22])(=[O:21])=[O:20]>CCOCC.C(OCC)(=O)C>[C:4]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=[C:2]([S:19]([Cl:22])(=[O:21])=[O:20])[CH:3]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: Brc1cccc(-c2ccccc2)c1
Agent: [Li]C(C)(C)C
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: O=S(=O)(Cl)c1cccc(-c2ccccc2)c1
Temperature: -78 °C
Yield: 49.5 %

Procedure:
3-Bromobiphenyl (1.5 g, 6.4 mmol) was dissolved in ether (15 ml) and cooled to -78° C. t-Butyllithium (1.7 M solution in hexane, 3.8 ml, 6.4 mmol) was added dropwise under constant stirring and an argon atmosphere. The resultant reaction mixture was stirred at -10° C. to -5° C. for 6 h. The reaction mixture was cooled to -78° C. and sulfuryl chloride (0.64 ml, 6.4 mmol) was added dropwise. After completion of the addition, the reaction mixture was allowed to attain ambient temperature slowly and stirred for 1 h. The reaction mixture was diluted with ethyl acetate (50 ml), washed with water and the organic layer dried over anhydrous MgSO4. Removal of the solvent under reduced pressure gave crude product, which was purified by column chromatography, using hexane followed by 5% ethyl acetate in hexane as eluent, to give 3-biphenylsulfonyl chloride as an oil (0.8 g, 49% yield).
Reaction SMILES: [CH3:1][C:2]1[C:3](O)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[N+:13]([CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])#[C-:14]>>[CH3:1][C:2]1[C:3]2[N:4]([CH:14]=[N:13][C:15]=2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: [C-]#[N+]CC(=O)OC(C)(C)C
Reactant: Cc1nc2ccccc2nc1O
Product: Cc1nc2ccccc2n2cnc(C(=O)OC(C)(C)C)c12

Procedure:
M.p. 176°-177° C., from 3-methyl-2-quinoxalinol and tert-butyl isocyanoacetate. (Compound 6)
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2[F:28])[CH:17]=[CH:16][C:3]=1[C:4]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[CH3:15])[C:9](O)=[O:10])=[O:5].[CH3:29][N:30]([CH3:32])[NH2:31]>>[CH3:29][N:30]([CH3:32])[NH:31][C:9](=[O:10])[C:8]1[CH:12]=[CH:13][C:14]([CH3:15])=[C:6]([C:4](=[O:5])[C:3]2[CH:16]=[CH:17][C:18]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=3[F:28])=[CH:19][C:2]=2[Cl:1])[CH:7]=1
Reactant: CN(C)N
Reactant: Cc1ccc(C(=O)O)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Product: Cc1ccc(C(=O)NN(C)C)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl

Procedure:
Compound 424 (50 mg, 0.12 mmol) and N,N-dimethyl-hydrazine (19 μL, 0.25 mmol) were treated as described for compound 337. Flash chromatography (ethyl acetate/petroleum ether: graduated from 67/33 to 80/20) provided the title compound. 13C NMR (DMSO-d6) δ 194.7, 163.2, 158.9 (dd), 155.9 (dd), 149.6, 139.6, 139.5, 133.9, 133.8, 131.3, 131.0, 129.1, 127.2, 126.7 (dd), 126.3, 124.2 (dd), 114.9, 112.0 (dd), 111.9, 105.1 (dd), 46.1, 19.6
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([NH:35][C:36](=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38])[CH:32]=[C:33]([CH3:34])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([NH:35][C:36](=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38])[CH:32]=[C:33]([CH3:34])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2c(C)cc(NC(=O)C(C)(C)C)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2c(C)cc(NC(=O)C(C)(C)C)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 1 from tert.-butyl 4'-[[2-n-butyl-4-methyl-6-(2,2-dimethylpropionylamino)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:11]=[C:10]([Cl:12])[N:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[F:13][C:14]1[CH:15]=[C:16]([CH:26]=[CH:27][CH:28]=1)[CH2:17][O:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1>C(#N)C>[Cl:12][C:10]1[N:9]=[CH:8][C:4]2[N:5]=[CH:6][N:7]=[C:2]([NH:23][C:22]3[CH:21]=[CH:20][C:19]([O:18][CH2:17][C:16]4[CH:26]=[CH:27][CH:28]=[C:14]([F:13])[CH:15]=4)=[CH:25][CH:24]=3)[C:3]=2[CH:11]=1
Reactant: Nc1ccc(OCc2cccc(F)c2)cc1
Reactant: Clc1cc2c(Cl)ncnc2cn1
Solvent: CC#N
Product: Fc1cccc(COc2ccc(Nc3ncnc4cnc(Cl)cc34)cc2)c1

Procedure:
4,6-Dichloro-pyrido[3,4-d]pyrimidine (1 g) and 4-(3-fluorobenzyloxy)aniline (1.08 g) in acetonitrile (70 ml) were reacted together as in Procedure A. The product was collected by filtration as a yellow solid (1.86 g); m/z 381 (M+1)+.
Reaction SMILES: [Li+].[OH-].[CH3:3][C:4]1([C:19]([O:21]C)=[O:20])[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:5]1>C(O)C>[CH2:12]([O:11][C:9]([N:6]1[CH2:7][CH2:8][C:4]([CH3:3])([C:19]([OH:21])=[O:20])[CH2:5]1)=[O:10])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)C1(C)CCN(C(=O)OCc2ccccc2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C(=O)O)CCN(C(=O)OCc2ccccc2)C1
Temperature: 78 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
A 3M LiOH solution (14.7 mL, 29.4 mmol) was added to 1-benzyl 3-methyl 3-methylpyrrolidine-1,3-dicarboxylate (2.72 g, 9.81 mmol) in ethanol (15 mL), and the reaction mixture was stirred at 78° C. (bath) for 1 hour. The ethanol was removed, and ether (30 mL) was added. The aqueous layer was separated and acidified with saturated potassium hydrogen sulfate to a pH of about 3 to about 4, extracted with ethyl acetate (50 mL), washed with brine and dried over sodium sulfate. After removal of the solvent, 1-(benzyloxycarbonyl)-3-methylpyrrolidine-3-carboxylic acid (2.56 g, 99% yield) was isolated as an oil.
Reaction SMILES: CS(C)=O.[CH2:5]([C:20]1[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[OH-].[K+].[CH3:29]I>O>[CH2:5]([C:20]1[CH:21]=[C:22]([O:26][CH3:29])[CH:23]=[CH:24][CH:25]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CI
Reactant: CCCCCCCCCCCCCCCc1cccc(O)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CCCCCCCCCCCCCCCc1cccc(OC)c1
Temperature: 25 °C
Yield: 99.5 %

Procedure:
Into a 2-liter round-bottomed flask was placed 500 milliliters (ml) of dimethyl sulfoxide, 100 grams (g) of 3-(n-pentadecyl)phenol (0.33 mol), and 73.55 g of potassium hydroxide (1.31 mol). To this mixture, 93.5 g of methyl iodide ( 0.66 mol) was added drop wise with stirring at room temperature. After the addition, the reaction mixture was stirred for a further 6 hours. Then the reaction mixture was poured into deionized water (1.5 liters). The organic material was extracted by addition of diethyl ether. The diethyl ether layer was separated, washed with water, dried over anhydrous sodium sulfate, and finally evaporated to afford the crude product as a viscous fluid. This material was purified by silica gel column chromatography using petroleum ether as the eluent to furnish 3-(n-pentadecyl) anisole (104.6 g, 97% of theoretical yield) having a melting range of 27-28° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:13])([CH3:12])[CH:10]=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:14][CH:15]([SiH3])[CH:16]=C(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C:9]([CH3:13])([CH3:12])[CH:10]([OH:11])[CH2:16][CH:15]=[CH2:14])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C=O)NC(=O)OC(C)(C)C
Reactant: CC(C)=CC(C)[SiH3]
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: C=CCC(O)C(C)(C)NC(=O)OC(C)(C)C
Reaction time: 0.17 h

Procedure:
To a solution of the product of step b (20 mmol, 3.74 g) in 20 ml of CH2Cl2 at −78° C., 22 ml of a solution 1 M of TiCl4 in CH2Cl2 is added. After 10 min, trimethyallylsilane (22 mmol, 3.5 ml) in 20 ml of CH2Cl2 is added. After one hour the reaction is quenched with water. The organic layer is separated and extracted with CH2Cl2 (3×25 ml). The solution is anhydrified (Na2SO4) and after concentration 1.14 g of product is obtained.
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([CH2:9][CH2:10][C:11]2[CH:29]=[CH:28][N:14]3[C:15](=[O:27])[C:16]([CH:25]=O)=[C:17]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[N:18]=[C:13]3[C:12]=2[O:30][CH3:31])[S:7][CH:8]=1)([CH3:3])[CH3:2].[C:32]([O:36][C:37]([CH:39]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:38])([CH3:35])([CH3:34])[CH3:33]>O1CCCC1.CN(C)C=O>[CH:1]([C:4]1[N:5]=[C:6]([CH2:9][CH2:10][C:11]2[CH:29]=[CH:28][N:14]3[C:15](=[O:27])[C:16](/[CH:25]=[CH:39]/[C:37]([O:36][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:38])=[C:17]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[N:18]=[C:13]3[C:12]=2[O:30][CH3:31])[S:7][CH:8]=1)([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1c(CCc2nc(C(C)C)cs2)ccn2c(=O)c(C=O)c(N3CCOCC3)nc12
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1c(CCc2nc(C(C)C)cs2)ccn2c(=O)c(/C=C/C(=O)OC(C)(C)C)c(N3CCOCC3)nc12
Temperature: 80 °C
Reaction time: 15 h
Yield: 57 %

Procedure:
The 8-[2-(4-isopropyl-1,3-thiazol-2-yl)ethyl]-9-methoxy-2-morpholino-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carbaldehyde (300 mg) obtained in (H) was dissolved in tetrahydrofuran (4 ml) and dimethylformamide (1 ml), added with (tert-butoxy-carbonylmethylene)triphenylphosphorane (767 mg), and stirred at 80° C. for 15 hours. After the solvent was evaporated, the residue was purified by silica gel column chromatography to obtain the title compound (209 mg) as yellow powder.
Reaction SMILES: O[C:2]1[N:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].P(Cl)(Cl)([Cl:16])=O>>[Cl:16][C:2]1[N:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cc([N+](=O)[O-])cnc1O
Reactant: O=P(Cl)(Cl)Cl
Product: O=C(O)c1cc([N+](=O)[O-])cnc1Cl

Procedure:
A solution of 2-hydroxy-5-nitronicotinic acid (9.2 g, 0.05 mol) in phosphorus oxychloride (25 ml) was refluxed for 5 hours. The solvent was removed in vacuo and the residue dissolved in a mixture of tetrahydrofuran and ether. After cooling the solution in an ice bath, water was cautiously added dropwise with stirring until a clean separation of layers was obtained. The organic layer was washed with water and a saturated sodium chloride solution, dried (anhydrous magnesium sulfate) and concentrated. Recrystallization from ether gave 6.94 g (69% of theory) of pure product, m.p. 135° C. (dec).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])(C)C)=[N:6][CH:7]=1.Cl.[CH3:17][CH2:18][O:19]C(C)=O>[O-]CC.[Na+]>[CH2:18]([O:19][C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9](=[O:15])[O:10][CH2:11][CH3:14])=[N:6][CH:7]=1)[CH3:17]
Reactant: CC(C)(C)OC(=O)Nc1cnc(Cl)cn1
Reactant: CCOC(C)=O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Product: CCOC(=O)Nc1cnc(OCC)cn1
Temperature: 25 °C
Yield: 42.9 %

Procedure:
The mixed products from 1,1-dimethylethyl (5-chloro-2-pyrazinyl)carbamate were combined and refluxed in 24% sodium ethoxide for 5 days, then cooled to RT, neutralized with HCl, and the product extracted out with DCM. The DCM was washed with saturated NaHCO3, then concentrated to afford a black residue. Addition of EtOAc afforded solids that were filtered off, washed with EtOAc to give ethyl (5-ethoxypyrazin-2-yl)carbamate as a brown solid (3.5 g, 42.9%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14](=[O:24])[NH:15][CH2:16][C:17]3[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=3)[CH:11]=[C:10]([C:25](O)=[O:26])[CH:9]=2)=[CH:4][CH:3]=1.Cl.[CH3:29][NH:30][CH3:31].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:29][N:30]([CH3:31])[C:25]([C:10]1[CH:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)[CH:13]=[C:12]([C:14]([NH:15][CH2:16][C:17]2[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=2)=[O:24])[CH:11]=1)=[O:26]
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(C(=O)NCc3ccc(C)nc3)c2)cc1
Reactant: CNC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(C(=O)NCc3ccc(C)nc3)cc(C(=O)N(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4′-methyl-5-((6-methylpyridin-3-yl)methylcarbamoyl)biphenyl-3-carboxylic acid (50 mg, 0.14 mmol) in N,N-dimethylformamide (1 mL) were added dimethylamine hydrochloride (60 mg, 0.74 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (120 mg, 0.32 mmol) and N,N-diisopropylethylamine (0.50 mL, 2.87 mmol). The reaction mixture was stirred for 16 hours at 25° C. The reaction solution was purified by preparative HPLC to afford the final product as a light brown solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:5][CH:4]=1)#[N:2].[Cl:18][C:19]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:20]=1[C:21]([N:23]=[C:24]=[O:25])=[O:22]>C(Cl)Cl>[Cl:18][C:19]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:20]=1[C:21]([NH:23][C:24]([N:9]([C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)[NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:25])=[O:22]
Reactant: CC(C)(C)OC(=O)NNc1ccc(C#N)cc1
Reactant: O=C=NC(=O)c1c(F)cccc1Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NN(C(=O)NC(=O)c1c(F)cccc1Cl)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92414.5 %

Procedure:
To a solution of tert-butyl 2-(4-cyanophenyl)hydrazinecarboxylate (2.5 g, 0.01 mmol) in DCM (15 mL) was added 2-chloro-6-fluorobenzoyl isocyanate (Intermediate-8, 2.56 g, 0.012 mmol). The reaction mass was stirred at RT for 2 h. Excess of solvent was removed under vacuum to afford 4.0 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 1.42 (s, 9H), 7.25-7.38 (m, 2H), 7.47-7.60 (m, 3H), 7.82-7.85 (m, 2H), 9.96 (br s, 1H), 11.43 (br s, 1H); MS (m/z): 431.02 (M+H)+.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH:10]([NH:13][CH2:14][C:15]2[CH:20]=CC=C[CH:16]=2)[CH2:9]1)C1C=CC=CC=1.[CH4:21]>CO.[Pd]>[CH3:21][C:15]([CH3:16])([CH3:20])[CH:14]=[N:13][CH:10]1[CH2:11][CH2:12][NH:8][CH2:9]1
Reactant: C
Reactant: c1ccc(CNC2CCN(Cc3ccccc3)C2)cc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)C=NC1CCNC1
Yield: 58 %

Procedure:
36.8 g (0.138 mol) of 1-benzyl-3-benzylaminopyrrolidine are hydrogenated in 160 ml of methanol over 5 g of 5% strength palladium on active charcoal at 130° C. under a hydrogen pressure of 100 bar for 10 hours. The catalyst is filtered off and 16.6 g (0.138 mol ) of 71% strength pivalaldehyde are added to the filtrate, while stirring, after which the temperature rises from 20° C. to 28° C. The mixture is subsequently stirred for 30 minutes, the methanol is removed on a rotary evaporator and the residue is distilled. 12.7 g of 3-(2,2-dimethyl-propylidene-amino)-pyrrolidine of boiling point: 61° C./10 mbar are obtained with a purity, determined by gas chromatography, of 97%, corresponding to a yield of 58% of theory.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[C:5]([O:13][CH2:14][CH:15]2[CH2:17][CH2:16]2)=[CH:4][N:3]=1.[F-:18].[Cs+]>CS(C)=O.O>[F:18][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[C:5]([O:13][CH2:14][CH:15]2[CH2:17][CH2:16]2)=[CH:4][N:3]=1
Reactant: [F-]
Reactant: Fc1ccc2c(OCC3CC3)cnc(Cl)c2c1
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: Fc1ccc2c(OCC3CC3)cnc(F)c2c1
Temperature: 145 °C
Yield: 65.8 %

Procedure:
To a solution of 1-Chloro-4-(cyclopropylmethoxy)-7-fluoroisoquinoline (0.7 g, 2.78 mmol) in DMSO (5 mL) was added cesium fluoride (1.0 g, 6.95 mmol) at room temperature. The reaction vessel (Pressure tube) was sealed and heated at 145° C. for 18 h. The reaction mass was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography to get desired compound (0.43 g, 65%) as white solid. 1H NMR (400 MHz, CD3OD): δ ppm 8.35-8.33 (m, 1H), 7.77-7.74 (d, J=12 Hz, 1H) 7.73 (t, J=8 Hz, 1H), 7.52-7.51 (d, J=4 Hz, 1H), 4.10-4.08 (d, J=8 Hz, 2H), 1.42-1.40 (m, 1H), 0.74-0.69 (m, 2H), 0.49-0.46 (m, 2H); MS: MS m/z 237.0 (M++1).