Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)(Cl)=O.[F:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([OH:15])=O)=[CH:8][CH:7]=1.[S-:16][C:17]#[N:18].[K+].[NH2:20][C:21]1[CH:41]=[CH:40][C:24]([O:25][C:26]2[CH:31]=[CH:30][N:29]=[C:28]([NH:32][C:33]([N:35]3[CH2:39][CH2:38][CH2:37][CH2:36]3)=[O:34])[CH:27]=2)=[C:23]([F:42])[CH:22]=1>C(#N)C.C(OCC)C>[F:42][C:23]1[CH:22]=[C:21]([NH:20][C:17]([NH:18][C:13](=[O:15])[CH2:12][C:9]2[CH:8]=[CH:7][C:6]([F:5])=[CH:11][CH:10]=2)=[S:16])[CH:41]=[CH:40][C:24]=1[O:25][C:26]1[CH:31]=[CH:30][N:29]=[C:28]([NH:32][C:33]([N:35]2[CH2:36][CH2:37][CH2:38][CH2:39]2)=[O:34])[CH:27]=1
Reactant: Nc1ccc(Oc2ccnc(NC(=O)N3CCCC3)c2)c(F)c1
Reactant: O=C(O)Cc1ccc(F)cc1
Reactant: N#C[S-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOCC
Solvent: O=S(Cl)Cl
Product: O=C(Cc1ccc(F)cc1)NC(=S)Nc1ccc(Oc2ccnc(NC(=O)N3CCCC3)c2)c(F)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 54.4 %

Procedure:
Thionyl chloride (2.0 ml) was added to 2-(4-fluorophenyl)acetic acid (694 mg) under a nitrogen atmosphere, followed by stirring at 50° C. for 1 hr. The reaction mixture was concentrated under a reduced pressure to give a residue. The residue was dissolved in acetonitrile (100 ml) under a nitrogen atmosphere, and then potassium thiocyanate (875 mg) was added thereto at 50° C., followed by stirring at the same temperature for 2 hrs. The reaction mixture was cooled down to room temperature, and then 4-(4-amino-2-fluorophenoxy)-2-[(pyrrolidin-1-yl)carbonylamino]pyridine (949 mg) was added thereto, followed by stirring for 1 hr. The reaction mixture was concentrated under a reduced pressure to give a residue, which was then partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure to give a residue, which was then purified by silica gel column chromatography (eluent; hexane:ethyl acetate=1:2 to 1:3). Fractions containing the target compound were concentrated to give a residue, to which diethyl ether (20 ml) was added to precipitate crystals. The crystals were filtered off and dried under aeration to provide the titled compound (834.5 mg, 54%) as white crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:30]=[CH:31][CH:32]=1)[CH2:7][NH:8][CH2:9][CH2:10][N:11]1[CH:20]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([F:29])[CH:17]=2)[CH2:12]1)([O-:3])=[O:2].Br[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[CH2:38]([O:37][C:35](=[O:36])[CH2:34][N:8]([CH2:7][C:6]1[CH:30]=[CH:31][CH:32]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[CH2:9][CH2:10][N:11]1[CH:20]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([F:29])[CH:17]=2)[CH2:12]1)[CH3:39]
Reactant: CCOC(=O)CBr
Reactant: O=[N+]([O-])c1cccc(CNCCN2Cc3ccc(F)cc3CC2Cc2ccc(F)cc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)CN(CCN1Cc2ccc(F)cc2CC1Cc1ccc(F)cc1)Cc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.3 %

Procedure:
106 mg of N-(3-nitrobenzyl)-2-[6-fluoro-3-(4-fluorobenzyl)-3,4-dihydroisoquinolin-2(1H)-yl]ethanamine obtained in Example 123-b), 40 mg of ethyl bromoacetate, and 33 mg of potassium carbonate were dissolved in 1 mL of acetonitrile, followed by stirring at room temperature for 3 hours. After completion of the reaction, water was added to the reaction liquid, followed by extraction with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue obtained was purified using PLC (chloroform:methanol=20:1) to obtain 97 mg (yield 76%) of a title compound as a pale yellow oily substance.
Reaction SMILES: [NH:1]=[C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[CH2:5][CH2:4][S:3]1.[N+:14]([O-])([OH:16])=[O:15]>S(=O)(=O)(O)O>[N+:14]([N:1]=[C:2]1[N:6]([CH2:7][C:8]2[CH:9]=[CH:10][N:11]=[CH:12][CH:13]=2)[CH2:5][CH2:4][S:3]1)([O-:16])=[O:15]
Reactant: N=C1SCCN1Cc1ccncc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])N=C1SCCN1Cc1ccncc1
Reaction time: 0.5 h

Procedure:
5.8 g of 2-imino-3-(4-pyridylmethyl)thiazolidine was added to 20 ml of conc. sulfuric acid at -5~0° C. 6 ml of fuming nitric acid was then added dropwise to the solution at the same temperature. After stirring for 30 minutes at 0~5° C., the reaction mixture was poured onto crushed ice. Twice extract with dichloromethan followed by treating in the usual way yielded 1.4 g of desired 2-nitroimino-3-(4-pyridylmethyl)thiazolidine.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]1[C:12]([CH3:13])=[CH:11][N:10]=[C:9](O)[C:8]1=[O:15])=[O:5])[CH3:2].P(Br)(Br)([Br:18])=O.[NH4+].[OH-]>C(Cl)(Cl)Cl>[Br:18][C:9]1[C:8](=[O:15])[N:7]([CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:12]([CH3:13])=[CH:11][N:10]=1
Reactant: O=P(Br)(Br)Br
Reactant: CCOC(=O)Cn1c(C)cnc(O)c1=O
Agent: [NH4+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)Cn1c(C)cnc(Br)c1=O
Temperature: 25 °C

Procedure:
A stirred slurry of 505 mg (2.38 mmol) of 1-(ethoxycarbonyl-methyl)-3-hydroxy-6-methylpyrazinone and 756 mg (2.64 mmol) of phosphorous oxybromide in 1.7 ml of CHCl3 was stirred at 50° C. under a slow stream of Ar for 1.5 h, then allowed to cool to rt overnight. The reaction mixture was diluted with CHCl3 and ice water, basified with NH4OH, and extracted with CHCl3. The combined organic layers were dried over Na2SO4, treated with activated carbon, filtered and concentrated to give 2-5 as an orange colored solid: 1H NMR (CDCl3) δ7.06 (s, 1H), 4.77 (s, 2H), 4.27 (q, 2H, 7.2 Hz), 2.24 (s, 3H), 1.31 (t, 3H, 7.2 Hz).
Reaction SMILES: [N:1]#[N:2].[S:3]([NH:19][C@H:20]([C:28]([OH:30])=[O:29])[CH2:21][CH2:22][CH2:23][NH:24][C:25](=[NH:27])[NH2:26])([C:6]1[C:18]2[CH:17]=[CH:16][CH:15]=[C:11]([N:12]([CH3:14])[CH3:13])[C:10]=2[CH:9]=[CH:8][CH:7]=1)(=[O:5])=[O:4].O.[C:32]1([CH3:42])[CH:37]=[CH:36][C:35]([S:38]([OH:41])(=[O:40])=[O:39])=[CH:34][CH:33]=1.C1C=CC=CC=1.[Cl:49][CH2:50][CH2:51][CH2:52]O>>[N:1]#[N:2].[C:32]1([CH3:42])[CH:33]=[CH:34][C:35]([S:38]([OH:41])(=[O:39])=[O:40])=[CH:36][CH:37]=1.[C:32]1([CH3:42])[CH:33]=[CH:34][C:35]([S:38]([OH:41])(=[O:39])=[O:40])=[CH:36][CH:37]=1.[Cl:49][CH2:50][CH2:51][CH2:52][O:29][C:28](=[O:30])[C@H:20]([CH2:21][CH2:22][CH2:23][NH:24][C:25](=[NH:26])[NH2:27])[NH:19][S:3]([C:6]1[C:18]2[CH:17]=[CH:16][CH:15]=[C:11]([N:12]([CH3:13])[CH3:14])[C:10]=2[CH:9]=[CH:8][CH:7]=1)(=[O:4])=[O:5]
Reactant: OCCCCl
Reactant: CN(C)c1cccc2c(S(=O)(=O)N[C@@H](CCCNC(=N)N)C(=O)O)cccc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N#N
Solvent: c1ccccc1
Solvent: O
Product: CN(C)c1cccc2c(S(=O)(=O)N[C@@H](CCCNC(=N)N)C(=O)OCCCCl)cccc12
Temperature: 100 °C
Yield: 88 %

Procedure:
A mixture of 1.0 gram of N2 -dansyl-L-arginine and 1.4 gram of p-toluenesulfonic acid monohydrate in 10 ml of 3-chloro-1-propanol was heated for 30 minutes at 100° C. To the thus obtained clear solution, 100 ml of benzene was added, and the mixture was refluxed for 5 hours, removing water by azeotropic distillation. After the solvent was removed by distillation, 100 ml of ethyl ether was added to the residue to give a crystalline mass. Crystallization from acetone gave N2 -dansyl-L-arginine 3-chloropropyl ester di(p-toluenesulfonate) in 88% yield; mp. 140°-145° C.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[F:5][C:6]([F:17])([F:16])[C:7]1[NH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2.Cl[CH:19]([O:21]C(Cl)Cl)Cl.Cl>C(Cl)Cl.O.[N+](C)([O-])=O>[F:17][C:6]([F:5])([F:16])[C:7]1[NH:8][C:9]2[C:14]([C:15]=1[CH:19]=[O:21])=[CH:13][CH:12]=[CH:11][CH:10]=2
Reactant: ClC(Cl)OC(Cl)Cl
Reactant: FC(F)(F)c1cc2ccccc2[nH]1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Solvent: ClCCl
Solvent: O
Product: O=Cc1c(C(F)(F)F)[nH]c2ccccc12
Temperature: -65 °C
Reaction time: 0.25 h

Procedure:
6.1 g of aluminum chloride and 20 ml of methylene chloride were mixed together at -65° C. under an inert atmosphere and a solution of 4.61 g of 2-trifluoromethyl-(1H)-indole (J. Org. Chem., 1974 Vol. 39, p. 1836), 1.4 ml of nitromethane and 20 ml of methylene chloride were added at -60° C. 3.3 ml of dichloromethyl ether in solution in 10 ml of methylene chloride were added to the suspension of the resulting mixture was stirred for 15 minutes at -65° C. The temperature was allowed to rise and at about -10° C., a strong evolution of hydrochloric acid was observed which ceased at about 0° C. The black solution obtained was stirred for 30 minutes at 25° C. and the reaction mixture was poured into water and extracted with methylene chloride. The organic phases were washed with an aqueous solution of sodium bicarbonate, then with water and concentrated to dryness under reduced pressure to obtain 4.6 g of 2-trifluoromethyl-3-formyl-(1H)-indole.
Reaction SMILES: [CH:1]([NH2:3])=[O:2].[CH:4](=O)[CH3:5].C[Si](Cl)(C)C.[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](O)(=[O:20])=[O:19])=[CH:14][CH:13]=1.C(OC(C)(C)C)(C)(C)C>C1(C)C=CC=CC=1.C(#N)C>[CH3:22][C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH:4]([NH:3][CH:1]=[O:2])[CH3:5])(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: NC=O
Reactant: CC=O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: CC(C)(C)OC(C)(C)C
Agent: C[Si](C)(C)Cl
Solvent: Cc1ccccc1
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)C(C)NC=O)cc1
Temperature: -30 °C
Reaction time: 1 h

Procedure:
A stirred mixture of dry acetonitrile (500 mL) and dry toluene (500 mL) was cooled to −30° C., followed by the addition of formamide (50.7 g, 1.1 mol), acetaldehyde (37 g, 0.85 mol) and TMSCl (106.4 g, 0.98 mol) at −30° C. under N2 atmosphere. The reaction mixture was stirred at rt for 1 h and warmed to 55° C., then p-toluene sulphonic acid was added and stirred the reaction mixture at this temperature overnight. The reaction mixture was cooled to 0° C. and followed by the addition of 300 mL of tert-butyl ether and stirred for 1 h. The white precipitate formed was filtered off and dried. The crude product was taken into next step without further purification. Yield (crude): 110 g.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][NH:6][CH2:7]2.[C:12](OCC)(=[O:14])[CH3:13]>>[C:12]([N:6]1[CH2:5][CH2:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[NH2:1])[CH2:7]1)(=[O:14])[CH3:13]
Reactant: Nc1cccc2c1CCNC2
Reactant: CCOC(C)=O
Product: CC(=O)N1CCc2c(N)cccc2C1

Procedure:
A stirred mixture of 5-amino-1,2,3,4-tetrahydroisoquinoline (10.0 g) isopropenyl acetate (7.2 g) and ethyl acetate (150 ml) was heated under reflux for 24 hours. The cooled, filtered solution was evaporated under reduced pressure to a small volume. The residual oil was purified by elution from a silica column with ethyl acetate/methanol mixtures followed by crystallisation from ethyl acetate to give 2-acetyl-5-amino-1,2,3,4-tetrahydroisoquinoline as a white solid 6.6 g, m.p. 107°-108° C.
Reaction SMILES: CO.[C:3]([C:8]1[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=1)(=O)[CH2:4][CH2:5][CH3:6].[F:19][C:20]([F:35])([F:34])[C:21]1[CH:26]=[CH:25][C:24]([C:27]2[N:32]=[CH:31][C:30]([NH2:33])=[CH:29][N:28]=2)=[CH:23][CH:22]=1.[B][B][B][B][B][B][B][B][B][B]>Cl>[F:35][C:20]([F:19])([F:34])[C:21]1[CH:22]=[CH:23][C:24]([C:27]2[N:28]=[CH:29][C:30]([NH:33][CH:3]([C:8]3[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=3)[CH2:4][CH2:5][CH3:6])=[CH:31][N:32]=2)=[CH:25][CH:26]=1
Reactant: CCCC(=O)c1ccc(C(=O)OCC)cc1
Reactant: Nc1cnc(-c2ccc(C(F)(F)F)cc2)nc1
Agent: Cl
Agent: [B][B][B][B][B][B][B][B][B][B]
Solvent: CO
Product: CCCC(Nc1cnc(-c2ccc(C(F)(F)F)cc2)nc1)c1ccc(C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24 %

Procedure:
Methanol (0.70 mL) was added to a flask containing ethyl 4-butyrylbenzoate (82.8 mg, 0.376 mmol), 2-(4-(trifluoromethyl)phenyl)pyrimidin-5-amine (90.0 mg, 0.376 mmol) and decaborane (46.0 mg, 0.376 mmol) at room temperature under nitrogen. The resulting solution was stirred at room temperature overnight. The mixture was diluted with 1N HCl and extracted with ethyl acetate twice. The combined organic layers were dried over sodium sulfate, filtered and concentrated. Purification by column chromatography (0-35% ethyl acetate in heptane) gave ethyl 4-(1-(2-(4-(trifluoromethyl)phenyl)pyrimidin-5-ylamino)butyl)benzoate (40.0 mg, 24%). 1H NMR (400 MHz, CDCl3, δ): 8.32 (d, J=8.19 Hz, 2H), 8.07 (s, 2H), 7.98-8.04 (m, 2H), 7.63 (d, J=8.19 Hz, 2H), 7.36-7.41 (m, 2H), 4.38-4.43 (m, 2H), 4.35 (q, J=7.02 Hz, 2H), 1.75-1.91 (m, 2H), 1.36 (t, J=7.02 Hz, 3H), 1.20-1.52 (m, 2H), 0.94 (t, J=7.32 Hz, 2H). MS (M+1): 444.3.
Reaction SMILES: [NH2:1][C:2]1[C:6]([NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:13]=2)=[N:5]S(=O)[N:3]=1.[ClH:25]>CO>[ClH:25].[ClH:25].[ClH:25].[N:19]1([CH2:18][C:14]2[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=2)[O:11][CH2:10][CH2:9][CH2:8][NH:7][C:6](=[NH:5])[C:2](=[NH:1])[NH2:3])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: NC1=NS(=O)N=C1NCCCOc1cccc(CN2CCCC2)c1
Agent: Cl
Solvent: CO
Product: N=C(N)C(=N)NCCCOc1cccc(CN2CCCC2)c1

Procedure:
A suspension of 3-amino-4-[3-(3-pyrrolidinomethylphenoxy)propylamino]-1,2,5-thiadiazole 1-oxide (13.4 g; 38.3 mmoles) [prepared according to the procedure of U.S. Pat. No. 4,374,248] in 350 ml of methanol was treated with 25.5 mL of concentrated HCl. The resultant solution was stirred for 3 hours at ambiet temperature. Concentration of the solution followed by azeotropic removal of water with absolute ethanol gave the product. The crystalline residue was triturated with 150 mL of absolute ethanol, filtered and dried to give 10.8 g of the title compound, m.p. 195°-203° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])=[CH:4]C(C#N)=[N:6][CH:7]=1.[OH-:16].[K+].[CH2:18]([OH:20])[CH3:19]>C(OC(=O)C)C>[Cl:1][C:2]1[C:3]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])=[CH:4][C:19]([C:18]([OH:16])=[O:20])=[N:6][CH:7]=1
Reactant: N#Cc1cc(OCC(F)(F)F)c(Cl)cn1
Reactant: [OH-]
Reactant: CCO
Agent: [K+]
Solvent: CCOC(C)=O
Product: O=C(O)c1cc(OCC(F)(F)F)c(Cl)cn1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 62.5 %

Procedure:
To a solution of 5-Chloro-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carbonitrile (Example 24b, 800 mg, 3.38 mmol) in ethanol (10 ml) was added 4.0M aqueous solution of potassium hydroxide (4.65 ml, 18.6 mmol). The reaction was stirred for 30 min at 90° C. under microwave radiation. The reaction mixture was diluted with ethylacetate, poured into a separatory funnel and extracted with 1N aqueous solution hydrochloric acid. The organic phase was collected, dried over sodium sulfate and evaporated down to dryness to yield a crude product (540 mg, 62.5%) which was used without any further purification. MS (ESI, m/z): 256.4 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[N:7]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[F:19])[C:15](=[O:20])[N:14]([C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][CH:22]=1)[CH:13]=[CH:12]2)[CH3:8])([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C.C(O)C.[Pd]>[C:1]([O:5][C:6](=[O:30])[N:7]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[F:19])[C:15](=[O:20])[N:14]([C:21]1[CH:22]=[CH:23][C:24]([NH2:27])=[CH:25][CH:26]=1)[CH:13]=[CH:12]2)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C(=O)OC(C)(C)C)c1cc2ccn(-c3ccc([N+](=O)[O-])cc3)c(=O)c2cc1F
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CN(C(=O)OC(C)(C)C)c1cc2ccn(-c3ccc(N)cc3)c(=O)c2cc1F
Reaction time: 2 h
Yield: 92.4 %

Procedure:
To a suspension of [7-Fluoro-2-(4-nitro-phenyl)-1-oxo-1,2-dihydro-isoquinolin-6-yl]-methyl-carbamic acid tert-butyl ester (0.33 g, 0.79 mmol) in ethyl acetate (6 mL) and ethanol (2 mL) under Ar was added 10% Pd/C (0.13 g, 0.12 mmol Pd). The mixture was hydrogenated under 1 atm H2 for 2 hr, filtered through Celite and concentrated to give 0.28 g (92%) of [2-(4-Amino-phenyl)-7-fluoro-1-oxo-1,2-dihydro-isoquinolin-6-yl]-methyl-carbamic acid tert-butyl ester. RP-HPLC: 3.83 min; ES-MS (M+H)+=384.0; 1H-NMR (DMSO-d6) δ (ppm): 1.32 (s, 9), 3.17 (s, 3), 5.31 (br s, 2), 6.60 (m, 3), 7.00 (d, 2), 7.32 (d, 2), 7.75 (d, 1), 7.86 (d, 1).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1)=[O:10].[C:21]1([NH2:28])[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[NH2:27].C(N(CC)C(C)C)(C)C.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.CN(C=O)C>[NH2:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[NH:28][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1)=[O:10]
Reactant: Nc1ccccc1N
Reactant: O=C(CCCCCCCBr)c1ccc2ccccc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Nc1ccccc1NCCCCCCCC(=O)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 3.3 %

Procedure:
To a solution of 1-bromo-7-[(2-naphthoyl)]heptane 72 (62 mg, 0.17 mmol) in toluene (2 mL) and DMF (1 mL) was added 1,2-phenylenediamine (60 mg, 0.56 mmol) and N,N-diisopropylethylamine (36 μL, 0.21 mmol) and the reaction mixture was stirred at room temperature for 2 hours then at 75° C. for two hours and finally refluxed for 5 hours. Saturated sodium bicarbonate solution (5 mL) was added and the mixture was extracted with dichloromethane (2×20 mL). The combined organic layers were washed with deionized water (20 mL), washed with brine (10 mL), and dried (MgSO4). The solvents were removed in vacuo and the title compound 73 (2 mg, 3%) was isolated by column chromatography (3:7-4:6 ethyl acetate:hexane) followed by recrystallization from ether and hexane. 1H NMR (400 MHz, DMSO-d6): δ 8.69 (s, 1H), 8.14 (d, J=8.0 Hz, 1H), 8.00 (m, 3H), 7.64 (m, 2H), 6.52 (m, 1H), 6.47 (m, 1H), 6.38 (m, 2H), 4.46 (s, 2H), 4.30 (m, 1H), 3.17 (t, J=7.4 Hz, 2H), 2.99 (m, 2H), 1.69 (m, 2H), 1.60 (m, 2H), 1.39 (m, 6H).
Reaction SMILES: [CH2:1]([Sn](CCCC)(CCCC)CCCC)[CH:2]=[CH2:3].N#N.Br[C:20]1[CH:39]=[N:38][C:23]2[N:24]([CH2:36][CH3:37])[C:25]3[N:33]=[C:32]([F:34])[CH:31]=[C:30]([CH3:35])[C:26]=3[NH:27][C:28](=[O:29])[C:22]=2[CH:21]=1.O>CN(C=O)C.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>[CH2:36]([N:24]1[C:23]2[N:38]=[CH:39][C:20]([CH2:3][CH:2]=[CH2:1])=[CH:21][C:22]=2[C:28](=[O:29])[NH:27][C:26]2[C:30]([CH3:35])=[CH:31][C:32]([F:34])=[N:33][C:25]1=2)[CH3:37]
Reactant: CCN1c2ncc(Br)cc2C(=O)Nc2c(C)cc(F)nc21
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Solvent: O
Solvent: CN(C)C=O
Product: C=CCc1cnc2c(c1)C(=O)Nc1c(C)cc(F)nc1N2CC
Temperature: 90 °C
Yield: 44.4 %

Procedure:
Allyltributyltin (7.77 mL, 25.1 mmol) and Pd(Ph3P)4 (1.32 g, 1.14 mmol) were added to a degassed (N2 through solution for 30 min) solution of 8-bromo-5,11-dihydro-11-ethyl-2-fluoro-4-methyl-6H-dipyrido[3,2-b:2′,3′-e][1,4]diazepin-6-one (8.0 g, 22.8 mmol) in DMF (114 mL). The mixture was heated to 90° C. for 3 h. The mixture was poured into water (250 mL) and extracted with EtOAc (4×250 mL). The combined organic layers were washed with 20% aqueous NH40H (250 mL) and brine (250 mL), dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (hexanes:EtOAc, 4:1 to 1:1) to give the title compound (3.16 g, 51% yield).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[CH3:15][C:16]([CH3:18])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)C.C(O)(=O)C>[CH:16]([NH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1)([CH3:18])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)N[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 60 °C

Procedure:
Commercially available tert-butyl (3R)-3-aminopiperidine-1-carboxylate (6.67 g) was dissolved in ethanol (100 ml), and thereto were added acetone (12.2 ml) and acetic acid (2.0 ml), and the mixture was heated at 60° C. with stirring. Seven hours later, to the mixture was added sodium triacetoxyborohydride (9.67 g), and the mixture was stirred at room temperature for 14 hours. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with chloroform. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over sodium hydrogen sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (the developing solvent: chloroform/methanol=30/1, 15/1, 10) to give the title compound (7.78 g) as a white solid.
Reaction SMILES: [CH2:1]([S:8](Cl)(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([CH2:25][CH2:26][O:27][C:28]2[C:33]([NH2:34])=[C:32]([NH:35][CH2:36][CH:37]3[CH2:45][CH2:44][C:40]4([CH2:43][CH2:42][CH2:41]4)[CH2:39][CH2:38]3)[N:31]=[C:30]([C:46]#[N:47])[N:29]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].N1C=CC=CC=1>C(Cl)Cl.CN(C1C=CN=CC=1)C.CCOC(C)=O>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([CH2:25][CH2:26][O:27][C:28]2[C:33]([NH:34][S:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)(=[O:10])=[O:9])=[C:32]([NH:35][CH2:36][CH:37]3[CH2:45][CH2:44][C:40]4([CH2:43][CH2:42][CH2:41]4)[CH2:39][CH2:38]3)[N:31]=[C:30]([C:46]#[N:47])[N:29]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(CCOc2nc(C#N)nc(NCC3CCC4(CCC4)CC3)c2N)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC(CCOc2nc(C#N)nc(NCC3CCC4(CCC4)CC3)c2NS(=O)(=O)Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Benzylsulfonylchloride (0.50 mmol) is added to a solution of 4-(2-{5-amino-2-cyano-6-[(spiro[3.5]non-7-ylmethyl)amino]pyrimidin-4-yloxy}ethyl)piperidine-1-carboxylic acid t-butyl ester (167 mg) and pyridine (0.66 mmol) in CH2Cl2 (3 mL) are added at 0° C. After stirring at room temperature for 1 h, benzylsulfonylchloride (0.50 mmol), pyridine (0.66 mmol) and DMAP (catalytic amount) are added to the reaction mixture again. The reaction mixture is stirred at room temperature for 1 h and diluted with AcOEt. The organic layer is washed with H2O and evaporated in vacuo. The resulting residue is purified by silica gel column chromatography to give 4-(2-{2-cyano-5-phenylmethanesulfonylamino-6-[(spiro[3.5]non-7-ylmethyl)amino]pyrimidin-4-yloxy}ethyl)piperidine-1-carboxylic acid tert-butyl ester.