Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[CH:13]=[CH:12][N:11]=[C:10]([O:15]C)[C:9]=3[C:8]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][C:24]#[N:25])=[CH:19][CH:18]=3)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[I-].[Na+].Cl[Si](C)(C)C.O>C(#N)C>[CH:1]1([N:6]2[C:14]3[CH:13]=[CH:12][NH:11][C:10](=[O:15])[C:9]=3[C:8]([C:17]3[CH:18]=[CH:19][C:20]([CH2:23][C:24]#[N:25])=[CH:21][CH:22]=3)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1nccc2c1c(-c1ccc(CC#N)cc1)nn2C1CCCC1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: N#CCc1ccc(-c2nn(C3CCCC3)c3cc[nH]c(=O)c23)cc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 93.9 %

Procedure:
To a solution of (4-(1-cyclopentyl-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl)phenyl)acetonitrile (81.6 mg) in acetonitrile (10 mL) were added sodium iodide (73.6 mg) and chloro(trimethyl)silane (0.249 mL), and the mixture was stirred at 60° C. for 30 min. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and the obtained solid was washed with ethyl acetate/diisopropyl ether to give the title compound (73.4 mg).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:16]([C:22]([C:24]3[CH:25]=[N:26][C:27](Cl)=[CH:28][CH:29]=3)=[O:23])=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[NH4+:32]>C1COCC1>[NH2:32][C:27]1[N:26]=[CH:25][C:24]([C:22]([C:16]2[C:15]([NH:14][S:11]([C:8]3[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:10][CH:9]=3)(=[O:12])=[O:13])=[CH:20][C:19]([Cl:21])=[CH:18][N:17]=2)=[O:23])=[CH:29][CH:28]=1
Reactant: [NH4+]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2cc(Cl)cnc2C(=O)c2ccc(Cl)nc2)cc1
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2cc(Cl)cnc2C(=O)c2ccc(N)nc2)cc1
Temperature: 100 °C
Reaction time: 72 h

Procedure:
A sealed tube was charged with 4-tert-butyl-N-[5-chloro-2-(6-chloro-pyridine-3-carbonyl)-pyridin-3-yl]-benzenesulfonamide (320 mg, 0.631 mmol), concentrated ammonium hydroxide (3.2 mL), and THF (3.2 mL). The tube was sealed and stirred for 3 days at 100° C. The solvents were subsequently removed in vacuo and the residue purified by automated flash chromatography to provide the desired aminopyridine: 1H NMR (400 MHz, CDCl3) δ 10.72 (bs, 1H), 8.69 (d, 1H), 8.28 (dd, 1H), 8.16 (dd, 1H), 8.02 (dd, 1H), 7.71 (d, 2H), 7.40 (d, 2H), 6.46 (d, 1H), 5.00 (bs, 2H), 1.24 (s, 9H); MS (ES) M+H expect 445.1, found 445.1.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:19])[NH:10][C@H:11]([C:13](=[O:18])N(OC)C)[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:20][C:21]([F:34])([F:33])[C:22]1[CH:23]=[C:24](Br)[CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1>>[CH2:1]([O:8][C:9](=[O:19])[NH:10][C@@H:11]([CH3:12])[C:13]([C:24]1[CH:25]=[C:26]([C:28]([F:31])([F:29])[F:30])[CH:27]=[C:22]([C:21]([F:20])([F:34])[F:33])[CH:23]=1)=[O:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: FC(F)(F)c1cc(Br)cc(C(F)(F)F)c1
Reactant: CON(C)C(=O)[C@H](C)NC(=O)OCc1ccccc1
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
Prepared according to the procedure described in Example 16, Step 2, using the following starting materials: [(S)-1-(methoxy-methyl-carbamoyl)-ethyl]-carbamic acid benzyl ester and 3,5-bis(trifluoromethyl)bromobenzene.
Reaction SMILES: [C:1]([C:5]1[CH:33]=[CH:32][C:8]([C:9]([NH:11][C@@H:12]([CH2:16][C:17]2[CH:22]=[CH:21][C:20](B3OC(C)(C)C(C)(C)O3)=[CH:19][CH:18]=2)[C:13]([O-:15])=[O:14])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Br:34][C:35]1[CH:36]=[N:37][C:38](I)=[N:39][CH:40]=1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CC#N.C1COCC1.O>[Br:34][C:35]1[CH:36]=[N:37][C:38]([C:20]2[CH:19]=[CH:18][C:17]([CH2:16][C@H:12]([NH:11][C:9](=[O:10])[C:8]3[CH:32]=[CH:33][C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])=[CH:6][CH:7]=3)[C:13]([O:15][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:14])=[CH:22][CH:21]=2)=[N:39][CH:40]=1
Reactant: CC(C)(C)c1ccc(C(=O)N[C@@H](Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)C(=O)[O-])cc1
Reactant: Brc1cnc(I)nc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CC#N
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)[C@H](Cc1ccc(-c2ncc(Br)cn2)cc1)NC(=O)c1ccc(C(C)(C)C)cc1
Temperature: 110 °C
Yield: 58 %

Procedure:
Prepared using General Procedure 10. Into a degassed solution of (S)-2-(4-(tert-butyl)benzamido)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate INT-13 (1.0 g, 2.0 mmol), Na2HCO3 (420 mg, 3.9 mmol), and 5-bromo-2-iodopyrimidine (615 mg, 2.2 mmol) in 2/2/1 MeCN/THF/H2O was added Pd(dppf)Cl2 (140 mg, 0.2 mmol). The reaction mixture was heated at 110° C. for 1 h in a microwave reactor. The reaction mixture was concentrated, dissolved in DCM and washed with H2O. The organic layer was dried over Na2SO4, concentrated, and purified by chromatography (EA/hexanes) to provide 630 mg (58%) of tert-butyl (S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(4-(tert-butyl)benzamido)propanoate INT-14. LCMS-ESI (m/z) calculated for C28H32BrN4O3: 538.5; no m/z observed, tR=4.66 min (Method 1). 1H NMR (400 MHz, CDCl3) δ 8.84-8.78 (s, 2H), 8.31 (t, J=7.0 Hz, 2H), 7.75-7.64 (m, 2H), 7.46-7.38 (m, 2H), 7.30 (dd, J=12.9, 7.1 Hz, 2H), 6.65 (d, J=7.2 Hz, 1H), 5.10-4.94 (m, 1H), 3.43-3.20 (m, 2H), 1.45 (s, 9H), 1.32 (s, 9H).
Reaction SMILES: [Sn](Cl)Cl.[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]=[N:12][C:13]2[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:14]=2[C:15]#[N:16])=[CH:7][CH:6]=1>C(O)C>[Cl:4][C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C:15]([NH2:16])=[C:14]3[C:13]([CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17]3)=[N:12]2)=[CH:9][CH:10]=1
Reactant: N#Cc1cc(F)c(F)cc1N=Nc1ccc(Cl)cc1
Agent: Cl[Sn]Cl
Solvent: CCO
Product: Nc1c2cc(F)c(F)cc2nn1-c1ccc(Cl)cc1
Yield: 91.7 %

Procedure:
Tin(II) chloride (11.4 g, 60 mmol) was added to a solution of 2-(4-chloro-phenylazo)-4,5-difluoro-benzonitrile (3.3 g, 12 mmol) in ethanol (91 ml) under an argon atmosphere. The suspension was heated under reflux conditions for 16 h and the solvent removed under reduced pressure. The residue was taken up in half saturated aqueous NaHCO3 solution/EtOAc 1/1, the layers were separated and filtered separately over dicalite. The filtrate of the aqueous layer was extracted two times with EtOAc, the organic layers were combined, washed with ice water and dried over Na2SO4. The solvent was removed under reduced pressure to give the title compound (3.2 g, 11 mmol; 95%) as light brown solid which was used in the next step without further purification. MS: m/e=280.0 [M+H+].
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:7]([CH2:9][F:10])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[ClH:18]>CCOCC>[NH2:1][C@H:2]([C:7]([CH2:9][F:10])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[ClH:18]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)CF
Agent: Cl
Solvent: CCOCC
Product: CC(C)C[C@H](N)C(=O)CF
Reaction time: 1 h
Yield: 54 %

Procedure:
To a solution of Boc-LeuCH2F (1.53 g, 6.19 mmol) in ether (30 mL) was added a saturated solution of HCl in ether (20 mL). The mixture was stirred vigorously; a precipitate formed within 15 minutes. After 1 hour, the mixture was filtered, the solids were washed with ether (2×30 mL) and were then pumped dry overnight; a second crop was obtained from the filtrate, giving 0.60 g (54%) of LeuCH2F hydrochloride. Boc-Phe-Gly-LeuOH (synthesized in several steps via mixed anhydride coupling of the appropriate amino acid benzyl esters and subsequent hydrogenolyses, 0.762 g, 1.69 mmol) was dissolved in THF (10 mL), and was cooled to -20° C. NMM (0.186 mL, 1.69 mmol) was added, followed by IBCF (0.219 mL, 1.69 mmol). After 5 minutes, HCl.LeuCH2F (0.31 g, 1.69 mmol) was dissolved in DMF (2 mL), to which solution was added NMM (0.186 mL, 1.69 mmol). This mixture was swirled for approximately 15 seconds and was added to the mixed anhydride solution. After 45 minutes, the reaction was quenched with 1M HCl (20 mL), extracted with ethyl acetate (2×30 mL), the combined organics were washed with saturated aqueous NaHCO3 (30 mL), brine (20 mL), dried over MgSO4, filtered, and evaporated. The thick oil was then dissolved in 1:1 ether/CH2Cl2 (20 mL), and hexane (50 mL) was added. After one day, the supernatant was decanted from the impure product and was evaporated to dryness, yielding 0.14 g of Boc-Phe-Gly-Leu-LeuCH2F.
Reaction SMILES: [CH2:1]([C:8]1[O:12][C:11]([CH:13]([C:15]2[C:16]([CH3:27])=[N:17][O:18][C:19]=2[C:20]2[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=2)[OH:14])=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28]([O:30][C:31]([C:33]1([C:36]2[CH:41]=[CH:40][C:39](B3OC(C)(C)C(C)(C)O3)=[CH:38][CH:37]=2)[CH2:35][CH2:34]1)=[O:32])[CH3:29]>>[CH2:28]([O:30][C:31]([C:33]1([C:36]2[CH:41]=[CH:40][C:39]([C:23]3[CH:24]=[CH:25][C:20]([C:19]4[O:18][N:17]=[C:16]([CH3:27])[C:15]=4[CH:13]([C:11]4[O:12][C:8]([CH2:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)=[N:9][N:10]=4)[OH:14])=[CH:21][CH:22]=3)=[CH:38][CH:37]=2)[CH2:34][CH2:35]1)=[O:32])[CH3:29]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)c1nnc(Cc2ccccc2)o1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)c4nnc(Cc5ccccc5)o4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using (5-benzyl-[1,3,4]oxadiazol-2-yl)-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-methanol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:23]=[C:22]([N:24]([CH2:26][CH3:27])[CH3:25])[C:21]4[CH2:20][CH2:19][CH2:18][CH:17]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[C:16]=4[N:15]=3)=[CH:9][C:8]=2[O:34][CH3:35])[CH:6]=1>C(=O)=O.CO>[Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:23]=[C:22]([N:24]([CH2:26][CH3:27])[CH3:25])[C:21]4[CH2:20][CH2:19][CH2:18][C@H:17]([C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=5)[C:16]=4[N:15]=3)=[CH:9][C:8]=2[O:34][CH3:35])[CH:6]=1
Reactant: CCN(C)c1nc(Nc2ccc(-n3cnc(Cl)c3)c(OC)c2)nc2c1CCCC2c1ccccc1
Agent: O=C=O
Solvent: CO
Product: CCN(C)c1nc(Nc2ccc(-n3cnc(Cl)c3)c(OC)c2)nc2c1CCC[C@@H]2c1ccccc1

Procedure:
A racemic mixture of N2-(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-ethyl-N4-methyl-8-phenyl-5,6,7,8-tetrahydroquinazoline-2,4-diamine (183 mg, 0.206 mmol from Example 124) was purified using chiral supercritical fluid chromatography (SFC) to afford 54.7 mg of peak A (Example 124A) and 53.3 mg of peak B (Example 124B). SFC Method: Chiralpak OJ-H (30×250 mm, 5 μM), 30% methanol (0.1% diethylamine) in CO2, 35° C., flow rate 70 mL/min for 105 min, absorbance 220 nm, injection 0.75 mL of 26 mg/mL solution in methanol (multiple stacked injections), tR (peak A)=4.9 min, tR (peak B) 12.0 min. The absolute stereochemistry of individual enantiomers (Examples 124A and 124B) were not determined. LC-MS and 1H NMR analytical data for the separated enantiomers was identical to the racemate (Example 124).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]O)=[CH:4][C:3]=1[O:10][CH2:11][CH2:12][CH2:13][CH3:14].S(Cl)([Cl:17])=O>C(Cl)Cl>[CH2:11]([O:10][C:3]1[CH:4]=[C:5]([CH2:8][Cl:17])[CH:6]=[CH:7][C:2]=1[Br:1])[CH2:12][CH2:13][CH3:14]
Reactant: CCCCOc1cc(CO)ccc1Br
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CCCCOc1cc(CCl)ccc1Br
Reaction time: 8 h
Yield: 92 %

Procedure:
To a stirred solution of 20.2 (659.3 mg, 2544 μmol) in DCM (15 mL) at 23° C., was added thionyl chloride (371 μL, 5088 μmol). The resulting mixture was stirred overnight. The reaction was concentrated and then purified by combiflash (0 to 10% EtOAc/Hexanes) to provide 20.3 (650 mg, 92.0% yield).
Reaction SMILES: O[C:2]1[CH:3]=[CH:4][C:5]2[C:9]([C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][N:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)=[CH:14][CH:13]=3)=[O:11])=[C:8]([C:27]3[CH:32]=[CH:31][C:30](O)=[CH:29][CH:28]=3)[S:7][C:6]=2[CH:34]=1.[CH2:35]([N:39]=[C:40]=[O:41])[CH2:36][CH2:37][CH3:38]>C1COCC1>[CH2:35]([NH:39][C:40]([C:2]1[CH:3]=[CH:4][C:5]2[C:9]([C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][N:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)=[CH:14][CH:13]=3)=[O:11])=[C:8]([C:27]3[CH:32]=[CH:31][C:30]([C:40](=[O:41])[NH:39][CH2:35][CH2:36][CH2:37][CH3:38])=[CH:29][CH:28]=3)[S:7][C:6]=2[CH:34]=1)=[O:41])[CH2:36][CH2:37][CH3:38]
Reactant: CCCCN=C=O
Reactant: O=C(c1ccc(OCCN2CCCCC2)cc1)c1c(-c2ccc(O)cc2)sc2cc(O)ccc12
Solvent: C1CCOC1
Product: CCCCNC(=O)c1ccc(-c2sc3cc(C(=O)NCCCC)ccc3c2C(=O)c2ccc(OCCN3CCCCC3)cc2)cc1
Yield: 84.6 %

Procedure:
4.47 g (9 mmol) of [6-hydroxy-2-(4-hydroxyphenyl)benzo-[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone was dissolved in 250 mL of THF and 4 g (40 mmol) of n-butylisocyanate was added. The reaction mixture, at room temperature and under nitrogen, was allowed to react for 72 hours. The reaction mixture had evaporated by the end of this time and the residue was dissolved in a minimal amount of CHCl3. This solution was chromatographed (HPLC) on a silica gel column, eluted with a linear gradient of CHCl3 to CHCl3 --MeOH (19:1) to afford 4.87 g of the title compound as a tan amorphous powder.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:10][CH2:11][CH2:12][N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[C:7]([OH:9])[CH:8]=1.C(N(CC)CC)C.[Br:25][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][CH:35]=1)[C:32](=[O:36])[NH:31][C:30](=[O:37])/[C:29]/2=[CH:38]/OC.O>CN(C)C=O>[Br:25][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][CH:35]=1)[C:32](=[O:36])[NH:31][C:30](=[O:37])/[C:29]/2=[CH:38]\[NH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:10][CH2:11][CH2:12][N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[C:7]([OH:9])[CH:8]=1
Reactant: NCc1ccc(OCCN2CCCC2)c(O)c1
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(Br)cc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: O=C1NC(=O)c2ccc(Br)cc2/C1=C/NCc1ccc(OCCN2CCCC2)c(O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.6 %

Procedure:
An amount of 33.5 mg (0.142 mmol) of 5-Aminomethyl-2-(2-pyrrolidin-1-yl-ethoxy)-phenol, is dissolved in N,N-dimethylformamide (2 ML). 30 μl (0.213 mmol) of triethylamine is added followed by 20 mg (0.071 mmol) of (4E)-6-bromo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione. After the mixture is stirred at room temperature for 30 min, water (2 mL) is added and the reaction mixture is stirred for 60 min. The precipitate is filtered and washed several times with anhydrous ether. The crude solid is then purified by high performance liquid chromatography to give 23 mg of a yellow solid. MS (ESI) m/z 486.3 (M+1).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>C(Cl)Cl>[C:17]([C:14]1[CH:15]=[C:16]2[C:11]([CH2:10][CH2:9][NH:8]2)=[CH:12][CH:13]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(C(C)(C)C)cc21
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)c1ccc2c(c1)NCC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6-tert-Butyl-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (Prepared in Example HH; 12.0 g) in CH2Cl2 (100 mL) was cooled to 0° C. and treated with HCl gas for 10 minutes. The reaction mixture was warmed to room temperature and stirred for 1 hour. The solvents were evaporated; the residue was dissolved in EtOAc, washed with saturated NaHCO3 solution and brine, and dried (MgSO4) Concentration gave the title compound which was used without any further purification. MS(APCI): 176 (M+H).
Reaction SMILES: [CH3:1][C:2](=[O:7])[CH2:3][C:4](=[O:6])[CH3:5].[H-].[Na+].Cl.[CH3:11][Si:12]([CH3:38])([CH3:37])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1>COCCOC>[CH3:11][Si:12]([CH3:38])([CH3:37])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:28]1[CH:36]=[CH:35][C:31]([C:32]([CH:3]([C:2](=[O:7])[CH3:1])[C:4](=[O:6])[CH3:5])=[O:33])=[CH:30][CH:29]=1
Reactant: C[Si](C)(C)CCCCCCCCCCCCCCNc1ccc(C(=O)Cl)cc1
Reactant: CC(=O)CC(C)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(=O)C(C(C)=O)C(=O)c1ccc(NCCCCCCCCCCCCCC[Si](C)(C)C)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 14.2 g. of 2,4-pentanedione and 20 ml. of 1,2-dimethoxyethane is added to a suspension of 6.8 g. of sodium hydride in 110 ml. of 1,2-dimethoxyethane under argon. A solution of 14.0 g. of 4-[14-(trimethylsilyl)tetradecylamino]benzoyl chloride hydrochloride in 1,2-dimethoxyethane is then added. The reaction mixture is stirred at room temperature for 12 hours, cooled, poured on ice and extracted with ether. The ether solution is washed with water and saturated sodium chloride solution, dried with anhydrous sodium sulfate and evaporated. The residue is then chromatographed over silica gel to yield the product as a white solid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[SH:34][C:35]1[CH:53]=[CH:52][C:51]([N+:54]([O-:56])=[O:55])=[CH:50][C:36]=1[CH2:37][N:38]([CH3:49])[C:39](=[O:48])[O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.[CH3:57][O:58][CH2:59][C@H:60](O)[CH3:61]>C1COCC1>[CH3:57][O:58][CH2:59][C@@H:60]([S:34][C:35]1[CH:53]=[CH:52][C:51]([N+:54]([O-:56])=[O:55])=[CH:50][C:36]=1[CH2:37][N:38]([CH3:49])[C:39](=[O:48])[O:40][CH2:41][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)[CH3:61]
Reactant: COC[C@@H](C)O
Reactant: CN(Cc1cc([N+](=O)[O-])ccc1S)C(=O)OCc1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC[C@H](C)Sc1ccc([N+](=O)[O-])cc1CN(C)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 108.4 %

Procedure:
To a solution of triphenylphosphine (355 mg, 1.354 mmol) in THF (4 mL) at 0° C., was added DIAD (0.263 mL, 1.354 mmol) dropwise. The mixture was stirred at 0° C. for 10 min affording a colorless suspension. A solution of 6B (300 mg, 0.903 mmol) and (R)-1-methoxypropan-2-ol (0.133 mL, 1.354 mmol) in THF (2 mL) was added dropwise. The resultant dark red solution was stirred at 0° C. for 0.5 h, then was allowed to slowly warm to rt over night. The reaction mixture was concentrated. The crude product was purified by flash chromatography (loaded in chloroform onto a 40 g column and eluted with a gradient from 0 to 40% ethyl acetate/hexanes) to afford 6C (396 mg, 108% yield) as yellow oil/semi-solid. MS (ESI) m/z: 405.2 [M+1]+; 1H NMR (400 MHz, chloroform-d) δ ppm 8.07 (d, J=8.53 Hz, 1H) 7.96 (d, J=18.57 Hz, 1H) 7.32-7.51 (m, 6H) 5.11-5.26 (m, 2H) 4.59 (d, J=18.07 Hz, 2H) 3.58-3.68 (m, 1H) 3.47 (d, J=6.53 Hz, 2H) 3.37 (s, 3H) 2.99 (br. s., 3H) 1.40 (br. s., 3H).
Reaction SMILES: [CH:1]1([CH2:7][NH:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:18])[CH3:17])=[CH:11][C:10]=2[N+:19]([O-])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>C(OCC)(=O)C.[Pd]>[NH2:19][C:10]1[CH:11]=[C:12]([NH:15][C:16](=[O:18])[CH3:17])[CH:13]=[CH:14][C:9]=1[NH:8][CH2:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)Nc1ccc(NCC2CCCCC2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc(NCC2CCCCC2)c(N)c1
Yield: 85.8 %

Procedure:
The above crude product N-{4-[(cyclohexylmethyl)amino]-3-nitrophenyl}acetamide (6.60 g) was hydrogenated in ethyl acetate (300 mL) catalyzed by 10% Pd/C (0.5 g) at 20-30 psi H2 in Parr shaker for 4.5 h at room temperature. After filtration through celite and concentration, 5.08 g (97%) of a purple solid was obtained. which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3): δ 1.00 (m, 2H), 1.24 (m, 3H), 1.59 (m, 2H), 1.72 (m, 2H), 1.84 (m, 2H), 2.13 (s, 3H), 2.91 (d, J=6.64 Hz, 2H), 3.37 (s broad, 3H), 6.56 (d, J=8.40 Hz, 1H), 6.69 (dd, J=8.30, 2.25 Hz, 1H), 6.98 (s, 1H), 7.12 (d, J=2.34 Hz, 1H). MS (ESI) (M+H)+: 262.31.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([C:17]#[N:18])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[C:23](Cl)(=[O:31])[O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(OCC)(=O)C.O>CN(C)C=O.N1C=CC=CC=1>[C:17]([C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][C:13]=1[O:19][CH3:20])[N:10]=[CH:9][CH:8]=[C:7]2[O:6][C:5]1[CH:21]=[CH:22][C:2]([NH:1][C:23](=[O:31])[O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:3][CH:4]=1)#[N:18]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1C#N
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc2nccc(Oc3ccc(NC(=O)Oc4ccccc4)cc3)c2cc1C#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
The 4-(4-aminophenoxy)-6-cyano-7-methoxyquinoline (747 mg) obtained in Production Example 14 was dissolved in 7 ml of dimethylformamide and 0.34 ml of pyridine, and the solution was cooled to 0° C. under a nitrogen atmosphere. After adding 0.34 ml of phenyl chlorocarbonate to the solution, it was stirred at room temperature for 2 hours. Ethyl acetate and water were added to the reaction solution, and the precipitated solid was filtered out to obtain 590 mg of the title compound as light brown crystals (56% yield).
Reaction SMILES: [NH3:1].[Cl:2][C:3]1[N:8]=[C:7]([Cl:9])[C:6]([C:10](Cl)=[O:11])=[CH:5][N:4]=1.C(OCC)C>O1CCOCC1>[Cl:2][C:3]1[N:8]=[C:7]([Cl:9])[C:6]([C:10]([NH2:1])=[O:11])=[CH:5][N:4]=1
Reactant: N
Reactant: O=C(Cl)c1cnc(Cl)nc1Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: NC(=O)c1cnc(Cl)nc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 42.4 %

Procedure:
A solution of ammonia (14 g) in 1,4-dioxane (500 ml) was added drop-wise to an ice-cooled stirred solution of 2,4-dichloro-5-pyrimidinecarbonyl chloride (78 g, crude) in 1,4-dioxane (400 ml) under nitrogen. The ice-bath was removed and the solution was stirred for 30 min and concentrated. The solid residue was partitioned between ethyl acetate (500 ml) and saturated aqueous sodium bicarbonate (500 ml), the organic washed with saturated aqueous sodium bicarbonate (500 ml, ×2), followed by brine (300 ml). The organic phase was dried (sodium sulphate) and concentrated to give a yellow solid. To the residue was added diethyl ether (50 ml) and the resulting suspension was treated under ultrasonic wave for 8 min then filtered. The residue was washed with ethyl ether (50 ml) to give the title compound as a white solid (30 g).
Reaction SMILES: [CH:1]1([O:5][C:6]2[CH:15]=[C:14]([F:16])[C:13]([F:17])=[C:12]3[C:7]=2[CH:8]=[CH:9][C:10]([CH3:18])=[N:11]3)[CH2:4][CH2:3][CH2:2]1.[H][H]>CO>[CH:1]1([O:5][C:6]2[CH:15]=[C:14]([F:16])[C:13]([F:17])=[C:12]3[C:7]=2[CH2:8][CH2:9][C@H:10]([CH3:18])[NH:11]3)[CH2:2][CH2:3][CH2:4]1
Reactant: [H][H]
Reactant: Cc1ccc2c(OC3CCC3)cc(F)c(F)c2n1
Solvent: CO
Product: C[C@H]1CCc2c(OC3CCC3)cc(F)c(F)c2N1
Temperature: 25 °C
Reaction time: 24 h
Yield: 32.7 %

Procedure:
A 30-mL glass-lined stainless steel reactor was charged with 5-cyclobutoxy-7,8-difluoro-2-methylquinoline (4.2 g, 16.9 mmol), Cp*Ru(OTf)[(S,S)-TsDPEN](0.100 g, 0.13 mmol) and methanol (10 mL). The reactor was closed and hydrogen was introduced in at a pressure of 50 atm, before being reduced to 1 atm. After this procedure was repeated three times, the reactor was pressurized with hydrogen to 50 atm. The resulting mixture was stirred under this hydrogen pressure for 24 h at room temperature. After carefully releasing the hydrogen, the reaction mixture was concentrated under vacuum. The residue purified via column chromatography on silica gel (eluting with 25% ethyl acetate/petroleum ether) to afford (S)-5-cyclobutoxy-7,8-difluoro-2-methyl-1,2,3,4-tetrahydroquinoline (1.4 g, 33%, 87% ee) as colorless oil.