Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:28][CH2:27][C:5]2[N:6]([CH2:14][CH:15](OS(C)(=O)=O)[C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH:29]1([NH2:33])[CH2:32][CH2:31][CH2:30]1>O>[CH:29]1([NH:33][CH:15]([C:16]2[CH:17]=[CH:18][N:19]=[CH:20][CH:21]=2)[CH2:14][N:6]2[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]3[CH2:3][N:2]([CH3:1])[CH2:28][CH2:27][C:5]2=3)[CH2:32][CH2:31][CH2:30]1
Reactant: Cc1ccc2c(c1)c1c(n2CC(OS(C)(=O)=O)c2ccncc2)CCN(C)C1
Reactant: NC1CCC1
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2CC(NC2CCC2)c2ccncc2)CCN(C)C1
Temperature: 100 °C

Procedure:
Methanesulfonicacid2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-pyridin-4-yl-ethylester (300 mg, 0.75 mmol) was dissolved in 70% cyclobutylamine in water (6 mL) and heated at 100° C. for 18 h. The reaction mixture was concentrated to obtain the crude product, which was purified by reverse phase chromatography to obtained 90 mg of cyclobutyl-[2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-pyridin-4-yl-ethyl]-amine as the TFA salt.
Reaction SMILES: [F:1][C:2]1[C:3](=O)[C:4]2[C:12](=[C:13]([O:15][CH3:16])[CH:14]=1)[C:11]1[C:6](=[CH:7][C:8]([F:17])=[CH:9][CH:10]=1)[CH:5]=2.[CH2:19]([NH-:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[F:1][C:2]1[CH:14]=[C:13]([O:15][CH3:16])[C:12]2[C:11]3[C:6](=[CH:7][C:8]([F:17])=[CH:9][CH:10]=3)[C:5](=[N:26][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:4]=2[CH:3]=1
Reactant: COC1=C2C(=Cc3cc(F)ccc32)C(=O)C(F)=C1
Reactant: [NH-]Cc1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1cc(F)cc2c1-c1ccc(F)cc1C2=NCc1ccccc1
Temperature: 24 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
Titanium tetrachloride (0.127 mol, 127 mL of a 1.0 M methylene chloride solution) was added dropwise over a 15 minute to a mechanically stirred suspension of 2,7-difluoro-4-methoxyfluorenone (I) (50.0 g, 0.203 mol) and benzylamide (81 g, 0.76 mol) in methylene chloride (1 L) under nitrogen, keeping the temperature below 15° C. The mixture was stirred for 30 min while warming to 24° C., and then filtered through a pad of Florisil, washing with diethyl ether (4 L). The filtrate was concentrated to 500 mL and diluted with hexane (500 mL). The precipitated yellow imine was collected by filtration and combined with second and third crops obtained by concentration of the mother liquor to provide a total of 64 g (94%) of (II) as mixture of geometric isomers: IR (KBr) 1648, 1617, 1603, 1592, 1469, 1452, 1321, 1294 cm-1 ; 1H NMR (CDCl3, 200 MHz)δ7.95-6.40 (m, 10 H), 5.26 and 5.27 (singlets, total 2 H), 3.94 and 3.96 (singlets, total 6 H).
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[C:13]([C:19]([CH3:22])([CH3:21])[OH:20])[N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[NH3:23]>>[NH2:23][C:2]1[C:11]2[N:12]=[C:13]([C:19]([CH3:22])([CH3:21])[OH:20])[N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: N
Reactant: CC(C)Cn1c(C(C)(C)O)nc2c(Cl)nc3ccccc3c21
Product: CC(C)Cn1c(C(C)(C)O)nc2c(N)nc3ccccc3c21

Procedure:
4-Chloro-α,α-dimethyl-1-(2-methylpropyl)-1H-imidazo-[4,5-c]quinoline-2-methanol (Example 22) was aminated in a Parr bomb at 150° C. using 15% methanolic ammonia. The product was purified by silica gel column chromatography (5% methanol in ethyl acetate as eluent). The product was then recrystallized from ethyl acetate/hexane to give a solid, m.p. 214°-217° C. Analysis: Calculated: C, 68.4; H, 7.4; N, 18.8. Found: C, 68.2; H, 7.4; N, 18.7.
Reaction SMILES: F[C:2]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH2:11][CH:12]1[CH2:17][NH:16][CH:15]([CH3:18])[CH2:14][NH:13]1.Cl[C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([OH:30])[CH:28]=2)[N:23]=[CH:22][N:21]=1>>[F:10][C:9]1[C:2]([O:30][C:27]2[CH:28]=[C:29]3[C:24](=[CH:25][CH:26]=2)[N:23]=[CH:22][N:21]=[C:20]3[NH:11][C:12]2[CH:17]=[N:16][C:15]([CH3:18])=[CH:14][N:13]=2)=[C:3]([CH:6]=[CH:7][CH:8]=1)[C:4]#[N:5]
Reactant: N#Cc1cccc(F)c1F
Reactant: Oc1ccc2ncnc(Cl)c2c1
Reactant: CC1CNC(N)CN1
Product: Cc1cnc(Nc2ncnc3ccc(Oc4c(F)cccc4C#N)cc23)cn1

Procedure:
The compound of Example 157 was manufactured by the same method as in Example 95, by a similar method thereto or by a combination of such a method with a conventional method using 2,3-difluorobenzonitrile, 2-amino-5-methylpiperazine and 4-chloro-6-hydroxy-quinazoline.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]2[C:28](=[CH:29][CH:30]=1)[C:8]1[N:9](COCC[Si](C)(C)C)[N:10]=[C:11]([C:12]3[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[N:16][CH:17]=3)[C:7]=1[CH2:6]2.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[OH:66][C:67]1[CH:68]=[N:69][CH:70]=[CH:71][CH:72]=1>C1COCC1>[N:69]1[CH:70]=[CH:71][CH:72]=[C:67]([O:66][CH2:2][C:3]2[CH:4]=[C:5]3[C:28](=[CH:29][CH:30]=2)[C:8]2[NH:9][N:10]=[C:11]([C:12]4[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[N:16][CH:17]=4)[C:7]=2[CH2:6]3)[CH:68]=1
Reactant: C[Si](C)(C)CCOCn1nc(-c2ccc(C#N)nc2)c2c1-c1ccc(CO)cc1C2
Reactant: Oc1cccnc1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#Cc1ccc(-c2n[nH]c3c2Cc2cc(COc4cccnc4)ccc2-3)cn1
Temperature: 75 °C
Yield: 23.7 %

Procedure:
A mixture of Example 131A (60.0 mg, 0.143 mmol), di-t-butyl azodicarboxylate (39.6 mg, 0.172 mmol), Ph3P on solid support (3 mmol/g, 57.3 mg, 0.172 mmol), and 3-hydroxypyridine (16.4 mg, 0.172 mmol) in THF (2 mL) was stirred at room temperature overnight. The solid was filtered and the solvent was evaporated. The crude product was treated with HCl (concentrated, 4 drops) and EtOH (4 mL). The mixture was heated in a capped vial at 75° C. for 2 hours. The solvent was evaporated and the residue was purified using reversed-phase HPLC to give the desired product (12.4 mg) as TFA salt. MS (ESI) m/z: 366.0 (M+H)+. 1H NMR (300 MHz, DMSO-D6) δ ppm 4.01 (s, 2H) 5.83 (s, 2H) 7.58 (d, J=7.80 Hz, 1H) 7.74 (m, 1H) 7.80 (s, 1H) 7.93-8.05 (m, 2H) 8.18 (d, J=8.14 Hz, 1H) 8.40 (dd, J=8.14, 2.37 Hz, 1H) 8.62-8.84 (m, 2H) 9.19 (s, 1H) 12.14 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:18][C@H:19]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C@@H:20]([NH2:22])[CH3:21])=[C:14]([CH3:17])[CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[C:29](Cl)(=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:18][C@H:19]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[C@@H:20]([NH:22][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])[CH3:21])=[C:14]([CH3:17])[CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: Cc1cc2c(cnn2-c2ccc(F)cc2)cc1O[C@H](c1ccccc1)[C@H](C)N
Reactant: CC(C)(C)C(=O)Cl
Product: Cc1cc2c(cnn2-c2ccc(F)cc2)cc1O[C@H](c1ccccc1)[C@H](C)NC(=O)C(C)(C)C

Procedure:
Prepared as described in Example 1 using (1R,2S)-1-[1-(4-fluorophenyl)-6-methyl-indazol-5-yl]oxy-1-phenyl-propan-2-amine (50 mg, 0.13 mmol) and pivaloyl chloride (0.065 mL, 0.53 mmol). Yield 53 mg (87%).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]#[N:13])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:16]=2)[N:3]=1.CCN(CC)CC.[NH2:32][C@@H:33]1[CH2:37][CH2:36][CH2:35][C@@H:34]1[NH:38][C:39](=[O:45])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42].C([O-])(O)=O.[Na+]>CN(C=O)C>[C:41]([O:40][C:39]([NH:38][C@H:34]1[CH2:35][CH2:36][CH2:37][C@H:33]1[NH:32][C:2]1[CH:11]=[C:10]([C:12]#[N:13])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:16]=2)[N:3]=1)=[O:45])([CH3:44])([CH3:42])[CH3:43]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@H]1N
Reactant: COC(=O)c1c(C#N)cc(Cl)nc1Nc1cccc(S(C)(=O)=O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1c(C#N)cc(N[C@@H]2CCC[C@@H]2NC(=O)OC(C)(C)C)nc1Nc1cccc(S(C)(=O)=O)c1
Temperature: 60 °C
Reaction time: 12 h
Yield: 61.5 %

Procedure:
A mixture of methyl 6-chloro-4-cyano-2-(3-(methylsulfonyl)phenylamino)nicotinate (165.0 mg, 0.451 mmol), Et3N (0.15 mL, 1.076 mmol), and tert-butyl (1S,2R)-2-aminocyclopentylcarbamate (142.0 mg, 0.709 mmol) in DMF (6 mL) was stirred at 60° C. for 12 h. Saturated aq NaHCO3 (20 mL) was added to the mixture, which was subsequently extracted with EtOAc (2×30 mL). The organic layers were washed with saturated aq NaHCO3 (20 mL), water (20 mL) and brine (20 mL), were dried over anhydrous Na2SO4, and filtered (DM1020). The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, hexanes/EtOAc=1/1) and then triturated with IPE to provide the title compound (147 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.[O-]CC.[Na+].[N:13](OCCC(C)C)=O.[CH:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][C:22]=1[OH:31]>C(O)C>[CH3:8][C:4]1[N:3]=[C:2]([N:1]=[N:13][C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=[CH:23][C:22]=2[OH:31])[CH:7]=[CH:6][CH:5]=1
Reactant: Oc1ccc2ccccc2c1
Reactant: CC(C)CCON=O
Reactant: Cc1cccc(N)n1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cccc(N=Nc2c(O)ccc3ccccc23)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A reaction flask equipped with a cooling tube and a stirrer was loaded with 2-amino-6-methylpyridine (50 g), ethanol (250 ml), and sodium ethoxide (9.4 g), followed by dropwise addition of isopentyl nitrite (54 g) to the flask in 30 minutes with stirring. The resultant mixture was heated and further stirred at 75 to 80° C. for 4 hours for reaction. Thereafter, the heating was stopped, and the reaction mixture was cooled to room temperature, followed by dropwise addition of 2-naphthol (33.0 g) dissolved in ethanol (50 ml) in 30 minutes to the mixture. The resultant mixture was stirred at room temperature for one hour, heated, and stirred at 75 to 80° C. for additional two hours, followed by stopping the heating and then leaving the mixture to stand overnight. The reaction mixture was filtrated to remove insoluble components, and the filtrate was condensed by an evaporator for solidification. The resultant was dissolved in ethyl acetate (500 ml) and, after being successively washed with an aqueous solution of sodium hydroxide and water, the ethyl acetate layer (phase) was condensed by an evaporator, followed by addition of methanol to the residue for crystallization. The resultant was filtrated and the crystals were dried to give intended red orange crystals (2.1 g).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=2[F:22])[C:3]=1[CH3:23].[O:24]1[CH2:29][CH2:28][N:27]([C:30]2[C:35]([NH2:36])=[CH:34][C:33]([N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)=[CH:32][N:31]=2)[CH2:26][CH2:25]1>C1(C)C=CC=CC=1>[O:24]1[CH2:29][CH2:28][N:27]([C:30]2[C:35]([NH:36][C:2]3[C:11]4[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=4)[N:5]=[C:4]([C:13]4[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=4[F:22])[C:3]=3[CH3:23])=[CH:34][C:33]([N:37]3[CH2:38][CH2:39][O:40][CH2:41][CH2:42]3)=[CH:32][N:31]=2)[CH2:26][CH2:25]1
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Reactant: Cc1c(-c2cc([N+](=O)[O-])ccc2F)nc2cc(F)ccc2c1Cl
Solvent: Cc1ccccc1
Product: Cc1c(-c2cc([N+](=O)[O-])ccc2F)nc2cc(F)ccc2c1Nc1cc(N2CCOCC2)cnc1N1CCOCC1

Procedure:
Essentially prepared according to Procedure H using 4-chloro-7-fluoro-2-(2-fluoro-5-nitrophenyl)-3-methylquinoline (150.0 mg, 0.45 mmol) and 2,5-dimorpholinopyridin-3-amine in toluene to give N-(2,5-dimorpholinopyridin-3-yl)-7-fluoro-2-(2-fluoro-5-nitrophenyl)-3-methylquinolin-4-amine. 1H NMR (CDCl3) δ ppm 8.58 (1H, dd, J=6.2, 2.8 Hz), 8.39 (1H, ddd, J=9.0, 4.3, 2.9 Hz), 7.89 (1H, dd, J=9.0, 5.9 Hz), 7.79 (1H, dd, J=9.8, 2.5 Hz), 7.64 (1H, d, J=2.7 Hz), 7.32-7.44 (2H, m), 6.90 (1H, br. s.), 6.26 (1H, d, J=1.2 Hz), 3.94 (4H, t, J=4.6 Hz), 3.69-3.85 (4H, m), 3.13-3.32 (4H, m), 2.90-3.03 (4H, m), 2.19 (3H, d, J=2.0 Hz). Mass Spectrum (ESI) m/e=563.3 (M+1).
Reaction SMILES: [CH:1]1([CH2:6][N:7]2[C:11]3=[N:12][C:13]([C:16]4[CH:25]=[CH:24][CH:23]=[C:22]5[C:17]=4[CH:18]=[CH:19][CH:20]=[N:21]5)=[CH:14][N:15]=[C:10]3[NH:9][C:8]2=[O:26])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH:28]1(CN)CCCC1.C(N(CC)CC)C>C(O)C>[CH:1]1([CH:6]([N:7]2[C:11]3=[N:12][C:13]([C:16]4[CH:25]=[CH:24][CH:23]=[C:22]5[C:17]=4[CH:18]=[CH:19][CH:20]=[N:21]5)=[CH:14][N:15]=[C:10]3[NH:9][C:8]2=[O:26])[CH3:28])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: NCC1CCCC1
Reactant: O=c1[nH]c2ncc(-c3cccc4ncccc34)nc2n1CC1CCCC1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C1CCCC1)n1c(=O)[nH]c2ncc(-c3cccc4ncccc34)nc21
Yield: 36 %

Procedure:
1-Cyclopentylmethyl-6-quinolin-5-yl-1,3-dihydro-imidazo[4,5-b]pyrazin-2-one. A solution of N-bis-boc-3-bromo-5-(quinoline-5-yl)-pyrazin-2-ylamine (150 mg, 0.29 mmol), cyclopentylmethylamine hydrochloride (268 mg, 2 mmol), and triethylamine in ethanol (4 mL) was reacted and purified according to General Procedure E2 to give 25 mg (36% yield) of white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.96 (dd, J=4.1, 1.6, 1H), 8.54-8.61 (m, 2H), 8.12 (d, J=8.2, 1H), 7.77-7.90 (m, 2H), 7.47-7.59 (m, 2H), 3.11-3.19 (m, 2H), 1.98-2.12 (m, 1H), 1.67-1.77 (m, 2H), 1.49-1.65 (m, 4H), 1.15-1.30 (m, 2H); MS (ESI) m/z 346.4 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([N:15]2[C:19]3[CH:20]=[CH:21][C:22]([C:24]4[CH:25]=[N:26][N:27]([CH2:29][CH2:30][N:31]5[CH2:36][CH2:35][O:34][CH2:33][CH2:32]5)[CH:28]=4)=[CH:23][C:18]=3[N:17]=[CH:16]2)[CH:12]=[C:11]([NH:37]C(=O)C)[CH:10]=1.[CH:41]1([S:44](Cl)(=[O:46])=[O:45])[CH2:43][CH2:42]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([N:15]2[C:19]3[CH:20]=[CH:21][C:22]([C:24]4[CH:25]=[N:26][N:27]([CH2:29][CH2:30][N:31]5[CH2:36][CH2:35][O:34][CH2:33][CH2:32]5)[CH:28]=4)=[CH:23][C:18]=3[N:17]=[CH:16]2)[CH:12]=[C:11]([NH:37][S:44]([CH:41]2[CH2:43][CH2:42]2)(=[O:46])=[O:45])[CH:10]=1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: CC(=O)Nc1cc(-c2cc(F)ccc2F)cc(-n2cnc3cc(-c4cnn(CCN5CCOCC5)c4)ccc32)c1
Product: O=S(=O)(Nc1cc(-c2cc(F)ccc2F)cc(-n2cnc3cc(-c4cnn(CCN5CCOCC5)c4)ccc32)c1)C1CC1

Procedure:
The compound was prepared from the compound of Example 139 using the procedures of Example 140 and cyclopropane sulfonyl chloride. 1H NMR (400 MHz, DMSO-d6): δ 10.31 (s, 1H), 8.76 (s, 1H), 8.36 (s, 1H), 8.14 (s, 1H), 8.07 (s, 1H), 7.73 (d, 1H), 7.67-7.63 (m, 4H), 7.55 (s, 1H), 7.50-7.45 (m, 2H), 4.60 (t, 2H), 3.99-3.79 (m, 2H), 3.69-3.63 (m, 6H), 3.20-3.17 (m, 2H), 2.91-2.88 (m, 1H), 1.1-1.0 (d, 4H); LC-MS (ESI): Calculated mass: 604.67; Observed mass: 605.4 [M+H]+ (rt: 0.48 min).
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].CO[C:6](=[O:16])[CH2:7][NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]>>[C:12]([O:11][C:9]([NH:8][CH2:7][C:6]([NH:3][CH2:1][CH3:2])=[O:16])=[O:10])([CH3:13])([CH3:14])[CH3:15]
Reactant: COC(=O)CNC(=O)OC(C)(C)C
Reactant: CCN
Product: CCNC(=O)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethylamine (37 g, 0.82 mol) was condensed into a pressure vessel at 0° C. N-(tert-butoxycarbonyl)glycine methyl ester (50 mL, 0.34 mol) was added. The vessel was sealed and the mixture was stirred at room temperature overnight. The product mixture was concentrated under vacuum and the residue was passed through a pad of silica gel eluting with ethyl acetate. The solution was concentrated under vacuum to provide the title compound as a clear oil.
Reaction SMILES: [ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@@H:5]3[NH2:12])[CH2:3]1)[CH2:9]2.[S:13]1[C:17]2[CH:18]=[C:19]([C:22](O)=[O:23])[CH:20]=[CH:21][C:16]=2[N:15]=[CH:14]1.N>>[ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@@H:5]3[NH:12][C:22]([C:19]3[CH:20]=[CH:21][C:16]4[N:15]=[CH:14][S:13][C:17]=4[CH:18]=3)=[O:23])[CH2:3]1)[CH2:9]2
Reactant: O=C(O)c1ccc2ncsc2c1
Reactant: NC1C2CC3CC1CN(C3)C2
Agent: Cl
Agent: N
Product: O=C(NC1C2CC3CC1CN(C3)C2)c1ccc2ncsc2c1

Procedure:
Prepared from (4s)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine hydrochloride and benzothiazole-6-carboxylic acid (Maybridge); yield 99 mg, 0.28 mmol (77%) according to methods A and C: 1H NMR (300 MHz, methanol-d4) δ 1.99 (d, J=14 Hz, 2H), 2.22 (s, 1H), 2.37 (d, J=14 Hz, 2H), 2.50 (s, 2H), 3.59 (s, 2H), 3.70 (s, 4H), 4.45 (s, 1H), 8.03 (dd, J=8, 2 Hz, 1H), 8.16 (d, J=8 Hz, 1H), 8.62 (d, J=2 Hz, 1H), 9.41 (s, 1H); MS (DCI/NH3) m/z 314 (M+H)+; Anal. C17H19N3OS.HCl.0.3H2O: C, H, N.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH2:22][CH:23]4[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]4)=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[C:36]1([C:42]2[N:43]=[C:44]([C:47](O)=[O:48])[S:45][CH:46]=2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[CH3:20][O:19][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][C:15]=1[O:21][CH2:22][CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[N:12]=[CH:11][CH:10]=[C:9]2[O:8][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:47]([C:44]2[S:45][CH:46]=[C:42]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[N:43]=2)=[O:48])=[N:7][CH:6]=1
Reactant: O=C(O)c1nc(-c2ccccc2)cs1
Reactant: COc1cc2c(Oc3ccc(N)nc3)ccnc2cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc(NC(=O)c4nc(-c5ccccc5)cs4)nc3)ccnc2cc1OCC1CCNCC1
Temperature: 55 °C
Reaction time: 72 h

Procedure:
A mixture of tert-butyl 4-(((4-((6-aminopyridin-3-yl)oxy)-6-methoxyquinolin-7-yl)oxy)methyl)piperidine-1-carboxylate (70 mg, 0.14 mmol), 4-phenylthiazole-2-carboxylic acid (46 mg, 0.21 mmol), DIPEA (56 mg, 0.43 mmol) and HATU (110 mg, 0.29 mmol) in dry DMF (5 mL) was stirred for 72 h at 55° C. The solution was diluted with EtOAc (150 mL) and washed twice with aq.NaHCO3-solution and once with brine. The residue was dissolved in 50% TFA in DCM (5 mL) and stirred for 2 h at RT. The mixture was concentrated under reduced pressure. The residue was purified by reverse phase RP-HPLC (column: C18), using H2O and ACN as eluents. The desired fractions were lyophilized to yield the title compound X14 (25 mg, 30%) as a white powder. 1H NMR (400 MHz, d6-DMSO, 300K) δ 1.25 (m, 2H), 1.76 (d, J=12.0 Hz, 2H), 1.95 (m, 1H), 2.55 (t, J=11.0 Hz, 2H), 3.00 (d, J=12.0 Hz, 2H), 3.94 (s, 3H), 3.99 (d, J=6.3 Hz, 2H), 6.58 (d, J=5.2 Hz, 1H), 7.41 (m, 2H), 7.51 (m, 3H), 7.90 (dd, J=2.9 Hz, J=9.0 Hz, 1H), 8.17 (d, J=7.4 Hz, 2H), 8.29 (d, J=9.0 Hz, 1H), 8.48 (d, J=2.9 Hz, 1H), 8.50 (d, J=5.2 Hz, 1H), 8.55 (s, 1H). MS (ES) C3H29N5O4S requires: 567. Found: 568 (M+H)+.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][C@H:9]([NH2:13])[C:10]([OH:12])=[O:11])=[CH:3][CH:2]=1>C(OCC)(=O)C.O>[NH2:13][C@@H:9]([C:10]([OH:12])=[O:11])[CH2:8][CH2:7][C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1
Reactant: N[C@@H](CCc1ccccc1)C(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: N[C@H](CCc1ccccc1)C(=O)O

Procedure:
After the completion of the reaction, an extractant such as ethyl acetate is added to the reaction mixture which separates the reaction mixture into an upper layer and a lower layer. The upper layer contains D-HPAE in ethyl acetate and the lower layer contains L-HPA in water. After separating the lower layer from the upper layer, the extractant, i.e., ethyl acetate, can be vaporized to obtain D-HPAE, which can be chemically hydrolyzed to obtain D-homophenylalanine. L-HPA can be separated from the lower layer by adjusting its solution pH to about 6.3 to cause the precipitation thereof.
Reaction SMILES: [C:1]1([C:11]([OH:13])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:16])=O>>[C:1]1([C:11]([Cl:16])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cccc2ccccc12
Product: O=C(Cl)c1cccc2ccccc12
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A mixture of 1.03 g of 1-naphthoic acid and 4.86 g of thionyl chloride was stirred at 50° C. for 2 hours. An excess of thionyl chloride was removed under reduced pressure to give 1-naphthoyl chloride. A solution of 1-naphthoyl chloride in 10 ml of benzene was added dropwise to mixture of 1.06 g of N-methyl-4-tert-butylbenzylamine, 2 ml of pyridine and 10 ml of dry benzene and was stirred for 5 hours. The resultant was poured into water and extracted with benzene, and the benzene solution was washed successively with 3 % aqueous solution of sodium bicarbonate, 3 % hydrochloric acid and water, and then dried over anhydrous sodium sulfate. Oily product (1.74 g, amide) was obtained by distilling away benzene and was crystallized by leaving as it was.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][C@@H:14]2[CH2:16][C@@H:15]2[CH:17]2[CH2:22][CH2:21][N:20]([C:23]3[N:28]=[CH:27][C:26]([Cl:29])=[CH:25][N:24]=3)[CH2:19][CH2:18]2)(=O)=O)=CC=1.[N-:30]=[N+:31]=[N-:32].[Na+].O>O1CCOCC1>[N:30]([CH2:12][CH2:13][C@@H:14]1[CH2:16][C@@H:15]1[CH:17]1[CH2:22][CH2:21][N:20]([C:23]2[N:28]=[CH:27][C:26]([Cl:29])=[CH:25][N:24]=2)[CH2:19][CH2:18]1)=[N+:31]=[N-:32]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OCC[C@@H]2C[C@@H]2C2CCN(c3ncc(Cl)cn3)CC2)cc1
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: [N-]=[N+]=NCC[C@@H]1C[C@@H]1C1CCN(c2ncc(Cl)cn2)CC1
Temperature: 100 °C

Procedure:
2-{(1S,2R)-2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethyl 4-methylbenzenesulfonate (65 mg, 0.15 mmol) from step 1 of this example was dissolved in dioxane (1.2mL). Sodium azide (22.3 mg, 0.34 mmol) was added, then water (0.3 mL). The reaction was heated to 100° C. to reflux for 2 hours. The reaction was cooled to room temperature, water (10 mL) was added and extracted with EtOAc (10 mL×2). The combined organic phase was dried by magnesium sulfate, filter, concentrated and purified by column chromatography through a 12 gram RediSep Rf™ silica gel cartridge eluting with 5% ethyl acetate/hexanes to give the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C@H:8]([CH2:11]OS(C3C=CC(C)=CC=3)(=O)=O)[O:7][C:6]=2[C:23]=1[CH:24]=[N:25][OH:26].[NH:27]1[CH2:32][CH:31]=[C:30]([C:33]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[NH:35][CH:34]=2)[CH2:29][CH2:28]1.C(=O)(O)[O-].[Na+].[C:47](OCC)(OCC)(OCC)[CH3:48]>C1COCC1.CN(C=O)C>[NH:35]1[C:36]2[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:33]([C:30]2[CH2:29][CH2:28][N:27]([CH2:11][CH:8]3[O:7][C:6]4=[C:23]5[C:2](=[CH:3][CH:4]=[C:5]4[O:10][CH2:9]3)[N:1]=[C:47]([CH3:48])[N+:25]([O-:26])=[CH:24]5)[CH2:32][CH:31]=2)=[CH:34]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc(N)c(C=NO)c3O2)cc1
Reactant: CCOC(C)(OCC)OCC
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1nc2ccc3c(c2c[n+]1[O-])OC(CN1CC=C(c2c[nH]c4ccccc24)CC1)CO3

Procedure:
Toluene-4-sulfonic acid (2R)-7-amino-8-(hydroximino-methyl)-2,3-dihydro-1,4-benzodioxin-2-ylmethyl ester (1.0 g, 2.6 mmole) was suspended in triethyl orthoacetate (20 mL) and the mixture refluxed under nitrogen for two hours. The reaction mixture was cooled, and the solvent evaporated under vacuum. The crude residue (1.5 g) was dissolved in a mixture of THF/DMF 1:1 v/v (25 mL) and 3-(1,2,3,6-tetrahydro-4-pyridinyl)1H-indol (1.5 g, 7.5 mmole) and sodium bicarbonate (1.5 g) added. The mixture was refluxed under nitrogen for 20 hours. The reaction mixture was cooled, and the solvent evaporated. The residue was partitioned between methylene chloride and water. The layers were separated. The organic phase was washed with water and saturated sodium chloride solution, dried over magnesium sulfate and the solvent evaporated under vacuum. The crude residual oil (2.7 g) was chromatographed on silica gel using 1% methanol in chloroform, followed by 2% and 3% methanol in chloroform as eluants, to give the (S)-enantiomer of the title compound as a yellow solid (40 mg), m.p. 118-192° C.