Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:3]=1[O:4][C:5]1[CH2:9][N:8]([C@@H:10]([CH2:14][CH3:15])[C:11]([OH:13])=O)[C:7](=[O:16])[CH:6]=1.[CH3:22][C:23]1([CH3:35])[O:27][C@H:26]([CH2:28][N:29]2[CH:33]=[CH:32][C:31]([NH2:34])=[N:30]2)[CH2:25][O:24]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C>[F:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:2]([F:1])[C:3]=1[O:4][C:5]1[CH2:9][N:8]([C@@H:10]([CH2:14][CH3:15])[C:11]([NH:34][C:31]2[CH:32]=[CH:33][N:29]([CH2:28][C@@H:26]3[CH2:25][O:24][C:23]([CH3:35])([CH3:22])[O:27]3)[N:30]=2)=[O:13])[C:7](=[O:16])[CH:6]=1
Reactant: CC[C@@H](C(=O)O)N1CC(Oc2c(F)cccc2F)=CC1=O
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)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: CC[C@@H](C(=O)Nc1ccn(C[C@@H]2COC(C)(C)O2)n1)N1CC(Oc2c(F)cccc2F)=CC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.7 %

Procedure:
To a solution of (S)-2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-butyric acid (0.090 g, 0.30 mmol) in dry N,N-dimethylformamide (5 mL) was added 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-ylamine (prepared as in Example 49 0.075 g, 0.38 mmol), and benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (0.200 g, 0.45 mmol). To this mixture was added N,N-diisopropylethylamine (0.117 g, 0.91 mmol) and the resulting mixture stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with an ammonium chloride solution, a saturated sodium bicarbonate solution, saturated sodium chloride solution and then dried over sodium sulfate. The solvents were evaporated and the residue was purified by AnaLogix flash chromatography (AnaLogix SuperFlash Flash Column 23 g, 100% ethyl acetate) which afforded (S)-2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-N-[1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-butyramide (0.061 g, 42%) as a off-white solid: LR-ES-MS m/z calculated for C23H26F2N4O5 [M+H]+ 477 observed 477.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]([OH:12])=O)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[NH2:35][C:36]1[CH:37]=[C:38]2[C:43](=[CH:44][C:45]=1[O:46][CH2:47][CH:48]1[CH2:50][CH2:49]1)[N:42]=[CH:41][N:40]=[C:39]2[NH:51][C:52]1[CH:57]=[CH:56][C:55]([F:58])=[C:54]([Cl:59])[CH:53]=1.C(N(CC)CC)C>CN(C)C=O>[Cl:59][C:54]1[CH:53]=[C:52]([NH:51][C:39]2[C:38]3[C:43](=[CH:44][C:45]([O:46][CH2:47][CH:48]4[CH2:49][CH2:50]4)=[C:36]([NH:35][C:10](=[O:12])[CH2:9][P:4]([O:3][CH2:1][CH3:2])([O:6][CH2:7][CH3:8])=[O:5])[CH:37]=3)[N:42]=[CH:41][N:40]=2)[CH:57]=[CH:56][C:55]=1[F:58]
Reactant: Nc1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1OCC1CC1
Reactant: CCOP(=O)(CC(=O)O)OCC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOP(=O)(CC(=O)Nc1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1OCC1CC1)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
137 mg (diethoxyphosphoryl)-acetic acid and 225 mg benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate are added subsequently to a solution of 200 mg 6-amino-4-[(3-chloro-4-fluoro-phenyl)amino]-7-cyclopropylmethoxy-quinazoline and 0.11 ml triethylamine in 1 ml of anhydrous N,N-dimethyl-formamide. The reaction mixture is stirred for one hour at room temperature, quenched with 10 ml of water, and extracted with ethyl acetate/methanol (10:1). The combined extracts are washed with water and brine, dried over magnesium sulfate, and concentrated in vacuo. The crude product is recrystallized from diethyl ether. Yield: 190 mg (64% of theory), Melting point: 185-187° C. Mass spectrum (ESI*): m/z=537, 539 [M+H]*
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[S:12]([NH:15][C:16]([NH:18][CH:19]([CH3:21])[CH3:20])=S)(=[O:14])=[O:13].C(N(CC)CC)C.C(Cl)(Cl)=O>C1COCC1.C1(C)C=CC=CC=1>[CH:19]([NH:18][C:16]1[NH:1][C:2]2[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=2[S:12](=[O:14])(=[O:13])[N:15]=1)([CH3:21])[CH3:20]
Reactant: CC(C)NC(=S)NS(=O)(=O)c1ccc(S(C)(=O)=O)cc1N
Agent: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)NC1=NS(=O)(=O)c2ccc(S(C)(=O)=O)cc2N1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred mixture of N-(2-amino-4-(methanesulfonyl)benzenesulfonyl)-N′-isopropylthiourea (3.0 g) and triethylamine (1.7 g) in 30 ml of dry THF at 0° C. was added 5.2 ml of a 20% solution of phosgene in toluene during 5 min. The mixture was stirred at 0° C. for 1 h and then evaporated in vacuo. The white, solid residue was triturated with 50 ml of water for 45 min. and then the product was isolated by filtration. The filter cake was rinsed on the filter with water and dried to give the title compound as white crystals; m.p. >300° C.
Reaction SMILES: [CH2:1]([NH:8][C@@H:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[C:22]([O:26][C:27](=[O:36])[CH:28]=[CH:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([CH3:25])([CH3:24])[CH3:23].[Cl-].[NH4+].[O:39]1CCCC1>CCCCCC>[CH2:1]([N:8]([C@@H:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:10])[C@H:29]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C@@H:28]([OH:39])[C:27]([O:26][C:22]([CH3:25])([CH3:23])[CH3:24])=[O:36])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: C[C@@H](NCc1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)C=Cc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Product: C[C@H](c1ccccc1)N(Cc1ccccc1)[C@H](c1ccccc1)[C@@H](O)C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of (1R)-N-benzyl-1-phenyl-1-ethanamine (16.6 g, 79 mmol) in tetrahydrofuran (200 ml) at −10° C. was added n-butyl lithium (46 ml of a 1.6M solution in hexane, 74 mmol) dropwise. The purple solution was stirred for 15 minutes, cooled to −78° C. and a solution of tert-butylcinnamate (10.0 g, 49 mmol) in tetrahydrofuran (100 ml) added dropwise. After stirring for 2 hours (−)-camphorsulphonyl oxaziridine (18 g, 79 mmol) was added portionwise and the reaction stirred at −78° C. for 1 hour. The reaction was warmed to room temperature and saturated aqueous ammonium chloride solution added and the solvent removed under reduced pressure. The remaining aqueous mixture was extracted with dichloromethane (x2) and the combined organic layers were dried (MgSO4), filtered and evaporated under reduced pressure. The residue was dissolved in diethyl ether, filtered and the filtrate washed with water, dried (MgSO4), filtered and evaporated under reduced pressure. The pale yellow oily residue was purified by column chromatography on silica gel using a gradient elution of diethyl ether:hexane (0:100 to 10:90) to afford the title compound as a colourless oil, 10.0 g.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[C:13]([C:14](=[O:16])[CH:15]=1)=[CH:12][CH:11]=[C:10]([NH:17][C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[C:9]=2[CH2:24][CH:25]=[CH2:26])=[O:5])[CH3:2]>C(Cl)Cl.[Pd](Cl)Cl.C(#N)C.C(#N)C>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[C:13]([C:14](=[O:16])[CH:15]=1)=[CH:12][CH:11]=[C:10]([NH:17][C:18](=[O:23])[C:19]([F:20])([F:21])[F:22])[C:9]=2[CH:24]=[CH:25][CH3:26])=[O:5])[CH3:2]
Reactant: C=CCc1c(NC(=O)C(F)(F)F)ccc2c(=O)cc(C(=O)OCC)oc12
Agent: Cl[Pd]Cl
Solvent: CC#N
Solvent: ClCCl
Product: CC=Cc1c(NC(=O)C(F)(F)F)ccc2c(=O)cc(C(=O)OCC)oc12
Temperature: 25 °C
Yield: 88 %

Procedure:
To 8-allyl-4-oxo-7-(2,2,2-trifluoro-acetylamino)-4H-chromene-2-carboxylic acid ethyl ester (12.2 g, 32 mmole) in 500 mL of methylene chloride was added 1.5 g (5.8 mmole) of bis(acetonitrile) palladium (II) chloride. The mixture was refluxed under nitrogen for 24 hours. Upon cooling to room temperature, the mixture was filtered through 75 g of silica gel, with additional methylene chloride as needed to fully elute the product. Concentration in vacuum gave 10.4 g of the title compound as a yellow solid, m.p. 140-141° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.C([O-])([O-])=O.[K+].[K+].CC(C)([O-])C.[K+]>O.CN1CCCC1=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Nc1ccccn1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1ccc(Nc2ccccn2)cc1
Temperature: 60 °C
Reaction time: 6 h
Yield: 19.7 %

Procedure:
0.3 g of 4-fluoronitrobenzene, 0.4 g of 2-aminopyridine, and 0.353 g of K2CO3 were added to a solution of 2.5 ml of N-methylpyrrolidinone. The reaction medium was heated at 60° C. for 1 hour and 0.286 g of potassium tert-butoxide was then added. Heating was then continued for 6 hours and, after cooling to room temperature, the reaction medium was then poured into a water and ice mixture. The yellow precipitate formed was filtered off, reslurried in water and then dried over P2O5. 0.09 g of N-(4-nitrophenyl)pyrid-2-amine (5) was obtained.
Reaction SMILES: C([O:3][C:4](=[O:29])[CH2:5][C:6]1[N:7]=[C:8]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=2[C:22]([CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:23])=[O:13])[S:9][CH:10]=1)C.[Br:30]N1C(=O)CCC1=O>C(O)(=O)C>[Br:30][C:10]1[S:9][C:8]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=2[C:22]([CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:23])=[O:13])=[N:7][C:6]=1[CH2:5][C:4]([OH:3])=[O:29]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)Cc1csc(NC(=O)Nc2ccc(C)cc2C(=O)C2CCCC2)n1
Solvent: CC(=O)O
Product: Cc1ccc(NC(=O)Nc2nc(CC(=O)O)c(Br)s2)c(C(=O)C2CCCC2)c1
Reaction time: 8 h
Yield: 56.5 %

Procedure:
To a suspension of {2-[3-(2-cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid ethyl ester (0.20 g, 0.52 mmol) in 10 ml of acetic acid was added N-bromosuccinimide (0.10 g, 0.57 mmol). The reaction mixture was stirred under nitrogen in a pressure bottle excluded from light overnight at 25° C. The mixture was concentrated under reduced pressure, dissolved in DMSO and purified by preparative HPLC to afford the title compound (0.137 g, 57%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH2:9][NH:8][CH2:7][CH2:6]2.[C:15](OC(=O)C)(=[O:17])[CH3:16]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH2:9][N:8]([C:15](=[O:17])[CH3:16])[CH2:7][CH2:6]2
Reactant: COc1cc2c(cc1OC)CNCC2
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COc1cc2c(cc1OC)CN(C(C)=O)CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.6 %

Procedure:
To a stirred solution of 6,7-dimethoxy-1,2, 3,4-tetrahydroisoquinoline (3.00 g, 15.4 mmol, 1.00 equiv) in anhydrous pyridine (100 mL) under argon at room temperature was added acetic anhydride (14.5 mL, 154 mmol, 10.0 equiv) over 15 min. The resulting mixture was stirred at room temperature for 2 h, and then at reflux for 6 h. The volatiles were removed by rotary evaporation at 80° C. under high vacuum. The residue was flash chromatographed on silica gel (MeOH-CH2Cl2 8:92) to afford 3.21 g (89%) of viscous brown oil. The 1H NMR spectrum reflected the presence of two slowly interconverting conformers in a ratio of 1.2 :1 at room temperature. 1H NMR (300 MHz, CDCl3) for conformer 1: δ 2.18 (s, 3 H), 2.83 (t, J=5.9 Hz, 2 H), 3.67 (t, J=5.9 Hz, 2 H), 3.86 (s, 3 H), 3.87 (s, 3 H), 4.66 (s, 2 H), 6.63 (s, 1 H), 6.65(s, 1 H). For conformer 2:δ 2.19 (s, 3 H), 2.77 (t, J=5.9 Hz, 2 H), 3.81 (t, J=5.9 Hz, 2 H), 3.86 (s, 3 H), 3.87 (s, 3 H), 4.56 (s, 2 H), 6.59 (s, 1 H), 6.63 (s, 1 H).
Reaction SMILES: Br[CH2:2][C:3]1[O:4][C:5](=[O:19])[C:6]2[C:11]([C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.O.[N:21]1[C:29]([SH:30])=[C:28]2[C:24]([NH:25][CH:26]=[N:27]2)=[N:23][CH:22]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[N:21]1[C:29]([S:30][CH2:2][C:3]2[O:4][C:5](=[O:19])[C:6]3[C:11]([C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)=[C:28]2[C:24]([NH:25][CH:26]=[N:27]2)=[N:23][CH:22]=1
Reactant: Sc1ncnc2[nH]cnc12
Reactant: O=c1oc(CBr)c(-c2ccccc2)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1oc(CSc2ncnc3[nH]cnc23)c(-c2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
3-(Bromomethyl)-4-phenyl-1H-isochromen-1-one (Intermediate C1, 35 mg, 0.111 mmol), 9H-purine-6-thiol hydrate (18.9 mg, 0.111 mmol) and K2CO3 (15.35 mg, 0.111 mmol) were dissolved in DMF (1 ml) and stirred at RT for 1 hrs 30 min. The reaction mixture was then diluted with water (10 ml) and 0.1 N HClaqueous (1 ml). The mixture was extracted with EtOAc and the collected organic phases were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude was purified by Preparative HPLC (method 2) to give the title compound (24 mg, 56%).
Reaction SMILES: [NH2:1][C:2]([CH2:9][C:10](=[O:12])[O-:11])([CH2:4][N+:5]([CH3:8])([CH3:7])[CH3:6])O.[N:13]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:17]=1)=[C:14]=[O:15]>>[O:22]([C:18]1[CH:17]=[C:16]([NH:13][C:14](=[O:15])[NH:1][C@@H:2]([CH2:4][N+:5]([CH3:8])([CH3:7])[CH3:6])[CH2:9][C:10]([O-:11])=[O:12])[CH:21]=[CH:20][CH:19]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=C=Nc1cccc(Oc2ccccc2)c1
Reactant: C[N+](C)(C)CC(N)(O)CC(=O)[O-]
Product: C[N+](C)(C)C[C@@H](CC(=O)[O-])NC(=O)Nc1cccc(Oc2ccccc2)c1
Yield: 58 %

Procedure:
According to the method described in example S11, aminocamitine (1.28 HBr salt, 68 mg, 0.31 mmol) was reacted with 1-isocyanato-3-phenoxybenzene to yield the title compound as a white solid (69 mg, 58%). 1H NMR (400 MHz, CD3OD) 7.34 (t, J=7.96 Hz, 2 H), 7.17-7.23 (m, 2 H), 7.04-7.12 (m, 2 H), 6.95-7.00 (m, 1 H), 6.59 (dd, J=7.83, 2.02 Hz, 1 H), 4.57 (br. s, 1 H), 3.72 (dd, J=13.64, 9.09 Hz, 1 H), 3.46-3.56 (m, 1 H), 3.20 (s, 9 H), 2.42-2.56 (m, 2 H). MS ESI [M]+, calcd for [C20H24N3O4+H]+: 371.43 found m/z 371.7 (100).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([F:13])([CH3:12])[C:9]([O-:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.OS(O)(=O)=O.[S-:19][C:20]#[N:21].[Na+].O.[C:24]1(C)C=CC=CC=1>CCCCCC>[NH2:21][C:20]([NH:1][C:2]1[CH:3]=[C:4]([C:8]([F:13])([CH3:12])[C:9]([O:11][CH3:24])=[O:10])[CH:5]=[CH:6][CH:7]=1)=[S:19]
Reactant: CC(F)(C(=O)[O-])c1cccc(N)c1
Reactant: Cc1ccccc1
Reactant: N#C[S-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCCCCC
Solvent: O
Product: COC(=O)C(C)(F)c1cccc(NC(N)=S)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 80 %

Procedure:
To a solution of 2-(3-aminophenyl)-2-fluoropropanoate (0.8 g, 4.1 mmol) in toluene (6 ml), H2SO4 (0.1 mL, 2.0 mmol) was added and, after stirring for 20 min, sodium thiocyanate (0.405 g, 5.0 mmol) was added under vigorous stirring. The mixture was refluxed for 18 h. After cooling at room temperature, water (20 ml) was added and the mixture was trasferred into a separator funnel; the two phases were debated and separated and the aqueous one extracted with toluene (3×10 mL); the collected organic extracts were dried over Na2SO4 and evaporated under vacuum to give a crude that, after pulping in n-hexane, afforded pure methyl 2-{3-[(aminocarbonothioyl)amino]phenyl}-2-fluoropropanoate as orange oil (0.84 g, yield 80%).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]([C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1.[H][H]>[Pd].C(O)C>[CH3:1][C:2]1[C:11]2[NH:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]([C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)O)c2cccnc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(C(=O)O)c2c1NCCC2

Procedure:
0.1 mol of 8-methylquinoline-5-carboxylic acid was suspended in 1.5 1 of ethanol and admixed with 10.0 g of palladium on activated carbon (5%). In an autoclave, the mixture was reduced at 50° C. with hydrogen (1 bar) over a period of 48 hours (HPLC monitoring). The reaction mixture was subsequently filtered, the filter cake was washed with ethanol and the combined organic filtrates were concentrated.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[C:43]([O:47][C:48](=[O:56])[NH:49][CH2:50][CH2:51][C:52]([NH:54][NH2:55])=[O:53])([CH3:46])([CH3:45])[CH3:44]>C(Cl)Cl.C(N(CC)CC)C>[C:43]([O:47][C:48](=[O:56])[NH:49][CH2:50][CH2:51][C:52]([NH:54][NH:55][C:18]([C@@H:13]1[CH2:12][CH2:11][C@@H:10]2[CH2:17][N:14]1[C:15](=[O:16])[N:9]2[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:20])=[O:53])([CH3:46])([CH3:44])[CH3:45]
Reactant: CC(C)(C)OC(=O)NCCC(=O)NN
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCC(=O)NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.3 %

Procedure:
To a solution of the carboxylic acid (6b, 390 mg, 1.41 mmol) of Example 9 or 16 in methylene chloride (14.1 mL) were added triethylamine (393 μl), N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (406 mg), 1-hydroxybenzotriazole.monohydrate (324.6 mg), and tert-butyl(3-hydrazinyl-3-oxopropyl)carbamate (430.8 mg, prepared following a procedure analogous to Reference Example 2), followed by agitating at room temperature overnight. The reaction solution was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (ethyl acetate) to afford 347.3 mg of the title compound (yield 53.3%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Cl)=[CH:11][CH:10]=1.[Br:17][C:18]1[C:23]([OH:24])=[CH:22][CH:21]=[C:20]([I:25])[N:19]=1.O>CN(C)C=O>[Br:17][C:18]1[C:23]([O:24][CH2:13][C:12]2[CH:15]=[CH:16][C:9]([O:8][CH3:7])=[CH:10][CH:11]=2)=[CH:22][CH:21]=[C:20]([I:25])[N:19]=1
Reactant: Oc1ccc(I)nc1Br
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(COc2ccc(I)nc2Br)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 100 %

Procedure:
Potassium carbonate (12 g) and 4-methoxybenzyl chloride (8.8 mL) were added to a solution of 2-bromo-6-iodopyridin-3-ol (12 g) in N,N-dimethylformamide (130 mL), and the mixture was stirred at room temperature for six hours. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=90:1→0:100) to give 2-bromo-6-iodo-3-[(4-methoxybenzyl)oxy]pyridine as a colorless powder (18 g, 100%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:14]([OH:16])=O)[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][C:18]1([CH3:24])[NH:22][C:21](=[O:23])[CH2:20][NH:19]1.C1CCC(N=C=NC2CCCCC2)CC1>C1COCC1>[CH2:1]([O:8][C:9]([NH:11][CH:12]([CH3:13])[C:14]([N:19]1[CH2:20][C:21](=[O:23])[NH:22][C:18]1([CH3:24])[CH3:17])=[O:16])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)NCC(=O)N1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: CC(NC(=O)OCc1ccccc1)C(=O)N1CC(=O)NC1(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a stirred, ice-cold solution of N-(benzyloxycarbonyl)alanine (6.7 g) and 2,2-dimethyl-4-imidazolidinone (3.42 g) in 100 ml of THF, a solution of DCC (6.2 g) in 50 ml of THF was added dropwise during 15 minutes. The suspension was stirred at 0° C. for 2 hours and at room temperature for an additional 2 hours. The insoluble material was filtered off. The solvent was evaporated under reduced pressure. Crystallization of the residue from isopropanol gave the title product as a white powder m.p. 170°-171° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]2[CH2:19][CH2:18][CH:17]3[CH:12]([CH2:13][CH:14]([C:21](OCC)=[O:22])[C:15](=[O:20])[NH:16]3)[CH2:11]2)=[CH:5][CH:4]=1.[BH4-].[Li+].Cl>C1COCC1>[OH:22][CH2:21][CH:14]1[CH2:13][CH:12]2[CH:17]([CH2:18][CH2:19][CH:10]([CH2:9][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[CH2:11]2)[NH:16][C:15]1=[O:20]
Reactant: CCOC(=O)C1CC2CC(Cc3ccc(OC)cc3)CCC2NC1=O
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CC2CCC3NC(=O)C(CO)CC3C2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
In a manner analogous to Example 1 step b), but using THF solvent instead of CH2Cl2, ethyl 3,4,4a,5,6,7,8,8a-octahydro-6-((4-methoxyphenyl)methyl)quinolin-2[1H]-one-3-carboxylate was prepared as a 60:40 w/w mixture of (±)-(3RS,4aSR,6RS,8aRS) to (±)-(3SR,4aSR,6RS,8aRS) isomers). This product was suspended in THF (20 ml) at 0° C. and an ice cold solution of 1M lithium borohydride in THF (13.1 ml) was added. The mixture was left to stir 51/2 hours at 0° C. and then was added to methanolic hydrogen chloride (120 ml). The acidic solution was left to stand 18 hours and was then evaporated. The residue was dissolved in chloroform and washed with saturated sodium carbonate solution, water and then brine. The organic solution was dried (MgSO4), evaporated and the residual oil was left to stir in hexane containing a small quantity of ethyl acetate for 3 days. The resin obtained was purified by repeated chromatography on a 4 mm "Chromatotron" plate. The later running fractions were combined to give 0.2 g of (±)-(3RS,4aRS,6SR,8aSR)-3,4,4a,5,6,7,8,8a-octahydro-3-hydroxymethyl-6-((4-methoxyphenyl)methyl)quinolin-2[1H]-one.
Reaction SMILES: [F:1][C:2]1([C:6]2[C:7]([O:15][C@@H:16]([CH3:21])[C:17]([F:20])([F:19])[F:18])=[CH:8][C:9]([C:12](O)=[O:13])=[N:10][CH:11]=2)[CH2:5][O:4][CH2:3]1.[NH2:22][C@@H:23]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:24]([NH:26][CH3:27])=[O:25]>>[CH3:29][C:28]([CH3:31])([CH3:30])[C@H:23]([NH:22][C:12]([C:9]1[CH:8]=[C:7]([O:15][C@@H:16]([CH3:21])[C:17]([F:19])([F:20])[F:18])[C:6]([C:2]2([F:1])[CH2:5][O:4][CH2:3]2)=[CH:11][N:10]=1)=[O:13])[C:24]([NH:26][CH3:27])=[O:25]
Reactant: CNC(=O)[C@@H](N)C(C)(C)C
Reactant: C[C@H](Oc1cc(C(=O)O)ncc1C1(F)COC1)C(F)(F)F
Product: CNC(=O)[C@@H](NC(=O)c1cc(O[C@@H](C)C(F)(F)F)c(C2(F)COC2)cn1)C(C)(C)C

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-(3-fluorooxetan-3-yl)-4-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine-2-carboxylic acid (example 142b) and (S)-2-Amino-3,3,N-trimethyl-butyramide (CAN 89226-12-0) as starting materials and isolated (40 mg, 57%); MS (ESI, m/z): 436.6 (M+H+).