Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CON(C)[C:4]([C:6]1[C:7]([NH2:15])=[N:8][C:9]([S:12][CH2:13][CH3:14])=[N:10][CH:11]=1)=[O:5].[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Li].FC1C=CC=CC=1I>>[NH2:15][C:7]1[C:6]([C:4]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[F:17])=[O:5])=[CH:11][N:10]=[C:9]([S:12][CH2:13][CH3:14])[N:8]=1
Reactant: CCSc1ncc(C(=O)N(C)OC)c(N)n1
Reactant: [Li]c1ccccc1F
Agent: Fc1ccccc1I
Product: CCSc1ncc(C(=O)c2ccccc2F)c(N)n1

Procedure:
The same procedure was used as described in Example 2, starting from 4-amino-2-ethylsulfanyl-pyrimidine-5-carboxylic acid methoxy-methylamide (from Example 1) and a solution of 2-fluorophenyllithium (˜3 equiv, freshly prepared from 1-fluoro-2-iodobenzene as in Example 2A), to give (4-amino-2-ethylsulfanyl-pyrimidin-5-yl)-(2-fluoro-phenyl)-methanone. MS (M+H)+: 278.
Reaction SMILES: [C:1]1([CH2:11][N:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]([CH2:21][CH2:22][C:23](O)=[O:24])[C:13]2=[O:26])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:39]1([S:45]([NH2:48])(=[O:47])=[O:46])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.N12CCCN=C1CCCCC2.Cl>C1COCC1.O>[C:1]1([CH2:11][N:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]([CH2:21][CH2:22][C:23]([NH:48][S:45]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)(=[O:47])=[O:46])=[O:24])[C:13]2=[O:26])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CCn1c(=O)n(Cc2cccc3ccccc23)c2ccccc21
Reactant: NS(=O)(=O)c1ccccc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(CCn1c(=O)n(Cc2cccc3ccccc23)c2ccccc21)NS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.1 %

Procedure:
3-(3-Naphthalen-1-ylmethyl-2-oxo-2,3-dihydro-benzimidazol-1-yl)-propionic acid (80 mg, 0.23 mmol) is dissolved in dry THF (3.0 mL) and 1,1′-carbonyl diimidazole (84 mg, 0.52 mmol) is added into it. The mixture is stirred for 30 min at room temperature and then it is heated at 55° C. for 1 hr. After the mixture is cooled down to room temperature, benzenesulfonamide (73 mg, 0.46 mmol) is added and after 10 min, 1,8-diazabicyclo[5,4,0]undec-7-ene (0.07 mL, 0.46 mmol) is added. The mixture is again stirred for 8 heat room temperature. 1.0 M HCl aqueous solution (3 mL) is added followed by water (30 mL). The mixture is extracted with EtOAc (3×50 mL) and the organic layers are combined, dried and concentrated to give crude product. Purification by preparative TLC using 55% EtOAc in Hexanes affords 66 mg (59%) of N-[3-(3-Naphthalen-1-ylmethyl-2-oxo-2,3-dihydro-benzimidazol-1-yl)-propionyl]-benzenesulfonamide. LCMS (ESMS): m/z 486.05 (M+H+)
Reaction SMILES: O=[C:2]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([OH:5])=[O:4].[OH-].[Na+].Cl.[NH2:17][C@H:18]1[CH2:24][CH2:23][CH2:22][CH2:21][N:20]([CH2:25][C:26]([OH:28])=[O:27])[C:19]1=[O:29].C([BH3-])#N.[Na+]>O>[C:26]([CH2:25][N:20]1[CH2:21][CH2:22][CH2:23][CH2:24][C@H:18]([NH:17][CH:2]([C:3]([OH:5])=[O:4])[CH2:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:19]1=[O:29])([OH:28])=[O:27]
Reactant: O=C(O)C(=O)CCc1ccccc1
Reactant: N[C@H]1CCCCN(CC(=O)O)C1=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Product: O=C(O)CN1CCCC[C@H](NC(CCc2ccccc2)C(=O)O)C1=O
Reaction time: 48 h

Procedure:
Suspend 4.45 g 2-oxo-4-phenylbutyric acid in 25 ml water and adjust the pH to 7 with 50% NaOH. Add 1.14 g 3-(S)-amino-1-carboxymethylperhydroazepin-2-one hydrochloride and again adjust the pH to 7 with 50% NaOH. Dilute the resulting solution with water to a total volume of 60 ml then add 0.943 g sodium cyanoborohydride. After 2 days at room temperature, add 50 ml Dowex 50 (H+) and stir the mixture for 1 hour. Extract the mixture with ether and then add the Dowex 50 and aqueous portion to the top of a 100 ml. column of Dowex 50 (H+). Elute first with water until the eluate is neutral and then with 2% pyridine in water until no further product elutes (ninhydrin detection). Concentrate the product containing fractions at aspirator pressure, redissolve the residue in 50 ml water and freeze dry. Isolate the 1-carboxymethyl-3-(S)-[(1 -carboxy-3-phenylpropyl)amino]perhydroazepin-2-one as a white hygroscopic solid.
Reaction SMILES: [Na].CC(C)=O.Cl.[C:7]([NH2:13])(=[NH:12])[CH2:8][CH2:9][CH2:10][CH3:11].[N+:14]([C:17]1[CH:18]=[C:19]([N:23]=[C:24]=[O:25])[CH:20]=[CH:21][CH:22]=1)([O-:16])=[O:15]>C1C=CC=CC=1>[N+:14]([C:17]1[CH:18]=[C:19]([NH:23][C:24]([NH:12][C:7](=[NH:13])[CH2:8][CH2:9][CH2:10][CH3:11])=[O:25])[CH:20]=[CH:21][CH:22]=1)([O-:16])=[O:15]
Reactant: CCCCC(=N)N
Reactant: O=C=Nc1cccc([N+](=O)[O-])c1
Agent: Cl
Agent: [Na]
Solvent: c1ccccc1
Solvent: CC(C)=O
Product: CCCCC(=N)NC(=O)Nc1cccc([N+](=O)[O-])c1

Procedure:
Following a procedure similar to that described in Example 1 but using 2.3 g. sodium in 150 ml. dry acetone, 13.6 g. valeramidine hydrochloride, and 16.4 g. 3-nitrophenyl isocyanate in 300 ml. benzene, there was obtained after recrystallization from ethyl alcohol-ether 11.6 g. of the hydrochloride of 1-(3-nitrophenyl)-3-(pentanimidoyl)urea; m.p. 161°-163°C.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:18][CH:17]([CH:19]([OH:23])[CH:20]([CH3:22])[CH3:21])[CH2:16]1)=O)(C)(C)C>ClCCl>[NH:15]1[CH2:18][CH:17]([CH:19]([OH:23])[CH:20]([CH3:22])[CH3:21])[CH2:16]1
Reactant: CC(C)C(O)C1CN(C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C(O)C1CNC1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 88.8 %

Procedure:
Trifluoroacetic acid (3 mL) was added to a solution of 3-(1-hydroxy-2-methylpropyl)azetidine-1-carboxylic acid tert-butyl ester (0.84 g, 3.66 mmol) in dichloromethane (12 mL). The resulting reaction mixture was stirred at RT for 40 min. The solvents were reduced in vacuo. The resulting residue was loaded onto an Isolute® SCX-2 cartridge (5 g). The cartridge was washed with DCM/MeOH, the desired product was subsequently eluted using a mixture of 2M NH3 in MeOH and DCM. The solvents were reduced in vacuo to afford 1-Azetidin-3-yl-2-methylpropan-1-ol as a white solid (0.42 g, 88%). 1H NMR (400 MHz, CDCl3): δ 3.63-3.62 (3H, m), 3.53-3.51 (2H, m), 2.88-2.87 (1H, m), 1.62-1.62 (1H, m), 0.89 (6H, dd, J=6.84, 4.72 Hz)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:12]([NH2:17])[CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:18]([O:22][CH2:23][CH3:24])(=[O:21])[CH:19]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(O)(=O)C.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH:12]([NH:17][CH2:19][C:18]([O:22][CH2:23][CH3:24])=[O:21])[CH2:13][CH:14]([CH3:15])[CH3:16])[CH2:11][CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)C=O
Reactant: CC(C)CC(N)C1(c2ccc(Cl)cc2)CCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCOC(=O)CNC(CC(C)C)C1(c2ccc(Cl)cc2)CCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of cyclobutane amine 52a (0.68 g, 0.0027 mole) and ethyl glyoxylate (50% solution in toluene) (1.02 g, 0.01 mole) in 20 mL of a mixture of solvents DMF and acetic acid (ratio, 99:1) was added sodium triacetoxyborohydride (2.11 g, 0.01 mole) portion-wise over a period of 15 minutes at room temperature. The resulting mixture was stirred for 8 hours at room temperature and the progress of the reaction was monitored by TLC. The reaction mixture was poured in to saturated sodium bicarbonate solution (50 mL) and extracted with ethyl acetate (50 mL×3). The combined extract was washed with water (50 mL), dried over sodium sulfate (Na2SO4) and evaporated. The residue was purified by silica gel column chromatography using 0-50% gradient of ethyl acetate and hexane as eluents to give pure 54a as colorless liquid in 45% (0.41 g) yield. The 1H NMR and mass spectral data are identical to the compound synthesized using the protocol described for the synthesis of 54a-e (Example 3, Scheme 7).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[C:12]3[N:31]([CH3:32])[CH2:30][CH:29]=[CH:28][C:13]3=[C:14]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26]C)=[CH:22][CH:21]=3)[CH:15]=2)[N:10]=[CH:9]1.B(Br)(Br)Br>ClCCl>[OH:26][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][C:14]2[CH:15]=[C:16]3[C:11](=[C:12]4[N:31]([CH3:32])[CH2:30][CH:29]=[CH:28][C:13]=24)[N:10]=[CH:9][N:8]([C@H:3]2[CH2:4][CH2:5][CH2:6][CH2:7][C@@H:2]2[OH:1])[C:17]3=[O:18])=[CH:25][CH:24]=1
Reactant: COc1ccc(Cc2cc3c(=O)n([C@H]4CCCC[C@@H]4O)cnc3c3c2C=CCN3C)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CN1CC=Cc2c(Cc3ccc(O)cc3)cc3c(=O)n([C@H]4CCCC[C@@H]4O)cnc3c21
Temperature: -40 °C
Reaction time: 2 h

Procedure:
To a solution of 3-[(1S,2S)-2-hydroxycyclohexyl]-6-(4-methoxybenzyl)-10-methyl-9,10-dihydropyrido[3,2-h]quinazolin-4(3H)-one (0.250 g, 0.579 mmol) in 5 mL of dichloromethane at −78° C. was added boron tribromide (1 M in dichloromethane, 1.16 mL, 1.16 mmol). After 2 h, the mixture was warmed to −40° C., and additional boron tribromide was added (1 M in dichloromethane, 1.16 mL, 1.16 mmol). After 1 h, additional boron tribromide was added (1 M in dichloromethane, 1.16 mL, 1.16 mmol) and after 30 min, the reaction was quenched with methanol and concentrated in vacuo. The residue was diluted with ethyl acetate, then washed with saturated aqueous sodium bicarbonate and brine. The organic solution was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 0-5% methanol in dichloromethane, to provide the title compound that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 418.1 for [M+H]+: 1H NMR (400 MHz, CDCl3) δ 8.92 (s, 1H), 8.19 (d, J=8.5 Hz, 1H), 7.96 (s, 1H), 7.42-7.38 (m, 1H), 6.99-6.97 (m, 2H), 6.78-6.69 (m, 2H), 4.74-4.60 (m, 2H), 4.40-4.34 (m, 1H), 4.24 (s, 2H), 3.64-3.59 (m, 1H), 3.23 (s, 3H), 2.40 (br s, 1H), 2.21 (br s, 1H), 1.91-1.80 (m, 3H), 1.66-1.24 (m, 4H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][C@@H:9]1[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:16]([Mg]Br)[CH:17]=[CH2:18]>CCOCC>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:18][CH:17]=[CH2:16])([OH:14])[CH2:10][C@@H:9]1[CH3:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CC[Mg]Br
Reactant: C[C@H]1CC(=O)CCN1C(=O)OC(C)(C)C
Solvent: CCOCC
Product: C=CCC1(O)CCN(C(=O)OC(C)(C)C)[C@@H](C)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
In a argon flushed dry 25 ml 2-neckoundbottomflask (S)-2-methyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester (34) (0.6 g, 2.81 mmol) was dissolved in 10 ml of ether. A 1M solution of allylmagnesiumbromide in Et2O (3.66 ml, 3.66 mmol) was added dropwise at 0° C. The reaction mixture was stirred at 0° C. for 2 h. The mixture was quenched with NH4Cl solution and extracted with ether. The organic layer was washed with brine, dried over Na2 SO4 and evaporated. The crude product was purified by flash chromatography (silica gel, 20-30% EtOAc/cyclohexane) which furnished the product as white solid
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-])=O.NC1CC2CC1CC2.[Cl:22][C:23]1[CH:60]=[CH:59][C:26]([C:27]2[C:32]([C:33]3[CH:42]=[CH:41][C:40]4[C:35](=[CH:36][CH:37]=[C:38]([C:43]5N(CC)[C:46]6[CH:50]=[CH:51][C:52]([C:54](O)=O)=[CH:53][C:45]=6[N:44]=5)[CH:39]=4)[N:34]=3)=[CH:31][C:30]([O:57][CH3:58])=[CH:29][CH:28]=2)=[CH:25][CH:24]=1>>[CH:46]12[CH2:54][CH:52]([CH2:51][CH2:50]1)[CH2:53][CH:45]2[N:44]1[C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=2[N:11]=[C:43]1[C:38]1[CH:39]=[C:40]2[C:35](=[CH:36][CH:37]=1)[N:34]=[C:33]([C:32]1[C:27]([C:26]3[CH:59]=[CH:60][C:23]([Cl:22])=[CH:24][CH:25]=3)=[CH:28][CH:29]=[C:30]([O:57][CH3:58])[CH:31]=1)[CH:42]=[CH:41]2
Reactant: CCn1c(-c2ccc3nc(-c4cc(OC)ccc4-c4ccc(Cl)cc4)ccc3c2)nc2cc(C(=O)O)ccc21
Reactant: O=C(O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: NC1CC2CCC1C2
Product: COc1ccc(-c2ccc(Cl)cc2)c(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CC5CCC4C5)ccc3n2)c1

Procedure:
The title compound was prepared from Resin 534a and 2-aminonorbornane according to the procedure described in the preparation of Compound 534.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:13]([CH2:14][OH:15])=[C:12]([CH:16]([CH3:18])[CH3:17])[CH:11]=[N:10]1.[NH2:19][C:20]1[CH:25]=[CH:24][C:23](O)=[CH:22][C:21]=1[CH3:27].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[N:9]1[C:13]([CH2:14][O:15][C:23]2[CH:24]=[CH:25][C:20]([NH2:19])=[C:21]([CH3:27])[CH:22]=2)=[C:12]([CH:16]([CH3:18])[CH3:17])[CH:11]=[N:10]1
Reactant: Cc1cc(O)ccc1N
Reactant: CC(C)c1cnn(-c2c(Cl)cccc2Cl)c1CO
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: Cc1cc(OCc2c(C(C)C)cnn2-c2c(Cl)cccc2Cl)ccc1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 55.6 %

Procedure:
To a 0° C. solution of [2-(2,6-dichloro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-methanol (3.0 g, 10.6 mmol), 4-amino-3-methyl-phenol (2.0 g, 15.8 mmol), and tri-n-butylphosphine (3.2 g, 15.8 mmol) in toluene (30 mL) is added a solution of 1,1′-(Azodicarbonyl)-dipiperidine (4.0 g, 15.8 mmol) in toluene (40 mL). The reaction mixture is allowed to warm to room temperature and is stirred for 3.0 h. The reaction mixture is partitioned between EtOAc (50 mL) and water (60 mL). The organic layer is washed with brine (60 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to a residue. The residue is purified by flash chromatography (EtOAc/Hexane) to afford the title compound as a solid (2.3 g, 56%). LC-ES/MS m/e 390.0 (M+1).
Reaction SMILES: [NH2:1][CH:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][CH3:13])[CH:5]=1)[CH3:3].[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[BH4-].[Na+]>N1C=CC=CC=1.CO>[CH3:13][O:12][C:6]1[CH:5]=[C:4]([CH:2]([CH3:3])[NH:1][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:9]=[CH:8][C:7]=1[O:10][CH3:11]
Reactant: COc1ccc(C(C)N)cc1OC
Reactant: O=Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CO
Product: COc1ccc(C(C)NCc2ccccc2)cc1OC
Reaction time: 48 h
Yield: 100 %

Procedure:
A mixture containing 18.1 g of 1-amino-1-(3,4-dimethoxyphenyl)-ethane (J. Chem. Soc. 1963, 4289), 10,6 g of benzaldehyde and 1 drop of pyridine in 100 ml of methanol is let stand at 20° C. for 2 days, then 3.8 g of sodium borohydride are added during 30 minutes and stirred for additional 3 hours. After evaporation of the solvent, the residue is diluted with water, extracted with chloroform, the organic phase is dried and evaporated to give 27.1 g of the crude title compound, which can directly be used in the process described in Example 6.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([NH2:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:21]=[C:17]([C:18](O)=O)[C:16]([OH:22])=[CH:15][CH:14]=1.N1C=CC=CC=1.S(Cl)(Cl)=O>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][C:18]([C:17]3[CH:21]=[C:13]([Cl:12])[CH:14]=[CH:15][C:16]=3[OH:22])=[N:9][C:7](=[O:8])[C:6]=2[CH:10]=1
Reactant: O=C(O)c1cc(Cl)ccc1O
Reactant: NC(=O)c1cc(Cl)ccc1O
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1C
Product: O=c1nc(-c2cc(Cl)ccc2O)oc2ccc(Cl)cc12
Reaction time: 1 h

Procedure:
40.0 g of 5-chlorosalicyl-amide and 54.0 g of 5-chlorosalicylic acid are boiled under reflux in 400 ml of xylene after addition of 2.5 ml of pyridine. 38 ml of thionyl chloride are added in the course of 2 h, the mixture is stirred for a further 1 h and the solvent is then distilled off under reduced pressure. The residue is suspended in 200 ml of ethanol, filtered off and washed with ethanol. After drying, 6-chloro-2-(5-chloro-2-hydroxyphenyl)benz[e][1,3]oxazin-4-one is obtained as slightly yellow crystals of m.p. 246-248 C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C[Al](C)C.C[O:18][C:19]([C:21]1[C:30]2[C:25](=[CH:26][C:27]([O:31][C:32]3[CH:37]=[C:36]([CH2:38][O:39][CH3:40])[N:35]=[CH:34][N:33]=3)=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1)=O.[NH4+].[Cl-]>C1(C)C=CC=CC=1.C1COCC1.CCOC(C)=O.O>[CH3:12][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:19]([C:21]2[C:30]3[C:25](=[CH:26][C:27]([O:31][C:32]4[CH:37]=[C:36]([CH2:38][O:39][CH3:40])[N:35]=[CH:34][N:33]=4)=[CH:28][CH:29]=3)[CH:24]=[CH:23][CH:22]=2)=[O:18])=[CH:7][C:6]=1[C:8]([F:9])([F:10])[F:11]
Reactant: COCc1cc(Oc2ccc3c(C(=O)OC)cccc3c2)ncn1
Reactant: Cc1ccc(N)cc1C(F)(F)F
Agent: C[Al](C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COCc1cc(Oc2ccc3c(C(=O)Nc4ccc(C)c(C(F)(F)F)c4)cccc3c2)ncn1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
In a dried vessel, 68 mg (0.388 mMol) 5-amino-2-methylbenzotrifluoride are dissolved in 7 ml toluene and cooled in an ice bath. Then 580 μl Me3Al (2 M in toluene; 1.16 mMol) are added via syringe. After 1 h at rt, a solution of 126 mg (0.388 mMol) 6-(6-methoxymethyl-pyrimidin-4-yloxy)-naphthalene-1-carboxylic acid methyl ester in 1.5 ml THF is added and the solution is stirred for ½ h in an oil bath of 110° C. The solution is cooled in an ice bath and hydrolyzed with 13 ml of a sat. NH4Cl solution. After 15 min stirring, the mixture is diluted with EtOAc and water, the aq. phase separated off and extracted twice with EtOAc. The organic layers are washed with water and brine, dried (Na2SO4) and concentrated. Chromatography (Combi Flash; CH2Cl2/acetone 99:1→19:1) and crystallization from DIPE/hexane gives the title compound: m.p.: 188° C.; Anal.: C, H, N, F; MS: [M+1]+=468; TLC (CH2Cl2/acetone 9:1): Rf=0.32; 1H-NMR (DMSO-d6): δ ppm 10.85 (s, HN), 8.69 (s, 1H), 8.28 (d, 1H), 8.24 (s, 1H), 8.10 (d, 1H), 7.93 (d, 1H), 7.90 (s, 1H), 7.80 (d, 1H), 7.66 (t, 1H), 7.48 (d, 1H), 7.44 (d, 1H), 7.07 (s, 1H), 4.50 (s, H2C), 3.4 (s, H3C), 2.43 (s, H3C).
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=[O:15])[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)N1CCC(C(=O)O)CC1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCOC(=O)N1CCC(C(=O)OCc2ccccc2)CC1
Temperature: 60 °C

Procedure:
N-Butoxycarbonyl-4-piperidinecarboxylic acid (4.6 g) was dissolved in dimethylformamide (20 ml) and placed under an atmosphere of nitrogen. Benzyl bromide (2.9 ml) and potassium carbonate (8.3 g) were added and heated at 60° C. for 3 h. The dimethylformamide was removed in vacuo and azeotroped with toluene (three times). The residue was dispersed between ethyl acetate and water and the aqueous phase was extracted with ethyl acetate (3×100 ml). The combined organic phases were washed with brine and dried (MgSO4). The solution was filtered, evaporated to dryness and the residue was purified by chromatography on silica gel (eluting with isohexane containing increasing concentrations amounts of ethyl acetate 5-30%) to give benzyl N-butoxycarbonylpiperidine-4-carboxylate as a clear oil (7.68 g).
Reaction SMILES: [F:1][C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[O:14])[N:8]=1)=[O:5].[CH:27](=O)[CH2:28][CH3:29].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>CO.ClCCl>[F:26][C:21]1[CH:22]=[C:23]([F:25])[CH:24]=[C:2]([F:1])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([CH:15]2[CH2:16][CH2:17][N:18]([CH2:27][CH2:28][CH3:29])[CH2:19][CH2:20]2)=[O:14])[N:8]=1)=[O:5]
Reactant: O=C(Nc1cccc(C(=O)C2CCNCC2)n1)c1c(F)cc(F)cc1F
Reactant: CCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCCN1CCC(C(=O)c2cccc(NC(=O)c3c(F)cc(F)cc3F)n2)CC1
Reaction time: 1.5 h

Procedure:
Mix 2,4,6-trifluoro-N-[6-(piperidin-4-ylcarbonyl)-pyridin-2-yl]-benzamide (50 mg), propionaldehyde (80 mg), sodium triacetoxyborohydride (38 mg) and acetic acid (21 mg) with dichloromethane (5 mL) and stir for 1.5 hrs. Dilute with methanol and load on a SCX column (10 g), wash with methanol, elute the product with 2M NH3-methanol. Purify the product on a silica gel column (10 g, dichloromethane/2M NH3 in methanol, gradient) to obtain the title compound as a free base (26 mg). Mass spectrum (electrospray) m/z=406 (M+1); 1H NMR (CDCl3): 8.52 (d, 1H), 8.38 (br, 1H), 7.92 (t, 1H), 7.82 (dd, 1H), 6.82 (m, 2H), 3.61 (br, 1H), 3.00 (m, 2H), 2.34 (m, 2H), 2.11 (m, 2H), 1.87 (m, 3H), 1.60 (m, 5H), 0.90 (t, J=7.3 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:3]=1[NH2:4].Cl.Cl[C:13]1[CH:14]=CC(OC)=[C:17]2[C:22]=1N=C(C)C=C2.COC1C=CC=C2C=1CC[C@H](C)N2.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[F:1][C:2]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[C:5]2[C:3]=1[N:4]=[C:22]([CH3:17])[CH:13]=[CH:14]2
Reactant: COc1ccc(F)c(N)c1
Reactant: COc1ccc(Cl)c2nc(C)ccc12
Agent: COc1cccc2c1CC[C@H](C)N2
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: COc1ccc(F)c2nc(C)ccc12
Yield: 62 %

Procedure:
8-Fluoro-5-methoxy-2-methylquinoline was synthesized from 2-fluoro-5-methoxyaniline (30.0 g, 213 mmol) according to the procedures described above for 8-chloro-5-methoxy-2-methylquinoline hydrochloride (Intermediate 1, Step 1) with the following change: The hydrochloride salt was dissolved in dichloromethane (400 mL) and the pH of the resulting solution was adjusted to 8-9 with saturated aqueous potassium carbonate solution. The resulting mixture was extracted with dichloromethane, and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified via column chromatography on silica gel (eluting with 20% ethyl acetate-petroleum ether) to afford 8-fluoro-5-methoxy-2-methylquinoline (25.2 g, 62%) as a yellow solid. MS (ESI, pos. ion) m/z 192 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([NH2:11])=[CH:4][CH:3]=1.Cl[C:13](Cl)([O:15]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[OH:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:13](=[O:15])[O:8][C:7](=[O:9])[C:6]=2[CH:10]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ccc(O)cc1C(=O)O
Solvent: C1CCOC1
Product: O=c1[nH]c2ccc(O)cc2c(=O)o1
Temperature: 25 °C
Yield: 161.8 %

Procedure:
To a suspension of 5-hydroxyanthranilic acid (15.3 g, 100 mmol) in THF (400 mL) at 0° C. was added triphosgene (10.1 g, 34 mmol). The resultant mixture was stirred for 5 min at 0° C. and then allowed to warm to room temperature over 6 h. The reaction mixture was cooled at 0° C. overnight and the resultant gray precipitate collected by filtration to afford 6-hydroxy-1H-benzo[d][1,3]oxazine-2,4-dione (9.8 g, 55 mmol, 55%). The filtrate was concentrated in vacuo, the resultant solid triturated with diethyl ether and collected by filtration to afford additional product (7.3 g, 41 mmol, 41%).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=2)[CH:10]=O)=[CH:4][CH:3]=1.Cl.[NH2:18][OH:19]>CO>[F:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=2)/[CH:10]=[N:18]/[OH:19])=[CH:4][CH:3]=1
Reactant: O=Cc1cccc(Oc2ccc(F)cc2)c1
Reactant: NO
Agent: Cl
Solvent: CO
Product: O/N=C/c1cccc(Oc2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 94 %

Procedure:
To a mixture of 3-(4-fluorophenoxy)benzaldehyde (3.0 g, 13.8 mmol, 1.0 eq) in methanol was added hydroxylamine hydrochloride (1.06 g, 15.2 mmol, 1.1 eq). The reaction mixture was stirred at ambient temperature for 12 h, before being concentrated in vacuo. The residue was taken in ethyl acetate and washed with water. The organic layer was dried with anhydrous Na2SO4 and concentrated to obtain the desired product (3 g, 94%). 1H NMR (400 MHz, DMSO-d6) δ 8.12 (s, 1H), 7.42-7.38 (t, 1H), 7.32-7.31 (d, 1H), 7.27-7.23 (t, 2H), 7.16 (s, 1H), 7.13-7.10 (m, 2H), 7.01-6.99 (m, 1H). MS (ESI): 232.2 (M+H)+.