Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:3]=1[CH:4]=[O:5].Br[CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].C(=O)([O-])[O-].[K+].[K+]>[I-].[Na+].C(O)C>[CH:4]([C:3]1[C:6]([O:10][CH3:11])=[CH:7][CH:8]=[CH:9][C:2]=1[O:1][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[O:5]
Reactant: CCOC(=O)CCCCBr
Reactant: COc1cccc(O)c1C=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)CCCCOc1cccc(OC)c1C=O
Reaction time: 16 h
Yield: 67 %

Procedure:
2-Hydroxy-6-methoxybenzaldehyde (26.0 g, 0.17 M), ethyl 5-bromopentanoate (27.1 ml, 0.17 M), anhydrous potassium carbonate (25.4 g), sodium iodide (1.04 g) and ethanol (230 ml) were refluxed with stirring for 16 hours. The cooled reaction mixture was filtered and the solid washed well with ethanol. The filtrate was evaporated to dryness and the residue partitioned between ether (200 ml) and water (200 ml). The organic layer was separated and washed with 2 N sodium hydroxide solution (1×150 ml), water (1×150 ml), brine (1×150 ml), dried (magnesium sulphate) and evaporated to yield ethyl 5-(2-formyl-3-methoxyphenoxy)pentanoate 32.97 g, 67% yield, as a pale yellow oil that solidified on standing in the refrigerator.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:13]([OH:15])=[O:14])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.[OH-].[K+].ClCCl>C(O)CCC>[OH:1][C:2]1[C:3]([C:13]([O:15][CH2:3][CH2:2][CH2:11][CH3:6])=[O:14])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2
Reactant: Cc1ccc2ccc(C(=O)O)c(O)c2n1
Agent: [K+]
Agent: [OH-]
Solvent: CCCCO
Solvent: ClCCl
Product: CCCCOC(=O)c1ccc2ccc(C)nc2c1O
Temperature: 20 °C
Yield: 143.8 %

Procedure:
A mixture of 8-hydroxy-7-quinaldinecarboxylic acid 1 (12 g, 59 mmol) and polyphosphoric acid (30 g) in 60 ml of n-butanol is heated at 100° C. for 72 hours during which additional portions of 30 g of polyphosphoric acid and 30 ml of n-butanol are regularly added every 12 hours. After cooling to 20° C., the reaction mixture is brought to pH 4 with a 6 N potassium hydroxide solution, and then 200 ml of dichloromethane are added. The phases are separated, and the aqueous phase extracted with dichloromethane. The combined organic phases are dried over magnesium sulfate and concentrated under reduced pressure. The residue is chromatographed on a silica column, eluting with a 1/1 cyclohexane/ethyl acetate mixture so as to give 11 g (72%) of n-butyl 8-hydroxy-2-methylquinoline-7-carboxylate in the form of a white solid.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:6]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:5]=1.[Li].C(Cl)Cl>C1COCC1>[CH2:27]([O:26][C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7]=1[O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH2:3][OH:2])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: COC(=O)c1cc(OCc2ccccc2)c(OCc2ccccc2)c(OCc2ccccc2)c1
Agent: [Li]
Solvent: ClCCl
Solvent: C1CCOC1
Product: OCc1cc(OCc2ccccc2)c(OCc2ccccc2)c(OCc2ccccc2)c1

Procedure:
A solution of 20.0 g (0.044 mol) of 3,4,5-trisbenzyloxybenzoic acid methyl ester in 100 ml of THF is added dropwise with vigorous stirring, over a period of 60 minutes at room temperature, to a suspension of 4.00 g (0.11 mol) of lithium alanate in 100 ml of THF, in the course of which the temperature rises to 65° C. (reflux). After a further 2 hours at reflux, excess lithium alanate is cautiously hydrolysed, and the product is isolated in customary manner by extraction with methylene chloride. Amorphous powder, yield 12.0 g (64% of theory).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH2:10][NH:9][CH2:8][CH:7]2[CH2:14][CH2:15][NH:16][C:17](=[O:19])[CH3:18].C(=O)([O-])[O-].[K+].[K+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.Cl>CN(C=O)C.O>[CH2:26]([N:9]1[CH2:8][CH:7]([CH2:14][CH2:15][NH:16][C:17](=[O:19])[CH3:18])[C:6]2[C:11](=[CH:12][CH:13]=[C:4]([O:3][CH3:2])[CH:5]=2)[CH2:10]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: BrCc1ccccc1
Reactant: COc1ccc2c(c1)C(CCNC(C)=O)CNC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(c1)C(CCNC(C)=O)CN(Cc1ccccc1)C2
Temperature: 125 °C

Procedure:
The compound obtained in Example 4 (740 mg; 2.5 mmol) and potassium carbonate (720 mg; 5 mmol) are suspended in 20 ml of DMF, and then benzyl bromide (0.37 ml; 3 mmol) is added to the solution. The reaction mixture is heated at 125° C. for 4 hours with stirring. The solution is poured into 50 ml of water, acidified with 6N HCl and washed with ethyl acetate. The aqueous phase is then rendered alkaline with potassium carbonate and extracted with dichloromethane. The organic phase is dried over magnesium sulphate, filtered and evaporated under reduced pressure. The residue so obtained is purified by chromatography on silica gel (eluant: dichloromethane with the progressive addition of methanol until the proportions 9/1 are reached). The purified oil precipitates. The precipitate so formed is recrystallised from a 7/3 toluene/cyclohexane mixture to yield the title product in the form of a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([OH:16])=O)[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].OC1C2N=NNC=2C=CC=1.[F:27][C:28]([F:46])([F:45])[C:29]1[CH:30]=[C:31]([CH:42]=[CH:43][CH:44]=1)[CH2:32][N:33]1[CH2:37][C@H:36]2[C@H:38]([NH2:41])[CH2:39][CH2:40][C@H:35]2[CH2:34]1.CC[N+](CCCN(C)C)=C=N>ClCCl>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([NH:41][C@H:38]1[C@H:36]2[C@H:35]([CH2:34][N:33]([CH2:32][C:31]3[CH:42]=[CH:43][CH:44]=[C:29]([C:28]([F:46])([F:27])[F:45])[CH:30]=3)[CH2:37]2)[CH2:40][CH2:39]1)=[O:16])[CH2:10][CH:11]([CH3:12])[CH3:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: N[C@@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21
Agent: CC[N+](=C=N)CCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
N-(tert-Butoxycarbonyl)-L-leucine (180 mg, 0.778 mmol), hydroxybenzotriazole (119 mg, 0.778 mmol), and (3aS,4R,6aR)-2-(3-(trifluoromethyl)benzyl)octahydrocyclopenta[c]pyrrol-4-amine (201 mg, 0.707 mmol) from Example 154 Step A were combined in dichloromethane (1 mL). After 20 minutes, N-(3-dimethylaminopropyl)-N-ethylcarbodiimide (0.138 mL, 0.778 mmol) was added and the reaction stirred at room temperature for 24 hours. The reaction was quenched with water, and the layers were separated. The aqueous layer extracted with 1 mL of dichloromethane. The combined organic layers were applied to a silica gel cartridge (Analogix®, Burlington, Wis., RS15-24) and eluted with 1-10% methanol (2 N ammonia)/dichloromethane to give N2-(tert-butyloxycarbonyl)-N1-{(3aS,4R,6aR)-2-[3-(trifluoromethyl)benzyl]octahydrocyclopenta[c]pyrrol-4-yl}-L-leucinamide: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.66 (d, J=7.1, 1H), 7.97 (d, J=8.5, 1H), 7.73 (s, 1H), 7.56 (s, 2H), 7.44 (t, J=7.7, 1H), 4.70 (dd, J=5.9, 11.0, 1H), 4.40 (br s, 1H), 3.56 (d, J=13.5, 1H), 3.41 (d, J=13.5, 1H), 2.74 (d, J=8.9, 1H), 2.48 (s, 2H), 2.37-2.31 (m, 1H), 2.27 (d, J=8.4, 1H), 2.24-2.19 (m, 1H), 2.12 (dq, J=6.0, 12.0, 1H), 1.91-1.81 (m, 4H), 1.66 (td, J=7.4, 14.7, 1H), 1.50 (s, 9H), 1.43-1.35 (m, 1H), 0.87 (d, J=5.9, 3H), 0.84 (d, J=5.6, 3H); MS (ESI+) m/z 498 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=O)[CH2:16][CH2:17][C:18](=O)[CH3:19])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:22][CH2:23][CH2:24][CH2:25][OH:26].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:22]([CH2:23][CH2:24][CH2:25][OH:26])[C:18]([CH3:19])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)CCC(=O)c1ccc(OCc2ccccc2)cc1
Reactant: NCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ccc(OCc3ccccc3)cc2)n1CCCO
Yield: 79.1 %

Procedure:
A solution of 1-(4-benzyloxyphenyl)pentan-1,4-dione (5.00 g, 17.7 mmol), 3-amino-1-propanol (1.33 g, 17.7 mmol) and p-toluenesulfonic acid monohydrate (253 mg, 1.33 mmol) in toluene (100 ml) was refluxed for 12 hours under heating using Dean-Stark's apparatus, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give the object compound as a solid. 4.50 g (yield: 79.1%)
Reaction SMILES: CO[CH:3]=[CH:4][C:5](=[O:7])[CH3:6].[CH3:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH2:11][NH2:12]>>[C:9]1([CH3:8])[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH2:11][NH:12][CH:3]=[CH:4][C:5](=[O:7])[CH3:6]
Reactant: Cc1ccccc1CN
Reactant: COC=CC(C)=O
Product: CC(=O)C=CNCc1ccccc1C

Procedure:
The title compound 60 is prepared according to the procedure reported in step A of Example 18 with 4-methoxy-3-buten-2-one (0.1 g, 1 mmol) and 2-methylbenzylamine (0.125 g, 1 mmol) as reactants. Yellow solid. (Yield 0.19 g, 100%).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.O.[NH2:12][NH2:13]>O1CCOCC1>[NH:12]([C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1)[NH2:13]
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: NN
Solvent: O
Solvent: C1COCCO1
Product: NNc1ccc(C(=O)O)cn1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 57.5 %

Procedure:
A suspension of 6-chloronicotinic acid (30.0 g, 189 mmol) in 1,4-dioxane (29.0 mL) was treated with hydrazine hydrate (134 mL, 1.51 mol) and heated to 90° C. overnight. The mixture was cooled to ambient temperature and then in ice for 30 min. Precipitate formation was induced by etching the side of the flask and the precipitate was filtered and re-suspended in EtOH (500 mL) with vigorous stirring. The resulting suspension was filtered. The precipitate was dissolved in water (300 mL) and HCl (6N) was added until pH=1. The pH was then adjusted to 5 with NaOH (50%, aq.) and the resulting suspension was stirred for 1 h. The solids were collected by filtration and dried in vacuum to give the title compound (16.65 g, 57.7% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 6.70 (d, 1H) 7.86 (dd, J=8.97, 2.15 Hz, 1H) 8.32 (br. s., 1H) 8.52 (d, J=1.77 Hz, 1H). MS m/z [M+H]+ 154.
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[N:27]1([C:33]2[CH:41]=[CH:40][C:36]([C:37](O)=[O:38])=[CH:35][CH:34]=2)[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:37](=[O:38])[C:36]5[CH:35]=[CH:34][C:33]([N:27]6[CH2:32][CH2:31][O:30][CH2:29][CH2:28]6)=[CH:41][CH:40]=5)[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: O=C(O)c1ccc(N2CCOCC2)cc1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1)c1ccc(N2CCOCC2)cc1

Procedure:
The title compound, light yellow solid (97 mg, 75%), MS (ISP) m/z=518.4 [(M+H)+], mp 247° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and 4-(morpholine-4-yl)-benzoic acid.
Reaction SMILES: [CH:1]([O:4][C:5]1[N:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][C@H:20]([NH2:24])[CH:21]([CH3:23])[CH3:22])=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[C:25](OC(=O)C)(=[O:27])[CH3:26]>>[CH:1]([O:4][C:5]1[N:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][C@H:20]([NH:24][C:25](=[O:27])[CH3:26])[CH:21]([CH3:23])[CH3:22])=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)Oc1ccc(Oc2ccc(CC[C@H](N)C(C)C)cc2)cn1
Product: CC(=O)N[C@@H](CCc1ccc(Oc2ccc(OC(C)C)nc2)cc1)C(C)C

Procedure:
(S)-1-{2-[4-(6-Isopropoxypyridin-3-yloxy)phenyl]ethyl}-2-methylpropylamine (50 mg, 0.152 mmol) was reacted with acetic anhydride in analogy to example 2a. Yield: 49 mg (88%), M+H+: 371.3.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9](Cl)[C:8]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([NH:23][C:9]1[C:8]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([CH3:1])[CH:10]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cc1cc(Cl)c(S(C)(=O)=O)cc1C(=O)O
Reactant: NCc1ccccc1
Product: Cc1cc(NCc2ccccc2)c(S(C)(=O)=O)cc1C(=O)O

Procedure:
in stage c) 2-methyl-4-chloro-5-methylsulfonylbenzoic acid is reacted with benzylamine to give 4-benzylamino-5-methylsulfonyl-2-methylbenzoic acid,
Reaction SMILES: [CH3:1][C@H:2]1[C@H:6]([O:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[C:10]([C:18]3[NH:22][C:21](=[O:23])[NH:20][N:19]=3)[N:9]=2)[CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.[ClH:31].O1CCOCC1>>[ClH:31].[CH3:1][C@@H:2]1[CH2:3][NH:4][CH2:5][C@H:6]1[O:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10]([C:18]2[NH:22][C:21](=[O:23])[NH:20][N:19]=2)[N:9]=1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1Oc1nc(-c2n[nH]c(=O)[nH]2)cc2ccccc12
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H]1CNC[C@H]1Oc1nc(-c2n[nH]c(=O)[nH]2)cc2ccccc12
Reaction time: 0.5 h

Procedure:
A mixture of tert-butyl trans-3-methyl-4-((3-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)isoquinolin-1-yl)oxy)pyrrolidine-1-carboxylate (0.640 g, 1.555 mmol) and HCl in 1,4-dioxane (3.8 mL, 15.55 mmol) was stirred for 30 minutes, forming a mustard colored precipitate. The precipitate was filtered, washed with diethyl ether, and dried to give an HCl salt of the title compound (0.550 g, quantitative yield). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.19 (d, 3H), 2.68-2.74 (m, 1H), 3.03 (dd, 1H), 3.27-3.60 (m, 3H), 3.86 (dd, 1H), 5.73-5.85 (m, 1H), 7.69 (t, 1H), 7.78-7.90 (m, 1H), 8.02 (s, 1H), 8.04 (d, 1H), 8.21-8.30 (m, 1H), 9.48 (br s, 1H), 9.67 (br s, 1H), 11.8 (s, 0.5H), 12.01 (s, 0.5H); ESI-MS m/z [M+H]+ 312.6.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][C:8]([C:10]([O:12][CH3:13])=[O:11])=[C:7](OS(C(F)(F)F)(=O)=O)[CH2:6][CH2:5]1)[CH2:2][CH3:3].[CH2:22]([O:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=C(OCOCCOC)[C:26]=1[F:41])[CH3:23].B([O-])=O.[Na+].[OH-].[NH3+]N>O1CCCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH2:22]([O:24][C:25]1[C:26]([F:41])=[C:13]2[C:28]([C:7]3[CH2:6][CH2:5][CH:4]([CH2:1][CH2:2][CH3:3])[CH2:9][C:8]=3[C:10](=[O:11])[O:12]2)=[CH:29][CH:30]=1)[CH3:23]
Reactant: CCOc1ccc(B(O)O)c(OCOCCOC)c1F
Reactant: CCCC1CCC(OS(=O)(=O)C(F)(F)F)=C(C(=O)OC)C1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: N[NH3+]
Agent: O=B[O-]
Solvent: C1CCOC1
Solvent: O
Product: CCCC1CCc2c(c(=O)oc3c(F)c(OCC)ccc23)C1

Procedure:
18.2 g (56.6 mmol) of methyl 5-propyl-2-trifluoromethanesulfonyloxycyclohex-1-enecarboxylate, 21.5 g (74.6 mmol) of 4-ethoxy-3-fluoro-2-(2-methoxyethoxymethoxy)benzeneboronic acid, 1.5 ml of water, 33 g (120 mmol) of sodium metaborate, 1.12 g (1.6 mmol) of bis(triphenylphosphine)palladium(II) chloride and 0.1 ml (1.6 mmol) of hydrazinium hydroxide are heated under reflux overnight in 300 ml of tetrahydrofuran. After addition of water, the aqueous phase is separated off and extracted twice with MTB ether. The combined organic phases are washed with saturated sodium chloride soln. and dried over sodium sulfate. The solvent is removed under reduced pressure, and the residue is filtered through silica gel with n-heptane/MTB ether (6:4), giving 3-ethoxy-4-fluoro-8-propyl-7,8,9,10-tetrahydrobenzo[c]chromen-6-one as colourless crystals.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][NH:8][CH2:7][CH2:6]2.[CH3:15][S:16]([C:19]1[CH:20]=[CH:21][C:22]([O:28][C@@H:29]([CH3:34])[C:30]([F:33])([F:32])[F:31])=[C:23]([CH:27]=1)[C:24](O)=[O:25])(=[O:18])=[O:17]>>[CH3:15][S:16]([C:19]1[CH:20]=[CH:21][C:22]([O:28][C@@H:29]([CH3:34])[C:30]([F:31])([F:32])[F:33])=[C:23]([C:24]([N:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([C:2]([F:1])([F:13])[F:14])[CH:4]=3)[CH2:9]2)=[O:25])[CH:27]=1)(=[O:18])=[O:17]
Reactant: FC(F)(F)c1ccc2c(c1)CCNC2
Reactant: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)O)C(F)(F)F
Product: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCc2cc(C(F)(F)F)ccc2C1)C(F)(F)F

Procedure:
Prepared in analogy to example 1.1 from 6-trifluoromethyl-1,2,3,4-tetrahydro-isoquinoline and 5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid (example 2.2). MS (m/e): 496.0 (M+H+).
Reaction SMILES: [N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[N:4]([C:10]1[CH:11]=[C:12]([C:17]([N+:20]([O-:22])=[O:21])=[CH:18][N:19]=1)[C:13]([O:15]C)=[O:14])[CH2:3][CH2:2]2.[OH-].[Li+].CO.O>O1CCCC1>[N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[N:4]([C:10]1[CH:11]=[C:12]([C:17]([N+:20]([O-:22])=[O:21])=[CH:18][N:19]=1)[C:13]([OH:15])=[O:14])[CH2:3][CH2:2]2
Reactant: COC(=O)c1cc(N2CCN3CCC2CC3)ncc1[N+](=O)[O-]
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1cc(N2CCN3CCC2CC3)ncc1[N+](=O)[O-]
Reaction time: 8 h
Yield: 55.6 %

Procedure:
To a solution of methyl 2-(1,4-diazabicyclo[3.2.2]nonan-4-yl)5-nitroisonicotinate (Intermediate 27A) (6.0 g, 19.6 mmol) in tetrahydrofuran (15 mL) under nitrogen was added lithium hydroxide (2.47 g, 58.8 mmol), methanol (10 mL) and water (15 mL), reaction then stirred overnight. The reaction mixture was concentrated and purified by a 50 g silica column eluting with 10-40% methanol in DCM to afford 2-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-5-nitroisonicotinic acid (3.2 g, 10.9 mmol).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][CH2:11][CH:10]([NH:13][C:14]2[N:15]=[N:16][C:17]([C:20](=[O:27])[NH:21][CH2:22][CH2:23][CH:24]3[CH2:26][CH2:25]3)=[CH:18][CH:19]=2)[CH2:9]1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O.C1(CCNC(C2N=NC(NC3CCNC3)=CC=2)=O)CC1.[F:55][C:56]([F:67])([F:66])[C:57]1[CH:65]=[CH:64][CH:63]=[CH:62][C:58]=1C(Cl)=O>ClCCl.C(N(CC)CC)C>[CH:24]1([CH2:23][CH2:22][NH:21][C:20]([C:17]2[N:16]=[N:15][C:14]([NH:13][CH:10]3[CH2:11][CH2:12][N:8]([C:6](=[O:7])[C:58]4[CH:62]=[CH:63][CH:64]=[CH:65][C:57]=4[C:56]([F:67])([F:66])[F:55])[CH2:9]3)=[CH:19][CH:18]=2)=[O:27])[CH2:25][CH2:26]1
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(C(=O)NCCC3CC3)nn2)C1
Agent: O=C(NCCC1CC1)c1ccc(NC2CCNC2)nn1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCC1CC1)c1ccc(NC2CCN(C(=O)c3ccccc3C(F)(F)F)C2)nn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 54 %

Procedure:
3-[6-(2-Cyclopropylethylcarbamoyl)pyridazin-3-ylamino]pyrrolidine-1-carboxylic acid tert-butyl ester was treated with trifluoroacetic acid in dichloromethane (15 mL). The isolated 6-(pyrrolidin-3-ylamino)pyridazine-3-carboxylic acid (2-cyclopropylethyl)-amide (0.053 g, 0.19 mmol) was dissolved in dichloromethane (10 mL) and then 2-trifluoromethylbenzoyl chloride (0.040 g, 0.19 mmol) was added at ambient temperature in the presence of triethylamine (0.2 mL). The mixture was stirred at ambient temperature for 15 minutes. The solvent was evaporated and the residue was purified by column chromatography. The title compound was obtained as a white powder in 54% yield (0.046 g). 1H NMR (300 MHz, CDCl3) δ 8.01 (d, J=10.0 Hz, 1H), 7.7 (m, 2H), 7.6 (t, J=7.0 Hz, 1H), 7.5 (m, 2H), 6.7 (d, J=10.0 Hz, 1H), 6.2 (m, 1H), 4.8 (m, 1H), 3.9-3.60 (m, 2H), 3.5-3.4 (m, 2H), 2.4 (m, 1H), 2.2 (m, 1H), 1.4 (t, J=7.0 Hz, 2H), 0.7 (m, 1H), 0.4 (m, 2H), 0.07 (m, 2H). MS (ES+) m/z 448.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]2[CH2:19][CH2:18][C:13]3(OCC[O:14]3)[CH2:12][CH2:11]2)[CH:5]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O.CC(C)=O>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]2[CH2:19][CH2:18][C:13](=[O:14])[CH2:12][CH2:11]2)[CH:5]=1
Reactant: COC(=O)c1cccc(N2CCC3(CC2)OCCO3)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)c1cccc(N2CCC(=O)CC2)c1
Yield: 79.3 %

Procedure:
A mixture of methyl-3-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-benzoate (1.80 g, 6.49 mmol) and p-toluenesulfonic acid monohydrate (123 mg, 0.649 mmol) in water (30 mL) and acetone (15 mL) was heated at reflux for 17 hours. The organic solvent was removed in vacuo and the aqueous mixture was extracted with dichloromethane. The organic extract was washed with saturated NaHCO3(aq.), dried (MgSO4), filtered and concentrated. Elution through a flash column (silica gel 60, 230-400 mesh, 3:2 hexanes:EtOAc) followed by concentration gave the title compound as a yellow oil (1.20 g, 79%).
Reaction SMILES: C[O:2][C:3](=[O:24])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:14](=[O:23])[N:15]([CH3:22])[C:16](=[O:21])[N:17]([CH3:20])[C:18]=2[CH3:19])=[CH:9][CH:8]=1)[NH2:5].[CH3:25][CH2:26][CH2:27][C:28]1[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[C:29]=1[C:30](O)=[O:31]>>[CH3:25][CH2:26][CH2:27][C:28]1[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[C:29]=1[C:30]([NH:5][C@H:4]([C:3]([OH:2])=[O:24])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[C:14](=[O:23])[N:15]([CH3:22])[C:16](=[O:21])[N:17]([CH3:20])[C:18]=2[CH3:19])=[CH:11][CH:12]=1)=[O:31]
Reactant: CCCc1cccc(C)c1C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)cc1
Product: CCCc1cccc(C)c1C(=O)N[C@@H](Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)cc1)C(=O)O

Procedure:
N-[[2-(2-methylethyl)-6-methylphenyl]carbonyl]-4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine was prepared from 4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine methyl ester and 2-(2-methylethyl)-6-methylbenzoic acid using the general procedures described in example 7 and was obtained as an amorphous white solid. ES-HRMS m/e calcd for C27H31N3O5 (M+Na) 500.2156, found 500.2160.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([OH:14])[CH2:4][N:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1.[N:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][C:23]=2[O:25][CH2:26][C:27](OCC)=[O:28])[CH:18]=[CH:17][CH:16]=1>CCO>[OH:14][C@@H:3]([CH2:4][N:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:2][NH:1][C:27](=[O:28])[CH2:26][O:25][C:23]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:24]=1[N:15]=[CH:16][CH:17]=[CH:18]2
Reactant: NC[C@@H](O)CN1Cc2ccccc2C1
Reactant: CCOC(=O)COc1cccc2cccnc12
Solvent: CCO
Product: O=C(COc1cccc2cccnc12)NC[C@@H](O)CN1Cc2ccccc2C1
Temperature: 120 °C
Yield: 51 %

Procedure:
(R)-1-amino-3-(isoindolin-2-yl)propan-2-ol (100 mg, 0.52 mmol) and ethyl 2-(quinolin-8-yloxy)acetate (120 mg, 0.52 mmol) were dissolved in EtOH (1 mL) and heated under microwave conditions at 120° C. for 0.5 h. The reaction mixture was concentrated and purified by preparative HPLC purification. (100 mg, yield 51%) MS (ESI+) e/z: 378.1 [M+1]+. 1H NMR (MeOD, 400 MHz), δ ppm: 8.95-8.85 (m, 1H), 8.44-8.34 (m, 1H), 7.69-7.54 (m, 3H), 7.33-7.27 (m, 1H), 7.18 (s, 4H), 4.79 (s, 2H), 4.09-4.03 (m, 1H), 3.99 (s, 4H), 3.61-3.53 (m, 1H), 3.47-3.38 (m, 1H), 2.91-2.85 (m, 1H), 2.84-2.77 (m, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@@H:17]([CH3:25])[C:18]([O:20]C(C)(C)C)=[O:19])[C:13]1=[O:26])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@@H:17]([CH3:25])[C:18]([OH:20])=[O:19])[C:13]1=[O:26])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H](C(=O)OC(C)(C)C)N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](C(=O)O)N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100.1 %

Procedure:
tert-Butyl(2S)-2-((3S)-3-{[(benzyloxy)carbonyl]amino}-2-oxopyrrolidin-1-yl)propanoate (0.5 g) was dissolved in DCM (7 ml), and trifluoroacetic acid (4.7 ml) was added. The mixture was stirred at room temperature for 1.5 h and then concentrated under reduced pressure to give the title compound (0.423 g) as a colourless oil which after azeotroping with toluene, crystallised.