Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N[C:24]1[C:28](C2C=CC=CC=2)=CS[C:25]=1[C:35](OC)=O.C(OCC)(OCC)OCC.[C@H]1(N)C2C(=CC=CC=2)CCC1>C(O)(=O)C>[C:17]1([C:16]2[C:10]3[N:9]=[CH:8][N:7]([C@H:1]4[C:6]5[C:5](=[CH:28][CH:24]=[CH:25][CH:35]=5)[CH2:4][CH2:3][CH2:2]4)[C:12](=[O:13])[C:11]=3[S:14][CH:15]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)c1scc(-c2ccccc2)c1N
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Agent: N[C@@H]1CCCc2ccccc21
Solvent: CCOC(OCC)OCC
Solvent: CC(=O)O
Product: O=c1c2scc(-c3ccccc3)c2ncn1[C@@H]1CCCc2ccccc21
Yield: 47.6 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-phenylthiophene-2-carboxylate (100 mg, 0.43 mmol), triethyl orthoformate (1.0 ml), (R)-1,2,3,4-tetrahydronaphthalen-1-amine (0.141 ml, 0.99 mmol), and acetic acid (0.1 ml) were used to give 73.3 mg (0.20 mmol, 47.6% yield) of the title compound.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[S:25][C:24]([CH:26]=O)=[CH:23][C:9]=3[N:10]=[C:11]([C:13]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:14]=3[CH:15]=[CH:16][CH:17]=[N:18]4)[N:12]=2)[CH2:3][CH2:2]1.[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([CH2:26][C:24]2[S:25][C:8]3[C:7]([N:4]4[CH2:3][CH2:2][O:1][CH2:6][CH2:5]4)=[N:12][C:11]([C:13]4[CH:22]=[CH:21][CH:20]=[C:19]5[C:14]=4[CH:15]=[CH:16][CH:17]=[N:18]5)=[N:10][C:9]=3[CH:23]=2)[CH2:31][CH2:30]1
Reactant: CN1CCNCC1
Reactant: O=Cc1cc2nc(-c3cccc4ncccc34)nc(N3CCOCC3)c2s1
Product: CN1CCN(Cc2cc3nc(-c4cccc5ncccc45)nc(N4CCOCC4)c3s2)CC1

Procedure:
Following General Procedure L for reductive amination, 4-morpholino-2-(quinolin-5-yl)thieno[3,2-d]pyrimidine-6-carbaldehyde and 1-methylpiperazine were reacted to give 120. LCMS m/z: 461.6 (MH+)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:19])(/[CH:14]=[CH:15]\[CH2:16][C:17]#[N:18])[C:10]([O:12]C)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+:21]>O>[K+:21].[C:1]([O:5][C:6]([NH:8][C:9]([CH3:19])(/[CH:14]=[CH:15]\[CH2:16][C:17]#[N:18])[C:10]([O-:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C(C)(/C=C\CC#N)NC(=O)OC(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)OC(=O)NC(C)(/C=C\CC#N)C(=O)[O-]
Temperature: 50 °C
Reaction time: 3 h

Procedure:
The methyl (3Z)-2-[(tert-butoxycarbonyl)amino]-5-cyano-2-methylpent-3-enoate product of Example 1d is taken up in DI water. To this is added KOH and the reaction mixture is stirred at 50° C. for 3 h. It is then concentrated under reduced pressure to give the desired title product.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Mg].[C:16](OC(=O)C)(=[O:18])[CH3:17].[Cl-].[NH4+]>CCOCC>[C:9]1([CH2:8][CH2:7][O:6][CH2:5][CH2:4][CH2:3][CH2:2][C:16](=[O:18])[CH3:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: BrCCCCOCCc1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: CC(=O)CCCCOCCc1ccccc1
Temperature: 25 °C
Yield: 88 %

Procedure:
[2-(4-Bromobutoxy)ethyl]benzene (10.0 g) in dry ether (80 ml) was added dropwise to magnesium turnings (0.946 g) under nitrogen with stirring to give a gentle reflux. The reaction mixture was refluxed for 1 h, allowed to cool to room temperature and added dropwise to acetic anhydride (8.07 g) in dry ether (55 ml) at -70° under nitrogen with stirring over 1.5 h. The reaction mixtures was stirred at -70° for 2 h, allowed to warm to -10°, then treated with saturated ammonium chloride (100 ml). The organic layer was separated and the aqueous layer re-extracted with ER (150 ml). The combined organic extracts were washed with 2N aqueous sodium hydroxide (150 ml), brine (150 ml), dried and evaporated to give an oil (7.54 g) which was purified by FCC eluting with ER-CX (1:3) to give the title compound as a colourless oil (4.34 g). T.l.c. (ER-CX 1:3) Rf 0.25.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:25][CH2:26][CH2:27][CH3:28])=[C:8]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:15][C:13]=3[N:14]=2)[CH:9]=1)([O-])=O.[CH:29]1[C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]2[C:38]([O:40][C:41](=O)[C:31]=2[CH:30]=1)=[O:39]>>[CH2:26]([O:25][C:7]1[C:8]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:15][C:13]=3[N:14]=2)=[CH:9][C:4]([N:1]2[C:38](=[O:39])[C:32]3[C:31](=[CH:30][CH:29]=[C:34]([C:35]([OH:37])=[O:36])[CH:33]=3)[C:41]2=[O:40])=[CH:5][CH:6]=1)[CH2:27][CH3:28]
Reactant: CCCOc1ccc([N+](=O)[O-])cc1-c1nc2cc(-c3ccccc3)ccc2o1
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Product: CCCOc1ccc(N2C(=O)c3ccc(C(=O)O)cc3C2=O)cc1-c1nc2cc(-c3ccccc3)ccc2o1

Procedure:
Prepared by the method of Example 1b), from 2-(5-nitro-2-propoxyphenyl)-5-phenylbenzoxazole (125 mg, 0.36 mmol) and 1,2,4-benzenetricarboxylic anhydride (68 mg, 0.36 mmol) the title compound was obtained (37 mg, 21%). 1H NMR (DMSO) δ 8.47(d, 1H), 8.38(s, 1H), 8.25(d, 1H), 8.13(m, 2H), 7.89(d, 1H), 7.76(m, 4H), 7.49(m, 4H), 4.27(t, 2H), 1.92(m, 2H), 1.15(t, 3H). MS 519 m/z (M+H)+.
Reaction SMILES: ClC(Cl)(OC(=O)[O:6][C:7]([Cl:10])(Cl)Cl)Cl.[CH3:13][O:14][C:15]1[CH:35]=[CH:34][CH:33]=[CH:32][C:16]=1[CH2:17][NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Cl:10][C:7]([N:18]([CH2:17][C:16]1[CH:32]=[CH:33][CH:34]=[CH:35][C:15]=1[O:14][CH3:13])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:6]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1ccccc1CNc1ccccc1Oc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1CN(C(=O)Cl)c1ccccc1Oc1ccccc1
Yield: 267.5 %

Procedure:
To a solution of 775 mg of triphosgene in 14 ml of methylene chloride was added gradually dropwise a solution of 2.16 g of N-(2-methoxybenzyl)-2-phenoxyaniline and 1.10 g of diisopropylethylamine in 25 ml of methylene chloride with stirring, followed by stirring at room temperature for 15 minutes. The reaction mixture was concentrated under reduced pressure, poured into ethyl acetate, washed with 5% hydrochloric acid, a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, successively, and dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; ethyl acetate−hexane=1:15) to give 2.57 g of N-chlorocarbonyl-N-(2-methoxybenzyl)-2-phenoxyaniline.
Reaction SMILES: [CH2:1]1[C:5]2([CH2:10][CH2:9][C:8](=[O:11])[CH2:7][CH2:6]2)[CH2:4][CH2:3][NH:2]1.[C:12]([O-:15])([O-])=[O:13].[Na+].[Na+]>C1COCC1.O>[O:11]=[C:8]1[CH2:9][CH2:10][C:5]2([CH2:1][N:2]([C:12]([O:15][C:5]([CH3:6])([CH3:1])[CH3:4])=[O:13])[CH2:3][CH2:4]2)[CH2:6][CH2:7]1
Reactant: O=C1CCC2(CCNC2)CC1
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2(CCC(=O)CC2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 108.9 %

Procedure:
To a solution of 2-azaspiro[4.5]decan-8-one (10 g, 65.26 mmol) in a mixture of THF and H2O (3/1 (v/v), 200 mL) were added (Boc)20 (28.48 g, 130.53 mmol) and Na2CO3 (13.83 g, 130.53 mmol). The reaction mixture was stirred at rt for 2 h, then quenched with H2O (200 mL) and extracted with EtOAc (300 mL×3). The combined organic phases were washed with brine (500 mL), dried over Na2SO4, concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/PE (v/v)=1/10) to give the product as colorless oil (9 g, 54.5%).
Reaction SMILES: [Cl:1][C:2]1[C:16]([Cl:17])=[CH:15][C:5]2[NH:6][C:7]([C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1.Cl[CH2:19][CH2:20][OH:21].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Cl:17][C:16]1[C:2]([Cl:1])=[CH:3][C:4]2[NH:8][C:7]([C:9]3([C:10]([F:13])([F:11])[F:12])[O:21][CH2:20][CH2:19][O:14]3)=[N:6][C:5]=2[CH:15]=1
Reactant: O=C(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F
Reactant: OCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: FC(F)(F)C1(c2nc3cc(Cl)c(Cl)cc3[nH]2)OCCO1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1-(5,6-DiChloro-1H-benzoimidazol-2-yl)-2,2,2-trifluoro-ethanone (1.14 g; 4.02 mmol), 2-chloroethanol (0.83 mL; 12.4 mmol) and potassium carbonate (1.68 g; 12.2 mmol) were dissolved in DMF (18 mL). The reaction mixture was stirred for 18 hrs at ambient temperature, then diluted with ethyl acetate (80 mL), washed with water (50 mL) and brine (2×50 mL). The extracts were dried over Na2SO4, filtered, concentrated to a light brown solid and the light brown solid purified by column chromatography (SiO2; 30% ethyl acetate/hexanes) to yield the title compound as a tan solid.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].[O:26]1[CH2:30][CH2:29]OC1=O>O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:16]=[CH:17][CH:18]=1)[O:19][CH2:29][CH2:30][OH:26]
Reactant: O=C1OCCO1
Reactant: Oc1cccc(OCc2ccc3ccccc3n2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: OCCOc1cccc(OCc2ccc3ccccc3n2)c1
Yield: 81 %

Procedure:
3-(2-Quinolinyl-methoxy)phenol (12.5 g), potassium carbonate (10.4 g) and 1,3-dioxolan-2-one (44 g) were stirred on an oil bath at 100° C. for 2 hours. The mixture was cooled, poured into water and extracted with DCM. The organic layer was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 97/3). The pure fractions were collected and evaporated. The residue was stirred up in DIPE. The precipitate was filtered off and dried, yielding 11.9 g (80.6%) of 2-[3-(2-quinolinyl-methoxy)phenoxy]ethanol (intermediate 5).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]3[S:14](=[O:16])(=[O:15])[CH2:13][CH2:12][C:10]3=2)[N:5]=[CH:4][C:3]=1[C:17]#[N:18].[OH:19][C:20]1[CH:21]=[C:22]([CH:24]=[C:25]([O:27][CH3:28])[CH:26]=1)[NH2:23].O.[Cl-].[NH4+]>C(O)(C)C>[OH:19][C:20]1[CH:21]=[C:22]([NH:23][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]4[S:14](=[O:16])(=[O:15])[CH2:13][CH2:12][C:10]4=3)[N:5]=[CH:4][C:3]=2[C:17]#[N:18])[CH:24]=[C:25]([O:27][CH3:28])[CH:26]=1
Reactant: COc1cc(N)cc(O)c1
Reactant: N#Cc1cnc2ccc3c(c2c1Cl)CCS3(=O)=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CC(C)O
Product: COc1cc(O)cc(Nc2c(C#N)cnc3ccc4c(c23)CCS4(=O)=O)c1
Yield: 22.8 %

Procedure:
65 mg (0.23 mmol) of 9-chloro-1,2-dihydrothieno[3,2-f]quinoline-8-carbonitrile 3,3-dioxide are refluxed together with 39 mg (1.2 eq., 0.28 mmol) of 3-hydroxy-5-methoxyaniline in 2 ml of isopropanol for 2 hours. After the reaction is complete, the crude product is mixed with water and sat. ammonium chloride solution, extracted 3× with dichloromethane/methanol, washed 1× with sat. sodium chloride solution, dried over sodium sulphate and concentrated in vacuo. Final purification of the compound took place by chromatography. 20 mg (22%) of the desired product were obtained.
Reaction SMILES: [CH:1]1([O:7][CH2:8][C:9](=[O:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Na].[CH2:18](Br)[CH:19]=[CH2:20]>C(O)C>[CH:1]1([O:7][CH2:8][C:9]([CH:10]([CH2:20][CH:19]=[CH2:18])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)CC(=O)COC1CCCCC1
Reactant: C=CCBr
Agent: [Na]
Solvent: CCO
Product: C=CCC(C(=O)COC1CCCCC1)C(=O)OCC
Temperature: 50 °C
Reaction time: 2 h

Procedure:
320 g of ethyl 4-cyclohexyloxy-acetoacetate (1.4 mol) are initially introduced into a threenecked flask fitted with a stirrer, dropping funnel, drying tube and reflux condenser, and an Na ethanolate solution prepared from 32 g of sodium (1.4 mol) and 475 g of ethanol is added at 50° C. in the course of 30 minutes. 170 g of allyl bromide (1.4 mol) are then metered in at 50°-60° C. in the course of 30 minutes, while cooling. The mixture is subsequently stirred at 50° C. for 2 hours, the ethanol is then distilled off and the reaction mixture which remains is brought to pH=3 with hydrochloric acid. After the phases have been separated, the aqueous phase is extracted twice with 750 ml of toluene each time, the organic phases are combined and concentrated and the residue is distilled. Ethyl 2-(cyclohexyloxyacetyl)-4-pentenoate is obtained. (Temperature (bottom)=152°-179° C., temperature (top)=102°-127° C.; 1 mbar).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]3[CH:15]=[CH:14][NH:13][C:10]3=[N:11][CH:12]=2)[CH:2]=1.[CH2:16]([O:23][C:24]1[C:25]([F:33])=[C:26]([C:29]([F:32])=[CH:30][CH:31]=1)[CH:27]=[O:28])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[OH-].[K+].Cl>CO.O>[CH2:16]([O:23][C:24]1[C:25]([F:33])=[C:26]([CH:27]([C:15]2[C:9]3[C:10](=[N:11][CH:12]=[C:7]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)[CH:8]=3)[NH:13][CH:14]=2)[OH:28])[C:29]([F:32])=[CH:30][CH:31]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: c1cncc(-c2cnc3[nH]ccc3c2)c1
Reactant: O=Cc1c(F)ccc(OCc2ccccc2)c1F
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: OC(c1c(F)ccc(OCc2ccccc2)c1F)c1c[nH]c2ncc(-c3cccnc3)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine (20, 750.0 mg, 0.003842 mol, prepared as in Example 9) in methanol (20.0 mL) were added 3-benzyloxy-2,6-difluoro-benzaldehyde (27, 1.12 g, 4.5 mmol) and potassium hydroxide (1.50 g, 0.0267 mol) under an atmosphere of nitrogen. The reaction was stirred at room temperature overnight and then poured into water, acidified with 1N HCl to pH around 2 and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% ethyl acetate in hexane to give the compound (28, 700 mg, 35%).
Reaction SMILES: [CH:1](/[N:14]=[CH:15]/[C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:24]([N:37](C)C(=O)[C@@H](NC(NC1C=C(C(F)(F)F)C=C(C(F)(F)F)C=1)=S)C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>>[CH:1]([NH:14][C@@H:15]([C:24]#[N:37])[C:16]1[CH:17]=[CH:18][C:19]([C:20]#[N:21])=[CH:22][CH:23]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C(=O)[C@@H](NC(=S)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(C)(C)C)C(c1ccccc1)c1ccccc1
Reactant: N#Cc1ccc(/C=N/C(c2ccccc2)c2ccccc2)cc1
Product: N#Cc1ccc([C@H](C#N)NC(c2ccccc2)c2ccccc2)cc1
Reaction time: 20 h
Yield: 96 %

Procedure:
The reaction was run at 0° C. for 20 h with stirring using (E)-4-((benzhydrylimino)methyl)benzonitrile (296 mg, 1.0 mmol, 1.0 equiv) and 10 mol % of (S)—N-benzhydryl-2-(3-(3,5-bis(trifluoromethyl)phenyl)thioureido)-N,3,3-trimethyl butanamide (4e). The product was subjected to purification by flash column chromatography (9:1, hexanes:Et2O) to afford (R)-4-((benzhydrylamino) (cyano)methyl)benzonitrile (310 mg, 0.96 mmol, 96% yield) as a white solid. The enantiomeric excess was determined to be 93% by chiral HPLC analysis (OD-H, 5.0% IPA in hexanes, 1.0 mL/min, 230 nm, tR(major)=41.1 min, tR(minor)=56.4 min); [α]D24=+27.3° (c=1.0, CHCl3). 1H NMR (500 MHz, CDCl3): δ 7.72 (4H, s), 7.57 (2H, d, J=7.5 Hz), 7.45 (2H, d, J=7.5 Hz), 7.39 (2H, t, J=7.8 Hz), 7.29-7.34 (3H, m), 7.23-7.27 (1H, m), 5.25 (1H, s), 4.67 (1H, br s), 2.25 (1H, br s). 13C {1H} NMR (125 MHz, CDCl3): δ 142.2, 140.5, 139.7, 132.7, 129.1, 128.8, 128.2, 128.0, 127.9, 127.4, 127.0, 118.1, 117.7, 113.1, 65.7, 52.0. IR (cm−1): 3310 (m), 3296 (m), 3025 (w), 2925 (w), 2845 (w), 2232 (m), 1609 (w), 1492 (m), 1453 (m), 1349 (m), 1189 (m), 925 (m), 746 (s), 703 (s).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:29]C)[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([N:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:16][C:15]3=[O:28])=[CH:11][CH:12]=2)[CH:7]=[N:6]1.Cl.O>C1COCC1>[OH:29][CH:3]([O:2][CH3:1])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([N:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:16][C:15]3=[O:28])=[CH:11][CH:12]=2)[CH:7]=[N:6]1
Reactant: COC(Cn1ncc2cc(-n3ccc(CCc4ccccc4)cc3=O)ccc21)OC
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: COC(O)Cn1ncc2cc(-n3ccc(CCc4ccccc4)cc3=O)ccc21
Yield: 100.6 %

Procedure:
A solution of 1-(1-(2,2-dimethoxyethyl)-1H-indazol-5-yl)-4-phenethylpyridin-2(1H)-one (1.77 g, 4.39 mmol) in THF (20 mL) was treated with aqueous HCl (20 mL, 2.0 M). The solution was heated at 60° for 18 h, allowed to cool and then treated with H2O (50 mL). The mixture was extracted with EtOAc (3×100 mL), dried with Na2SO4, filtered and concentrated to give the title compound (1.72 g, 98%) as an orange solid: ESI MS m/z 390 [M+H]+.
Reaction SMILES: O[Li].O.[C:4]([O:8][C:9](=[O:36])[CH2:10][CH2:11][CH2:12][CH2:13][C:14]1[N:15]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[C:16](=[O:28])[C:17]2[C:22]([CH:23]=1)=[CH:21][C:20]([C:24]([O:26]C)=[O:25])=[CH:19][CH:18]=2)([CH3:7])([CH3:6])[CH3:5]>CO.O1CCCC1.O.C(OCC)C>[C:4]([O:8][C:9](=[O:36])[CH2:10][CH2:11][CH2:12][CH2:13][C:14]1[N:15]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[C:16](=[O:28])[C:17]2[C:22]([CH:23]=1)=[CH:21][C:20]([C:24]([OH:26])=[O:25])=[CH:19][CH:18]=2)([CH3:7])([CH3:5])[CH3:6]
Reactant: COC(=O)c1ccc2c(=O)n(-c3ccc(F)cc3)c(CCCCC(=O)OC(C)(C)C)cc2c1
Agent: [Li]O
Solvent: CCOCC
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)CCCCc1cc2cc(C(=O)O)ccc2c(=O)n1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96 %

Procedure:
LiOH.H2O (0.229 g, 5.47 mmol) was added to a stirred, room temperature mixture of methyl 3-(5-(tert-butoxy)-5-oxopentyl)-2-(4-fluorophenyl)-1-oxo-1,2-dihydroisoquinoline-6-carboxylate (1.24 g, 2.73 mmol) in MeOH (5 mL), tetrahydrofuran (5.00 mL) and water (5.00 mL) and the mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with diethyl ether (10 mL), water (5 mL) was added, the aqueous layer was separated, acidified with hydrochloric acid (2 M) to pH 2-3, extracted with dichloromethane (2×30 mL), the combined organic was dried (MgSO4), filtered and concentrated to give 3-(5-(tert-butoxy)-5-oxopentyl)-2-(4-fluorophenyl)-1-oxo-1,2-dihydroisoquinoline-6-carboxylic acid (1.153 g, 2.62 mmol) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([NH:7][CH2:8][C:9]2[CH:19]=[CH:18][C:12]3[N:13]=[C:14]([S:16][CH3:17])[O:15][C:11]=3[CH:10]=2)=[C:5]([N+:22]([O-])=O)[CH:4]=1.CC(O)=O.CO>C(Cl)Cl.[Zn]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:22])[C:6]([NH:7][CH2:8][C:9]2[CH:19]=[CH:18][C:12]3[N:13]=[C:14]([S:16][CH3:17])[O:15][C:11]=3[CH:10]=2)=[CH:20][CH:21]=1
Reactant: COc1ccc(NCc2ccc3nc(SC)oc3c2)c([N+](=O)[O-])c1
Agent: [Zn]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc(NCc2ccc3nc(SC)oc3c2)c(N)c1
Reaction time: 2 h
Yield: 79 %

Procedure:
To a stirred solution of 4-methoxy-N-((2-(methylthio)benzo[d]oxazol-6-yl)methyl)-2-nitroaniline (1.07 g, 3.11 mmol), HOAc (3.7 mL) and MeOH (3.7 mL) in DCM (40 mL) at 0° C. was added zinc dust (2.02 g, 31.1 mmol) portionwise. After stirring for 2 h, the mixture was filtered. The filtrate was washed with aq NaHCO3 and brine, dried over Na2SO4 and concentrated under reduced pressure to give 4-methoxy-N1-((2-(methylthio)benzo[d]oxazol-6-yl)methyl)benzene-1,2-diamine (775 mg, 79.1%). 1H NMR (300 MHz, DMSO-d6) δ 7.60 (s, 1H), 7.55 (d, J=8.4 Hz, 1H), 7.35 (d, J=9.6 Hz, 1H), 6.26 (d, J=8.1 Hz, 1H), 6.21 (s, 1H), 5.97 (d, J=9.0 Hz, 2H), 4.74 (t, 1H), 4.68 (s, 1H), 4.31 (d, J=5.7 Hz, 1H), 3.55 (s, 3H), 2.74 (s, 3H). LCMS (ESI) m/z 316 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([N:14]([C:19]([C:21]2[N:25]([CH2:26][CH2:27][CH2:28][CH2:29][O:30][CH3:31])[C:24]3[C:32]([F:36])=[CH:33][CH:34]=[CH:35][C:23]=3[N:22]=2)=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:11][C@@H:10]([C:37](O)=[O:38])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH4+].[N:41]1(O)C2C=CC=CC=2N=N1.C(N(CC)CC)C.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[C:37]([C@@H:10]1[CH2:11][C@H:12]([N:14]([C:19]([C:21]2[N:25]([CH2:26][CH2:27][CH2:28][CH2:29][O:30][CH3:31])[C:24]3[C:32]([F:36])=[CH:33][CH:34]=[CH:35][C:23]=3[N:22]=2)=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:9]1)(=[O:38])[NH2:41]
Reactant: On1nnc2ccccc21
Reactant: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)O)CN(C(=O)OC(C)(C)C)C2)nc2cccc(F)c21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(N)=O)CN(C(=O)OC(C)(C)C)C2)nc2cccc(F)c21
Temperature: 50 °C
Reaction time: 1 h
Yield: 73.2 %

Procedure:
(3R,5S)-1-(tert-Butoxycarbonyl)-5-[{[7-fluoro-1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-3-carboxylic acid (360 mg), 1H-1,2,3-benzotriazol-1-ol ammonium salt (250 mg) and triethylamine (360 μl) were dissolved in DMF (10 ml), WSC.HCl (315 mg) was added, and the mixture was stirred at 50° C. for 1 hr. The reaction mixture was concentrated under reduced pressure, diluted with saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (3:7)-ethyl acetate-ethyl acetate-methanol (9:1) was concentrated under reduced pressure to give the object product (263 mg).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]([O:12][CH3:13])=[O:11])=[N:4][C:5](Br)=[C:6]([F:8])[CH:7]=1.[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=1B(O)O>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[NH2:1][C:2]1[C:3]([C:10]([O:12][CH3:13])=[O:11])=[N:4][C:5]([C:16]2[C:15]([F:14])=[CH:20][CH:19]=[CH:18][C:17]=2[F:21])=[C:6]([F:8])[CH:7]=1
Reactant: OB(O)c1c(F)cccc1F
Reactant: COC(=O)c1nc(Br)c(F)cc1N
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1nc(-c2c(F)cccc2F)c(F)cc1N
Yield: 94 %

Procedure:
Method 1 was followed using methyl 3-amino-6-bromo-5-fluoropicolinate (1.0 equiv.) and 2,6-difluorophenylboronic acid (1.3 equiv.) and Pd(dppf)Cl2-DCM (0.05 equiv.) to give methyl 3-amino-6-(2,6-difluorophenyl)-5-fluoropicolinate in 94% yield. LCMS (m/z): 283.0 (MH+), Rt=0.76 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[C:13]([C:15]([N:17]2[CH2:22][CH2:21][C:20]3([O:27][C:26]4[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=4[N:24]4[CH:32]=[CH:33][CH:34]=[C:23]34)[CH2:19][CH2:18]2)=[O:16])[CH:12]=[CH:11][C:4]=1[O:5][CH2:6][C:7]([O:9]C)=[O:8].[Li+].[OH-]>C1COCC1>[CH3:1][O:2][C:3]1[CH:14]=[C:13]([C:15]([N:17]2[CH2:18][CH2:19][C:20]3([O:27][C:26]4[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=4[N:24]4[CH:32]=[CH:33][CH:34]=[C:23]34)[CH2:21][CH2:22]2)=[O:16])[CH:12]=[CH:11][C:4]=1[O:5][CH2:6][C:7]([OH:9])=[O:8]
Reactant: COC(=O)COc1ccc(C(=O)N2CCC3(CC2)Oc2ccccc2-n2cccc23)cc1OC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc(C(=O)N2CCC3(CC2)Oc2ccccc2-n2cccc23)ccc1OCC(=O)O
Temperature: 25 °C
Reaction time: 19 h

Procedure:
To a solution of methyl 2-(2-methoxy-4-(spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-ylcarbonyl)phenoxy)acetate (140 mg, 0.303 mmol) in THF (4 mL) was added LiOH (600 μL of 2.0 M, 1.2 mmol) and the mixture was stirred at room temperature for 19 h. The mixture was filtered and was purified by HPLC using 5 mM HCl/water and MeOH to yield 2-(2-methoxy-4-(spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-ylcarbonyl)phenoxy)acetic acid. ESI-MS m/z calc. 448.2. found 449.3 (M+1)+; Retention time: 5.90 minutes (15 min run).