Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[N:14]([CH3:15])[N:13]=[C:12]([C:16]3[CH:17]=[C:18]([CH:22]([NH2:24])[CH3:23])[CH:19]=[CH:20][CH:21]=3)[CH:11]=2)=[CH:4][CH:3]=1.[F:25][C:26]([F:34])([F:33])[CH2:27][NH:28][S:29](Cl)(=[O:31])=[O:30].CCN(CC)CC>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]2[N:14]([CH3:15])[N:13]=[C:12]([C:16]3[CH:17]=[C:18]([CH:22]([NH:24][S:29]([NH:28][CH2:27][C:26]([F:34])([F:33])[F:25])(=[O:31])=[O:30])[CH3:23])[CH:19]=[CH:20][CH:21]=3)[CH:11]=2)=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)NCC(F)(F)F
Reactant: CC(N)c1cccc(-c2cc(CCc3ccc(F)cc3)n(C)n2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(NS(=O)(=O)NCC(F)(F)F)c1cccc(-c2cc(CCc3ccc(F)cc3)n(C)n2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
This amine was dissolved in CH2Cl2 (5 mL) and treated with 2,2,2-trifluoroethylsulfamoyl chloride (91 mg, 0.45 mmol) and Et3N (63 μL, 0.45 mmol) and stirred at RT for 30 min. The solvent was evaporated under reduced pressure and the residue purified by silica chromatography eluting with 2% MeOH/CH2Cl2 to yield the title sulfamide as a colourless gum (18 mg, 23% over 2 steps). 1H NMR (CDCl3, 500 MHz) δ 7.80-7.76 (1H, s), 7.65 (1H, d, J=7.8 Hz), 7.38 (1H, t, J=7.8 Hz), 7.23 (1H, d, J=7.8 Hz), 7.18-7.10 (2H, m), 6.98 (2H, t, J=8.7 Hz), 6.35 (1H, s), 4.66-4.56 (2H, m), 4.38-4.28 (1H, m), 3.69 (3H, s), 3.53-3.42 (1H, m), 3.42-3.30 (1H, m), 3.02-2.84 (4H, m), 1.62-1.52 (3H, m). MS (ES+) C22H24F4N4O2S requires: 484, found: 485 (M+H+).
Reaction SMILES: [CH2:1]([O:8][NH:9][C@H:10]1[CH2:15][N:14](C(OC(C)(C)C)=O)[C@H:13]([C:23](=[O:25])[NH2:24])[CH:12]=[C:11]1[CH2:26][CH2:27][N+:28]([O-:30])=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(ON([C@H]1CN[C@H](C(N)=O)C=C1C)S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O)C=C>>[CH2:1]([O:8][NH:9][C@H:10]1[CH2:15][NH:14][C@H:13]([C:23]([NH2:24])=[O:25])[CH:12]=[C:11]1[CH2:26][CH2:27][N+:28]([O-:30])=[O:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](NOCc2ccccc2)C(CC[N+](=O)[O-])=C[C@H]1C(N)=O
Agent: C=CCON([C@H]1CN[C@H](C(N)=O)C=C1C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Product: NC(=O)[C@@H]1C=C(CC[N+](=O)[O-])[C@@H](NOCc2ccccc2)CN1

Procedure:
The title compound was prepared from (2S,5R)-tert-butyl 5-(benzyloxyamino)-2-carbamoyl-4-(2-nitroethyl)-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 224, 0.800 g, 3.30 mmol) according to the procedure described for Intermediate 21. The desired product was obtained as a yellow oil (0.6 g, 98%).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][C:13]=2[O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:25]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[N:24][N:23]=3)=[CH:17][CH:16]=2)[CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:44][NH2:45]>C1COCC1>[CH3:44][NH:45][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][C:13]=2[O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:25]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[N:24][N:23]=3)=[CH:17][CH:16]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CN
Reactant: Fc1cc(-c2cnccc2Oc2ccc(Nc3nnc(-c4ccccc4)c4ccccc34)cc2)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CNc1cc(-c2cnccc2Oc2ccc(Nc3nnc(-c4ccccc4)c4ccccc34)cc2)ccn1
Temperature: 0 °C

Procedure:
A high pressure steel bomb was charged with N-(4-(3-(2-fluoropyridin-4-yl)pyridin-4-yloxy)phenyl)-4-phenylphthalazin-1-amine (0.115 g, 0.237 mmol), potassium carbonate (0.049 g, 0.355 mol) and 3.0 mL of THF. The bomb was sealed, cooled to 0° C. and pressurized with methylamine gas. The reaction mixture was allowed to warm to RT, and heated at 80° C. for 45 h. Upon cooling, the reaction mixture was filtered through a fritted funnel, washed with MeOH, and concentrated. This mixture was purified by silica gel chromatography, (ISCO, 40 g column 0-10% MeOH/dichloromethane) to provide N-(4-(3-(2-(methylamino)pyridin-4-yl)pyridin-4-yloxy)phenyl)-4-phenylphthalazin-1-amine as a light yellow solid. MS m/z=497 [M+H]+. Calc'd for C31H24N6O: 496.56.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:6]([O:13][N:14]1[C:19](=[O:20])[C:18]2[CH:21]=[C:22]([F:26])[C:23](Cl)=[N:24][C:17]=2[N:16]([C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)[C:15]1=[O:34])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>C(#N)C>[CH2:6]([O:13][N:14]1[C:19](=[O:20])[C:18]2[CH:21]=[C:22]([F:26])[C:23]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[N:24][C:17]=2[N:16]([C:27]2[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=2)[C:15]1=[O:34])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Cc1ccc(-n2c(=O)n(OCc3ccccc3)c(=O)c3cc(F)c(Cl)nc32)cc1
Reactant: C1CCNC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1ccc(-n2c(=O)n(OCc3ccccc3)c(=O)c3cc(F)c(N4CCCC4)nc32)cc1
Yield: 90.7 %

Procedure:
Using the method of Example N-4, pyrrolidine (0.04 mL, 0.52 mmol), 3-benzyloxy-7-chloro-6-fluoro-1-(4-methylphenyl)-1H-pyrido[2,3-d]pyrimidine-2,4-dione (Example T-2, 0.17 g, 0.42 mmol) and triethylamine (0.36 mL, 2.6 mmol) were combined in 20 mL of acetonitrile to give 0.17 g of the title compound as a solid, mp 192-194° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[OH:9][C:10]([CH3:17])([CH3:16])/[CH:11]=[CH:12]/B(O)O>C1COCC1.C([O-])(O)=O.[Na+]>[Cl:1][C:2]1[N:3]=[N:4][C:5](/[CH:12]=[CH:11]/[C:10]([CH3:17])([OH:9])[CH3:16])=[CH:6][CH:7]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: CC(C)(O)/C=C/B(O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(O)/C=C/c1ccc(Cl)nn1
Temperature: 85 °C

Procedure:
To a solution of 3,6-dichloropyridazine (250 mg, 1.68 mmol) and [(1E)-3-hydroxy-3-methylbut-1-en-1-yl]boronic acid (218 mg, 1.68 mmol) in THF (5 mL) and 2.0 M NaHCO3 (1.70 mL) was added palladium tetrakis triphenylphosphine (97 mg, 0.084 mmol). The solution was degassed with nitrogen and heated to 85° C. overnight. The residue was worked up with EtOAc and water, dried with MgSO4, filtered, and concentrated. Column chromatography on silica gel 100% Hex to 100% EtOAc provided the title compound.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][O:17][C:18](=[O:27])[CH2:19][C:20]1[CH:25]=[CH:24][C:23](O)=[CH:22][CH:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:16][O:17][C:18](=[O:27])[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:15][CH2:14][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:24][CH:25]=1
Reactant: COC(=O)Cc1ccc(O)cc1
Reactant: OCc1ccccc1Oc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc(OCc2ccccc2Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (2-phenoxyphenyl)methanol (1.43 g) in tetrahydrofuran (25 ml), 1.19 g of methyl(4-hydroxyphenyl)acetate, 2.82 g of triphenylphosphine, and 4.86 ml of diethyl azodicarboxylate (45% toluene solution) were added, and the reaction solution was stirred at room temperature for 30 minutes. The reaction solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (eluent: ethyl acetate/hexane (5:95-30:70)) to afford the title compound as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.[C:17]([C:19]1[CH:20]=[C:21]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH:22]=[CH:23][CH:24]=1)#[CH:18].C(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C.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>[N:11]1([C:3]2[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=2[C:18]#[C:17][C:19]2[CH:20]=[C:21]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])[CH:22]=[CH:23][CH:24]=2)[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: O=[N+]([O-])c1ccc(N2CCOCC2)c(Br)c1
Reactant: C#Cc1cccc(NC(=O)OC(C)(C)C)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)Nc1cccc(C#Cc2cc([N+](=O)[O-])ccc2N2CCOCC2)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 70 %

Procedure:
A solution of 4-(2-bromo-4-nitrophenyl)morpholine (0.27 g, 0.95 mmol), tert-butyl (3-ethynylphenyl)carbamate, and bis(triphenylphosphine)palladium(II) chloride (67 mg, 95 μmol) in N,N-dimethylformamide (4.4 mL) was treated with N,N-diisopropylethylamine (0.21 mL, 1.2 mmol) and stirred at 80° C. for 16 h. The reaction mixture was diluted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, filtered, and evaporated to give a crude residue. This material was purified by flash column chromatography to give the desired product (0.28 g, 70%) as a solid. LCMS for C23H26N3O5 (M+H)+: m/z=424.0.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH:7]=O)=[CH:4][CH:3]=1.[NH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.C([Sn](Cl)(Cl)CCCC)CCC.C1([SiH3])C=CC=CC=1>C1COCC1>[Br:1][C:2]1[S:6][C:5]([CH2:7][N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)s1
Reactant: C1CCNCC1
Agent: CCCC[Sn](Cl)(Cl)CCCC
Agent: [SiH3]c1ccccc1
Solvent: C1CCOC1
Product: Brc1ccc(CN2CCCCC2)s1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
5-Bromo-2-thiophenecarboxaldehyde (10 mmol) and piperidine (10 mmol) were mixed in THF (10 mL) and dibutyltin dichloride (0.2 mmol) was added. After stirring at RT for 5 minutes, phenylsilane (11 mmol) was added and the reaction allowed to stir at room temperature for a further 17 h. The reaction was then concentrated in vacuo and the residue purified by flash chromatography (silica gel, DCM) to give 1-(5-bromo-thiophen-2-ylmethyl)-piperidine: m/z=260, 262 in MS ES+ as a golden oil which was used directly in the subsequent step. A reaction tube containing a magnetic stirrer bar was charged with 4-carboxyphenylboronic acid (0.05 mmol), the thiophene bromide (0.05 mmol), Pd(PPh3)4 (0.025 mmol), acetonitrile (2 mL) and 1M Na2CO3 (aq) (2 mL). The reaction tube was then sealed and heated by microwave irradiation (100 W, 4 mins) to 150° C. and held at that temperature for 10 mins. After being allowed to cool to room temperature the reaction were acidified to pH 1 with 1M HCl and the resulting precipitate filtered off. This crude product was then passed through a silica plug to remove any inorganic species and concentrated to give a the title compound as a brown powder m/z=304 in MS ES+, which was characterised by hplc and MS and used in the next step without any further purification.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:8]=[CH:7][NH:6][N:5]=1.[H][H].[Cl:11][C:12]1[C:17]([C:18]([N:20]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[CH2:24][N:23]3[CH:31]=[CH:32][CH:33]=[C:22]3[CH2:21]2)=[O:19])=[CH:16][CH:15]=[C:14](Cl)[N:13]=1>CN(C)C=O.[Cl-].[Na+].O>[Cl:11][C:12]1[C:17]([C:18]([N:20]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[CH2:24][N:23]3[CH:31]=[CH:32][CH:33]=[C:22]3[CH2:21]2)=[O:19])=[CH:16][CH:15]=[C:14]([N:6]2[CH:7]=[CH:8][C:4]([CH3:3])=[N:5]2)[N:13]=1
Reactant: Cc1cc[nH]n1
Reactant: O=C(c1ccc(Cl)nc1Cl)N1Cc2cccn2Cc2ccccc21
Reactant: [H][H]
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccn(-c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)c(Cl)n2)n1
Temperature: 110 °C
Yield: 28.5 %

Procedure:
To a suspension of 60% sodium hydride in oil (0.1 g) in dimethylformamide (25 ml) was added dropwise 3-methylpyrazole (0.15 g). After hydrogen gas evolution ceased, (2,6-dichloropyridin-3-yl)(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone (0.67 g) was added and the reaction mixture was heated in a sand bath at 110° C.) for 18 hours. The mixture was poured onto ice, diluted with brine, and extracted with dichloromethane. The combined extracts were dried over anhydrous sodium sulfate and filtered through a short column of anhydrous sodium magnesium silicate. The crude product was purified by preparative hplc (Dynamax c60 silica cartridge) eluting with 40% ethyl acetate in hexanes to give 0.21 g of colorless crystals, m.p. 171-172° C. MS, m/z: 404.2 (M+H)+, 807.1 (2M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]([CH:8]=[CH:9][C:10]([OH:12])=[O:11])=[C:6]([F:15])[CH:5]=1)([O-])=O.C(O)C.[H][H]>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:14]=[CH:13][C:7]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[C:6]([F:15])[CH:5]=1
Reactant: O=C(O)C=Cc1ccc([N+](=O)[O-])cc1F
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1ccc(CCC(=O)O)c(F)c1
Reaction time: 3 h
Yield: 81.2 %

Procedure:
4-nitro-2-fluorocinnamic acid (3.32 g, 17 mmol) was dissolved in ethyl acetate (50 mL) and ethanol (10 mL) in the reaction flask of a PAR reactor. Pd/C (100 mg) was added and the reactor charged with 100 psi hydrogen. The reactor was recharged to 100 psi after 3 hours and the reaction stirred overnight. The reaction mixture was filtered through a bed of celite and the product isolated in vacuo, 2.53 g 3-(4-amino-2-fluorophenyl)propionic acid (81.2%).
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]([OH:12])[C:8](=[CH:10][CH:11]=1)[OH:9])[CH:2]([CH3:4])[CH3:3].[CH3:13][C:14]([CH3:16])=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([C:5]1[CH:11]=[CH:10][C:8]2[O:9][C:14]([CH3:16])([CH3:13])[O:12][C:7]=2[CH:6]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cc1ccc(O)c(O)c1
Reactant: CC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)Cc1ccc2c(c1)OC(C)(C)O2

Procedure:
The same procedures as described in Example 10 were carried out by using 4.16 g (25 mM) of 4-isobutylcatechol, 15 ml of acetone, 30 mg of p-toluenesulfonic acid monohydrate and 15 ml of toluene. 5-Isobutyl-2,2-dimethyl-1,3-benzodioxol was obtained in the yield of 4.69 g (23 mM) as colorless transparent liquid having a boiling point of 79°-83° C./2 mmHg.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:18][CH2:19][O:20][C:21]3[CH:22]=[CH:23][C:24]4[C:28]([CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])=[CH:27][S:26][C:25]=4[CH:36]=3)[N:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1COCC1.[OH-].[Na+]>O>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:18][CH2:19][O:20][C:21]3[CH:22]=[CH:23][C:24]4[C:28]([CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[CH:27][S:26][C:25]=4[CH:36]=3)[N:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CCc1csc2cc(OCCc3ccc4c(n3)N(C(=O)OC(C)(C)C)CCC4)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCc2ccc(CCOc3ccc4c(CCC(=O)O)csc4c3)nc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.1 %

Procedure:
7-{2-[3-(2-Ethoxycarbonyl-ethyl)-benzo[b]thiophen-6-yloxy]-ethyl}-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester (338 mg, 0.66 mmol) was dissolved THF (5ml). Then a solution of sodium hydroxide (132 mg, 3.30 mmol) in water (1 ml) was added. The reaction was stirred at room temperature for 16 hours. After that period, the solvent was evaporated under vacuum and the crude was extracted with ethyl acetate and hydrochloric acid (1M). The organic layer was collected, dried with anhydrous sodium sulfated, filtrated and evaporated under vacuum to yield 268 mg (84%) of 7-{2-[3-(2-Carboxy-ethyl)-benzo[b]thiophen-6-yloxy]-ethyl}-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester. NMR 1H Cl3CD δ: 7.59 (d, 1H, J=8.8 Hz), 7.47 (d, 1H, J=7.7 Hz), 7.35 (d, 1H, J=2.3 Hz), 7.05 (d, 1H, J=7.6 Hz), 7.01 (s, 1H), 6.96 (dd, 1H, J=2.3, 8.8 Hz), 4.35 (t, 2H, J=6.5 Hz), 3.73 (m, 2H), 3.18 (m, 2H), 3.05 (m, 2H), 2.72 (m, 2H), 2.66 (m, 2H), 1.88 (m, 2H), 1.49 (s, 9H).
Reaction SMILES: C(OC([N:8]1[CH:17]([C:18](O)=[O:19])[CH2:16][C:15]2[CH:14]=[C:13]3[O:21][CH2:22][C@H:23]([C:25]4[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]5[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([Cl:40])[CH:34]=5)=[CH:27][CH:26]=4)[O:24][C:12]3=[CH:11][C:10]=2[CH2:9]1)=O)(C)(C)C.[CH3:41][O:42][C:43](=[O:59])[C@@H:44]([NH2:58])[CH2:45][C:46]1[CH:51]=[CH:50][C:49]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)=[CH:48][CH:47]=1>>[ClH:39].[CH3:41][O:42][C:43](=[O:59])[C@@H:44]([NH:58][C:18]([CH:17]1[CH2:16][C:15]2[CH:14]=[C:13]3[O:21][CH2:22][C@H:23]([C:25]4[CH:26]=[CH:27][C:28]([O:31][CH2:32][C:33]5[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([Cl:40])[CH:34]=5)=[CH:29][CH:30]=4)[O:24][C:12]3=[CH:11][C:10]=2[CH2:9][NH:8]1)=[O:19])[CH2:45][C:46]1[CH:51]=[CH:50][C:49]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)=[CH:48][CH:47]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1Cc2cc3c(cc2CC1C(=O)O)OC[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3
Product: COC(=O)[C@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Product: Cl
Yield: 112.5 %

Procedure:
(S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7,8-dicarboxylic acid 7-tert-butyl ester (59 mg) was coupled with (S)-2-amino-3-biphenyl-4-yl-propionic acid methyl ester (31 mg) according to General Procedure A. The resulting Boc-protected amine was treated as described in General Procedure C to give (S)-3-Biphenyl-4-yl-2-({(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino-[2,3-g]isoquinoline-8-carbonyl}-amino)-propionic acid methyl ester hydrochloride salt (43 mg).
Reaction SMILES: C([S:9][CH2:10][CH2:11][CH:12]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:13]([N:15]1[CH2:22][CH2:21][CH2:20][C@H:16]1[C:17]([OH:19])=[O:18])=[O:14])(=O)C1C=CC=CC=1.C(SCCCC(N1CCC[C@H]1C(O)=O)=O)(=O)C1C=CC=CC=1>>[SH:9][CH2:10][CH2:11][CH:12]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:13]([N:15]1[CH2:22][CH2:21][CH2:20][C@H:16]1[C:17]([OH:19])=[O:18])=[O:14]
Reactant: O=C(SCCC(Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O)c1ccccc1
Agent: O=C(SCCCC(=O)N1CCC[C@H]1C(=O)O)c1ccccc1
Product: O=C(O)[C@@H]1CCCN1C(=O)C(CCS)Cc1ccccc1

Procedure:
By substituting 1-(4-benzoylthio-2-benzylbutanoyl)-L-proline for the 1-(4-benzoylthiobutanoyl)-L-proline in the procedure of Example 45, 1-(4-mercapto-2-benzylbutanoyl)-L-proline is obtained.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH:9][C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[N:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[CH2:28][C:29]1[CH:50]=[CH:49][C:32]([CH2:33][O:34][C:35]2[CH:40]=[CH:39][C:38]([CH2:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])=[C:37]([F:48])[CH:36]=2)=[CH:31][CH:30]=1.Cl>CN(C)C=O>[F:48][C:37]1[CH:36]=[C:35]([O:34][CH2:33][C:32]2[CH:49]=[CH:50][C:29]([CH2:28][N:9]([CH2:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:10]3[S:11][CH:12]=[C:13]([C:15]4[CH:16]=[CH:17][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:19][CH:20]=4)[N:14]=3)=[CH:30][CH:31]=2)[CH:40]=[CH:39][C:38]=1[CH2:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44]
Reactant: FC(F)(F)c1ccc(-c2csc(NCCc3ccccc3)n2)cc1
Reactant: CCOC(=O)CCc1ccc(OCc2ccc(CCl)cc2)cc1F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1ccc(OCc2ccc(CN(CCc3ccccc3)c3nc(-c4ccc(C(F)(F)F)cc4)cs3)cc2)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-(2-phenylethyl)-4-[4-(trifluoromethyl)phenyl]-1,3-thiazole-2-amine (500 mg, 1.43 mmol) in N,N-dimethylformamide (5 mL) was added sodium hydride (50 mg, in oil, 1.3 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hr. Ethyl 3-(4-{[4-(chloromethyl)benzyl]oxy}-2-fluorophenyl)propanoate (350 mg, 1.0 mmol) was added, and the mixture was further stirred at room temperature for 2 hr. The reaction mixture was poured into 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:19-3:2 in volume ratio) to give the title compound as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=O)[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][CH2:18][C@H:17]([OH:21])[CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C([O-])(=O)C.[NH4+].C([BH3-])#[N:28].[Na+]>CO.C(#N)C>[NH2:28][CH:12]([C:10]1[C:9]([N:15]2[CH2:20][CH2:19][CH2:18][C@H:17]([OH:21])[CH2:16]2)=[C:8]2[C:3]([CH:4]=[CH:5][CH:6]=[N:7]2)=[C:2]([Cl:1])[CH:11]=1)[CH3:13]
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCC[C@H](O)C1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: CC(N)c1cc(Cl)c2cccnc2c1N1CCC[C@H](O)C1
Temperature: 65 °C

Procedure:
A mixture of 1-{5-chloro-8-[(3S)-3-hydroxypiperidin-1-yl]quinolin-7-yl}ethanone (18 mg, 0.059 mmol) and ammonium acetate (45.5 mg, 0.591 mmol) in methanol (0.33 mL) and acetonitrile (0.34 mL) was heated at 65° C. in a sealed tube for 30 minutes. After cooling to room temperature, sodium cyanoborohydride (7.42 mg, 0.118 mmol). The reaction was heated at 65° C. for another 4 hours, then cooled to room temperature and quenched with sat. sodium bicarbonate, extracted with dichloromethane. The combined extracts were dried over magnesium sulfate and evaporated to dryness. The crude amine was used directly in the next step. LCMS calculated for C16H21ClN3O (M+H)+: m/z=306.1; Found: 306.1.
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].ClOC(C)(C)C.ClNC1C(=CC=CC=1)C([O-])=O.[S:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>C(Cl)Cl.C(N(CC)CC)C>[NH2:4][C:3]1[C:5]([CH:30]2[CH2:31][CH2:32][CH2:33][S:29]2)=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1ccccc1N
Reactant: C1CCSC1
Agent: CC(C)(C)OCl
Agent: O=C([O-])c1ccccc1NCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc(C2CCCS2)c1N
Reaction time: 2 h

Procedure:
A solution of methyl anthranilate (75.5 g; 0.5 mole) in CH2Cl2 (1.0 l) is cooled to -70° and a solution of tert-butyl hypochlorite (54 g; 0.5 mole) in CH2Cl2 (150 ml) is added slowly keeping the temperature at -70°. The resultant N-chloroanthranilate solution is stirred for 1.0 hr and then tetrahydrothiophene (110 ml) is added at such a rate as to maintain the exotherm to less than 10°. The dark solution is stirred at -70° for 2.0 hr, triethylamine (125 ml) is added dropwise, and the solution is stirred for 24 hrs. The solvents are removed and the residue is diluted with CH2Cl2, washed with (1 N) NaOH solution, water and dried. Removal of solvents gives an oil. Unreacted methyl anthranilate is removed under reduced pressure (b.p. 95°-100°/0.35 mm) at bath temperature at 150°. The residue is dissolved in CH 2 Cl2 and partially chromatographed through silica gel. The solid residue is recrystallized from methanol. Yield 27.0 g; mp 75°-9°.
Reaction SMILES: C([O:3][C:4](=[O:19])[C:5]1[CH:10]=[CH:9][C:8]([P:11]([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][CH:6]=1)C.[OH-].[Li+]>CO.O>[CH2:17]([O:16][P:11]([C:8]1[CH:9]=[CH:10][C:5]([C:4]([OH:19])=[O:3])=[CH:6][CH:7]=1)([O:13][CH2:14][CH3:15])=[O:12])[CH3:18]
Reactant: CCOC(=O)c1ccc(P(=O)(OCC)OCC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCOP(=O)(OCC)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 4-(diethoxyphosphoryl)-benzoic acid ethyl ester (2b) (2.46 g, 8.59 mmol) in methanol (86 mL) was slowly added lithium hydroxide (monohydrate, 0.36 g, 8.59 mmol) in water (86 mL). The resulting reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated to remove methanol and diluted with brine, then extracted with EtOAc (3—100 mL) until the aqueous layer showed little or no evidence of product by HPLC. The combined organics were dried over Na2SO4 and concentrated on a rotary evaporator. The desired product was purified by crystallization from hexane/ethyl acetate (2.37 g), m.p. 101° C. 1H NMR (300 MHz, CDCl3) δ (ppm)): 1.27 (t, J=7.03 Hz, 6H), 4.03 (q, J=7.03 Hz, 4H), 7.85 (m, 2H), 8.09 (m, 2H), 12.65 (bs, 1H). 31P NMR (121 MHz, CDCl3) δ 21.611.