Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:8]([O:9][CH:10]([CH3:12])[CH3:11])=[CH:7][C:5]([NH2:6])=[C:4]([F:13])[CH:3]=1.C[Al](C)C.[NH:18]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:19]1[C:20](OCC)=[O:21].Cl>C(Cl)Cl.O>[Cl:1][C:2]1[C:8]([O:9][CH:10]([CH3:11])[CH3:12])=[CH:7][C:5]([NH:6][C:20]([CH:19]2[CH2:25][CH2:26][CH2:27][CH2:28][NH:18]2)=[O:21])=[C:4]([F:13])[CH:3]=1
Reactant: CC(C)Oc1cc(N)c(F)cc1Cl
Reactant: CCOC(=O)C1CCCCN1
Agent: C[Al](C)C
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CC(C)Oc1cc(NC(=O)C2CCCCN2)c(F)cc1Cl
Reaction time: 48 h

Procedure:
The product of Example 1, Step A (4.25 g, 26.37 mmol) was dissolved in CH2Cl2 (200 mL). A solution of 2.0M trimethylaluminum (52.75 mmol) was added dropwise under nitrogen at 0° C. The resultant mixture was stirred at room temperature overnight. Ethyl pipecolinate (4.15 g) was added dropwise to the mixture and the mixture was stirred for 2 days. To the reaction mixture 6N HCl (100 mL) was added dropwise at 0° C. 200 mL of H2O was added, followed by the addition of 150 mL of methylene chloride. The aqueous layer was separated and basicified to pH 10 with 50% aqueous NaOH. 500 mL of CH2Cl2 was added. The organic layer was separated, dried over MgSO4, filtered and evaporated to dryness under vacuum to give the title compound of Step A as a white solid, 4.7 g. m.p. 96°-98° C. 1H NMR (CDCl3): δ9.25 (br s,1H), 8.17 (d,1H), 7.13 (d,1H) 4.58 (m,1H), 3.20 (M,1H), 3.10 (m,1H), 2.79 (m,1H), 2.00 (m,1H), 1.89 (m,2H), 1.60-1.40 (m,4H), 1.36 (d,6H).
Reaction SMILES: Cl.[CH2:2]([S:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([NH2:9])=[NH:8])[CH3:3].[Na].C([O:17][CH:18]=[C:19]([C:25](OCC)=O)[C:20]([O:22][CH2:23][CH3:24])=[O:21])C.C(O)(=O)C>C(O)C>[O:17]=[C:18]1[NH:9][C:7]([C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[S:4][CH2:2][CH3:3])=[N:8][CH:25]=[C:19]1[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCSc1ccccc1C(=N)N
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: Cl
Agent: [Na]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)c1cnc(-c2ccccc2SCC)[nH]c1=O
Temperature: 0 °C
Yield: 67 %

Procedure:
2-Ethylthiobenzamidine hydrochloride (2.12 g., 10.0 mmoles) was added to a cooled (ice-water) solution of sodium (0.46 g., 20 mg.-atoms) in ethanol (12 ml.). To this mixture was added a solution of diethyl ethoxymethylenemalonate (2.16 g., 10.0 mmoles) in ethanol (4 ml.). The mixture was heated under reflux for 3.5 hours. The cooled mixture was poured into ice-water (400 ml.) and acidified to pH 6 with glacial acetic acid. The precipitate was collected and recrystallized from acetonitrile to give the title compound (2.04 g., 64.6%), m.p. 117°-120°.
Reaction SMILES: [C:1]([C:3]1[C:4]([NH:18][C:19](=[O:23])OCC)=[N:5][CH:6]=[C:7]([CH2:9][N:10]2[CH2:15][C@@H:14]([CH3:16])[O:13][C@@H:12]([CH3:17])[CH2:11]2)[CH:8]=1)#[N:2].[CH:24]([NH:26]N)=O.C([N:30](C(C)C)C(C)C)C>CC(N(C)C)=O>[CH3:17][C@H:12]1[CH2:11][N:10]([CH2:9][C:7]2[CH:6]=[N:5][C:4]3[NH:18][C:19](=[O:23])[N:2]4[N:30]=[CH:24][N:26]=[C:1]4[C:3]=3[CH:8]=2)[CH2:15][C@@H:14]([CH3:16])[O:13]1
Reactant: CCOC(=O)Nc1ncc(CN2C[C@@H](C)O[C@@H](C)C2)cc1C#N
Reactant: CCN(C(C)C)C(C)C
Reactant: NNC=O
Solvent: CC(=O)N(C)C
Product: C[C@@H]1CN(Cc2cnc3[nH]c(=O)n4ncnc4c3c2)C[C@H](C)O1
Temperature: 25 °C
Yield: 167.7 %

Procedure:
Ethyl 3-cyano-5-(((2S,6R)-2,6-dimethylmorpholino)methyl)pyridin-2-ylcarbamate (35 mg, 0.11 mmol), formyl hydrazine (8 mg, 0.13 mmol) and N-ethyl N-isopropylpropan-2-amine (0.01 mL, 0.055 mmol) were heated in DMA (1 mL) at 125° C. for 15 h. The reaction was cooled to room temperature and purified directly (HPLC, 10-70% ACN-water) to afford the title compound as a solid (29 mg, 84%). 1H NMR (400 MHz, DMSO-d6) δ 1.04 (d, J=6.15 Hz, 6H), 1.73 (t, J=10.67 Hz, 2H), 2.72 (d, J=10.79 Hz, 2H), 3.53-3.66 (m, 4H), 8.45 (s, 1H), 8.57 (s, 1H), 8.62 (s, 1H), 12.82 (br s, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](O)=O.C(=O)(O)O.[NH2:11][NH:12][C:13]([NH2:15])=[NH:14].[N+]([O-])(O)=O.[C:20](OC)(=[O:25])[CH2:21][C:22]([CH3:24])=O>C(O)(=O)C.O>[OH:25][C:20]1[N:12]2[N:11]=[C:4]([CH2:3][O:2][CH3:1])[N:15]=[C:13]2[N:14]=[C:22]([CH3:24])[CH:21]=1
Reactant: N=C(N)NN
Reactant: COCC(=O)O
Reactant: COC(=O)CC(C)=O
Agent: O=C(O)O
Solvent: CC(=O)O
Solvent: O
Solvent: O=[N+]([O-])O
Product: COCc1nc2nc(C)cc(O)n2n1
Reaction time: 4 h

Procedure:
A mixture of 90 g of methoxy acetic acid, 68 g of aminoguanidine bicarbonate, 40 ml of water and 0.5 ml of conc. nitric acid was stirred under reflux for 24 hours, and then condensed. To the resulting residue were added 250 ml of methyl acetoacetate and 5 ml of acetic acid and the mixture was stirred in a bath of 100 to 120° C. After 4 hours, the mixture was cooled by allowing to stand and crystals were collected by filtration, washed with isopropanol and dried to obtain 82 g of the title compound.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][OH:12])=[N:9][N:10]=2)[N:7]=1.[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[C:13]1([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([CH2:11][OH:12])=[N:9][N:10]=3)[N:7]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OCc1nnc2ccc(Cl)nn12
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: OCc1nnc2ccc(-c3ccccc3)nn12
Temperature: 85 °C

Procedure:
A suspension of (6-chloro[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methanol (0.289 mmol, 1 eq), phenylboronic acid (0.665 mmol, 2.3 eq), Pd(PPh3)4 (45.9 mg, 0.0405 mmol, 14 mol %), and K2CO3 (132 mg, 0.955 mmol, 3.3 eq) in a 4:1 ratio of dioxane (4 mL) to H2O (1 mL) was evacuated and charged with nitrogen several times. The reaction sample was then heated conventionally at 85° C. for 1 h. CH2Cl2 and H2O were added and a standard aqueous workup was performed. The crude material was purified by pTLC [Silicycle, 1000 μM, 20×20 plate], which required two developments in a 3% MeOH in EtOAc solvent system. 1H NMR (400 MHz, CDCl3): δ=1.69 (br s, 1H), 5.35 (s, 2H), 7.56-7.60 (m, 3H), 7.64 (d, J=9.6 Hz, 1H), 7.97-8.02 (m, 2H), 8.22 (d, J=9.6 Hz, 1H). MS (ES+): m/z 227.08 (100) [MH+]. HPLC: tR=2.42 min (ZQ3, polar—5 min).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:16]=[C:15]([C:17](=O)[CH3:18])[O:14][N:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH3:20][C:21]1[N:22]=[C:23]([C:29]2S[CH:31]=[CH:32][CH:33]=2)S[C:25]=1[C:26](=O)[CH3:27].[NH3:34]>>[Cl:1][C:2]1[C:3]([C:12]2[CH:16]=[C:15]([C:17]3[CH:18]=[CH:8][C:6]4[C:5](=[CH:31][CH:32]=[C:33]([CH2:29][CH2:23][N:22]5[CH2:27][CH2:26][CH2:25][C@H:21]5[CH3:20])[CH:7]=4)[N:34]=3)[O:14][N:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: N
Reactant: CC(=O)c1sc(-c2cccs2)nc1C
Reactant: CC(=O)c1cc(-c2ncc(C(F)(F)F)cc2Cl)no1
Product: C[C@@H]1CCCN1CCc1ccc2nc(-c3cc(-c4ncc(C(F)(F)F)cc4Cl)no3)ccc2c1

Procedure:
The title compound was prepared using the procedure described in Example 1G using 1-[3-(3-chloro-5-trifluoromethyl-pyridin-2-yl)-isoxazol-5-yl]-ethanone (Key Organics Limited/Bionet Research, catalog number 10G-001) for 1-(4-methyl-2-thiophen-2-yl-thiazol-5-yl)-ethanone. 1H NMR (300 MHz, CDCl3) δ 1.13 (d, J=6.10 Hz, 3H), 1.46 (m, 1H), 1.79 (m, 2H), 1.95 (m, 1H), 2.25 (q, J=8.59 Hz, 1H), 2.40 (m, 2H), 3.04 (m, 2H), 3.15 (m, 1H), 3.29 (td, J=8.56, 2.88 Hz, 1H), 7.69 (m, 3H), 8.10 (m, 3H), 8.27 (d, J=8.48 Hz, 1H), 8.93 (d, J=2.03 Hz, 1H); MS (DCI-NH3) [M+H]+ at 487.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:18]2[CH:17]=[C:16]([CH2:19][OH:20])[CH:15]=[CH:14][C:13]=2[C:12]2[N:21](COCC[Si](C)(C)C)[N:22]=[C:23]([NH:24][CH:25]3[CH2:30][CH2:29][N:28]([S:31]([CH3:34])(=[O:33])=[O:32])[CH2:27][CH2:26]3)[C:11]=2[N:10]=1.C(O)(C(F)(F)F)=O.N>C(Cl)Cl.O>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:9]1[C:18]2[CH:17]=[C:16]([CH2:19][OH:20])[CH:15]=[CH:14][C:13]=2[C:12]2[NH:21][N:22]=[C:23]([NH:24][CH:25]3[CH2:30][CH2:29][N:28]([S:31]([CH3:34])(=[O:32])=[O:33])[CH2:27][CH2:26]3)[C:11]=2[N:10]=1
Reactant: C[Si](C)(C)CCOCn1nc(NC2CCN(S(C)(=O)=O)CC2)c2nc(-c3c(F)cccc3F)c3cc(CO)ccc3c21
Agent: N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)N1CCC(Nc2n[nH]c3c2nc(-c2c(F)cccc2F)c2cc(CO)ccc23)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 35.8 %

Procedure:
A 30 ml round-bottomed flask equipped with a magnetic stirrer and with a septum having a top-mounted argon intake is charged with 46 mg of [5-(2,6-difluorophenyl)-3-{[1-(methylsulphonyl)piperidin-4-yl]amino}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]isoquinolin-7-yl]methanol in 4 ml of DCM. After cooling to 0° C. using an ice bath, 0.45 ml of TFA are added and the mixture is stirred at RT for 2 h. It is concentrated under RP and the solid obtained is taken up in 25 ml of water and 0.75 ml of a 0.75M aqueous ammonia solution. It is extracted with AcOEt, washed with saturated NaCl solution, dried over MgSO4, filtered and concentrated under RP. Chromatography on silica gel (20-45 μm), eluting with a mixture of DCM and methanol (92.5/7.5 by vol.), gives 13 mg of [5-(2,6-difluorophenyl)-3-{[1-(methylsulphonyl)piperidin-4-yl]amino}-1H-pyrazolo[4,3-c]isoquinolin-7-yl]methanol (yellow solid). MS (E/I): m/z=487 (M+); 1H NMR: 1.67 (m, 2H); 2.11 (m, 2H); 2.87 (s, 3H); 2.90 (m, 2H); 3.56 (m, 2H); 3.79 (m, 1H); 4.63 (d,. J=57 Hz, 2H); 5.34 (t, J=5.7 Hz, 1H); 5.98 (d, J=7.8 Hz, 1H); 7.31 (m, 2H); 7.59 (broad s, 1H); 7.66 (m, 1H); 7.83 (broad d, J=8.3 Hz, 1H); 8.35 (d, J=8.3, 1H); 12.68 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])=[CH:4][CH:3]=1.[CH3:17][C:18]1[C:22]([CH2:23][CH2:24][C:25](O)=[O:26])=[C:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:20][N:19]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[CH2:12]([O:11][P:7]([CH2:6][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:25](=[O:26])[CH2:24][CH2:23][C:22]2[C:18]([CH3:17])=[N:19][O:20][C:21]=2[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[CH:16][CH:15]=1)([O:8][CH2:9][CH3:10])=[O:14])[CH3:13]
Reactant: Cc1noc(-c2ccccc2)c1CCC(=O)O
Reactant: CCOP(=O)(Cc1ccc(N)cc1)OCC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CCOP(=O)(Cc1ccc(NC(=O)CCc2c(C)noc2-c2ccccc2)cc1)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.1 %

Procedure:
A mixture of diethyl 4-aminobenzylphosphonate (0.58 g), 3-(3-methyl-5-phenyl-4-isoxazolyl)propionic acid (0.50 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.37 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.46 g) and N,N-dimethylformamide (15 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate and then saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and N-(4-diethylphosphonomethylphenyl)-3-(3-methyl-5-phenyl-4-isoxazolyl)propionamide (0.87 g, yield 88%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 114–115° C.
Reaction SMILES: C([O:5][CH2:6][C@H:7]1[CH2:11][O:10][C:9](=[N:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[N:19]=[CH:18][N:17]=[C:16]3[NH:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][O:31][C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=3)=[C:26]([Cl:39])[CH:25]=2)[N:8]1[CH3:40])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl.ClCCCl>[Cl:39][C:26]1[CH:25]=[C:24]([NH:23][C:16]2[C:15]3[C:20](=[CH:21][CH:22]=[C:13]([N:12]=[C:9]4[N:8]([CH3:40])[C@@H:7]([CH2:6][OH:5])[CH2:11][O:10]4)[CH:14]=3)[N:19]=[CH:18][N:17]=2)[CH:29]=[CH:28][C:27]=1[CH2:30][O:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=1
Reactant: CN1C(=Nc2ccc3ncnc(Nc4ccc(COc5cccc(F)c5)c(Cl)c4)c3c2)OC[C@@H]1COC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: CN1C(=Nc2ccc3ncnc(Nc4ccc(COc5cccc(F)c5)c(Cl)c4)c3c2)OC[C@@H]1CO
Temperature: 0 °C
Reaction time: 3 h
Yield: 64 %

Procedure:
(S)-(2-{4-[3-Chloro-4-(3-fluoro-phenoxymethyl)-phenylamino]-quinazolin-6-ylimino}-3-methyl-oxazolidin-4-yl)-methanol is prepared from (S)—N6-(4-tert-butoxymethyl-3-methyl-oxazolidin-2-ylidene)-N4-[3-chloro-4-(3-fluoro-phenoxymethyl)-phenyl]-quinazoline-4,6-diamine. TFA (1 ml) is added to (S)—N6-(4-tert-butoxymethyl-3-methyl-oxazolidin-2-ylidene)-N4-[3-chloro-4-(3-fluoro-phenoxymethyl)-phenyl]-quinazoline-4,6-diamine (0.104 g, 0.184 mmol) in 1 ml methylene chloride at 0° C. After stirring for 2 hours at 0° C. and 3 hours at room temperature, the reaction mixture is diluted with 1,2-dichloroethane and concentrated. The residue is diluted with methylene chloride and washed with 10% Na2CO3. The aqueous layer is extracted with methylene chloride, and the combined organic extracts dried (Na2SO4) and concentrated to give 60 mg (64%) pure desired product. MS ESI (+) m/z 508, 510 (M+1, Cl pattern) detected; 1H NMR (400 MHz, CDCl3) δ 8.7 (s, 1H), 8.1 (s, 1H), 7.8-7.4 (m, 6H), 7.2 (m, 1H), 6.8-6.7 (m, 3H), 5.1 (s, 2H), 4.5 (m, 2H), 4.0 (dd, 1H, J=13, 3.9 Hz), 3.9 (m, 1H), 3.8 (br d, 1H, J=13.0 Hz), 3.1 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([O:8][C:9]1[CH:21]=[CH:20][C:19]([N:22]([CH2:27][CH:28]2[CH2:30][CH2:29]2)[S:23]([CH3:26])(=[O:25])=[O:24])=[CH:18][C:10]=1[C:11]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:31][C:32]1[CH:33]=[N+:34]([O-:57])[CH:35]=[C:36]([Cl:56])[C:37]=1[CH2:38][C@@H:39]([C:41]1[CH:46]=[CH:45][C:44]([O:47][CH:48]([F:50])[F:49])=[C:43]([O:51][CH2:52][CH:53]2[CH2:55][CH2:54]2)[CH:42]=1)O.C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([O:5][C:6]([O:8][C:9]1[CH:21]=[CH:20][C:19]([N:22]([CH2:27][CH:28]2[CH2:29][CH2:30]2)[S:23]([CH3:26])(=[O:25])=[O:24])=[CH:18][C:10]=1[C:11]([O:13][CH2:14][C:15]([O:17][C@H:39]([C:41]1[CH:46]=[CH:45][C:44]([O:47][CH:48]([F:49])[F:50])=[C:43]([O:51][CH2:52][CH:53]2[CH2:54][CH2:55]2)[CH:42]=1)[CH2:38][C:37]1[C:36]([Cl:56])=[CH:35][N+:34]([O-:57])=[CH:33][C:32]=1[Cl:31])=[O:16])=[O:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Oc1ccc(N(CC2CC2)S(C)(=O)=O)cc1C(=O)OCC(=O)O
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)Oc1ccc(N(CC2CC2)S(C)(=O)=O)cc1C(=O)OCC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.4 %

Procedure:
A mixture of 2-(2-(tert-butoxycarbonyloxy)-5-(N-(cyclopropylmethyl)-methylsulfonamido)benzoyloxy)acetic acid (0.215 g, 0.485 mmol), (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (204 g, 0.485 mmol), EDC (0.279 g, 1.454 mmol), and DMAP (0.059 g, 0.485 mmol) in DCM (25 mL) was stirred at RT overnight. The mixture was diluted with DCM and washed with 1N HCl and 5% NaHCO3. The organic phase was dried over sodium sulfate and the solvent was removed. The crude was purified by chromatography on silica gel cartridge (DCM:MeOH=99:1) affording (S)-4-(2-(2-(2-(tert-butoxycarbonyloxy)-5-(N-(cyclopropylmethyl)methylsulfonamido)-benzoyloxy)acetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (0.326 g, 0.385 mmol, 80% yield, MS/ESI+ 845.1 [MH]+).
Reaction SMILES: C([S@@]([NH:7][C@H:8]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[Cl:35])[C:9]1[S:13][C:12]([NH:14][C:15]([C:17]2([C:20]3[CH:28]=[CH:27][C:23]4[O:24][CH2:25][O:26][C:22]=4[CH:21]=3)[CH2:19][CH2:18]2)=[O:16])=[N:11][CH:10]=1)=O)(C)(C)C.Cl.O1CCOCC1>CO>[NH2:7][C@@H:8]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[Cl:35])[C:9]1[S:13][C:12]([NH:14][C:15]([C:17]2([C:20]3[CH:28]=[CH:27][C:23]4[O:24][CH2:25][O:26][C:22]=4[CH:21]=3)[CH2:19][CH2:18]2)=[O:16])=[N:11][CH:10]=1
Reactant: CC(C)(C)[S@](=O)N[C@@H](c1cnc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)s1)c1ccccc1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: N[C@H](c1cnc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)s1)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 71.7 %

Procedure:
To a solution of (S)—N-(5-((R)-t-butylsulfinylamino-(2-chlorophenyl)methyl)thiazol-2-yl)-1-(benzo[d][1,3]dioxol-5-yl)cyclopropane-carboxamide (11.25 g, 21.19 mmol) in MeOH (100 mL) was added 4 M HCl in dioxane (32 mL, 128 mmol). The reaction mixture was stirred at 25° C. for 1.5 h and evaporated to dryness. The crude product was dissolved in CH2Cl2. The organic layer was washed with aqueous NaHCO3 (50 mL×2), brine (50 mL×1), dried over Na2SO4 and concentrated. The crude product was purified by column chromatography (0-2.5% Et3N-EtOAc) to provide (S)—N-(5-(amino(2-chlorophenyl)methyl)thiazol-2-yl)-1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (6.5 g, 72%, >99% ee). 1H-NMR (400 MHz, CDCl3) δ 8.51 (s, 1H), 7.60 (dd, J=7.7, 1.7 Hz, 1H), 7.33 (dd, J=7.9, 1.3 Hz, 1H), 7.29-7.25 (m, 1H), 7.20 (td, J=7.6, 1.7 Hz, 1H), 7.16 (d, J=1.0 Hz, 1H), 6.89 (td, J=7.8, 1.7 Hz, 2H), 6.80 (d, J=7.9 Hz, 1H), 6.01 (s, 2H), 5.79 (s, 1H), 1.86 (bs, 2H), 1.72-1.69 (m, 2H), 1.22-1.19 (m, 2H). HPLC ret. time 2.66 min, 10-99% CH3CN, 5 min run; ESI-MS 428.1 m/z (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH3:13])[CH3:2].[C:15]1(O)[C:24]2CCCCC=2C=C[CH:16]=1>>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][O:6][C:7]1[C:8]2[CH2:13][CH2:24][CH2:15][CH2:16][C:9]=2[CH:10]=[CH:11][CH:12]=1)[CH3:2]
Reactant: Oc1cccc2c1CCCC2
Reactant: CCOC(=O)COc1ccccc1C
Product: CCOC(=O)COc1cccc2c1CCCC2

Procedure:
The title compound was prepared according to the method described for preparing compound 10.1, using 5,6,7,8-tetrahydro-1-naphthol as the starting material.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].[CH2:7]([O:14][C:15]1[C:20](=[O:21])[CH:19]=[CH:18]O[C:16]=1[CH3:22])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH-].[Na+].Cl>O.C(O)C>[CH2:7]([O:14][C:15]1[C:20](=[O:21])[CH:19]=[CH:18][N:1]([CH2:2][CH2:3][C:4]([OH:6])=[O:5])[C:16]=1[CH3:22])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Cc1occc(=O)c1OCc1ccccc1
Reactant: NCCC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1c(OCc2ccccc2)c(=O)ccn1CCC(=O)O

Procedure:
β-Alanine (5 g) in water (50 ml) is added to 3-benzyloxy-2-methyl-4-pyrone (10 g) in 95% ethanol (100 ml) and sodium hydroxide (4 g) in water (50 ml) is then slowly added to the reaction mixture until a pH of 13 is obtained. The solution is refluxed for 15 minutes during which time the colour changes from yellow to amber. After cooling, the solution is acidified to pH 2.5 with concentrated HCl (about 2 ml) and is then rotary evaporated at 50° C. The resulting oil is subjected to a methylene chloride/water extraction. The solid which remains is triturated with acetone and recrystallised from water to give 3-benzyloxy-1-(2'-carboxyethyl)-2-methylpyrid-4-one, m.p. 81°-83° C.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C:13]([OH:15])=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(C#N)(Cl)(Cl)Cl.[NH2:41][C@@:42]([C:57]1[CH:62]=[CH:61][C:60]([O:63][CH2:64][CH2:65][CH2:66][C:67]([F:70])([F:69])[F:68])=[CH:59][CH:58]=1)([C:53]([F:56])([F:55])[F:54])[CH2:43][C:44]([C:46]1[CH:51]=[CH:50][C:49]([CH3:52])=[CH:48][CH:47]=1)=[O:45]>C(Cl)Cl.N1C=CC=CC=1>[O:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[CH2:12][C:13]([NH:41][C@:42]([C:57]1[CH:62]=[CH:61][C:60]([O:63][CH2:64][CH2:65][CH2:66][C:67]([F:68])([F:69])[F:70])=[CH:59][CH:58]=1)([CH2:43][C:44](=[O:45])[C:46]1[CH:47]=[CH:48][C:49]([CH3:52])=[CH:50][CH:51]=1)[C:53]([F:56])([F:55])[F:54])=[O:15]
Reactant: Cc1ccc(C(=O)C[C@](N)(c2ccc(OCCCC(F)(F)F)cc2)C(F)(F)F)cc1
Reactant: O=C(O)CN1C(=O)c2ccccc2C1=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: N#CC(Cl)(Cl)Cl
Product: Cc1ccc(C(=O)C[C@](NC(=O)CN2C(=O)c3ccccc3C2=O)(c2ccc(OCCCC(F)(F)F)cc2)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87 %

Procedure:
To a solution of 2-(1,3-dioxoisoindolin-2-yl)acetic acid (592 mg, 2.88 mmol) in dry DCM (10 mL) was added PPh3 (2269 mg, 8.65 mmol) fairy rapidly, and then CCl3CN (500 mg, 3.46 mmol) was added dropwise. The mixture was stirred at rt for 3 h and a solution of Intermediate 2F, isomer 2 (500 mg, 1.15 mmol) in dry DCM (3 mL), followed by pyridine (0.3 mL) were added. The mixture was stirred at rt overnight. The mixture was diluted with DCM (10 mL) and washed with sat'd NaHCO3 (2×8 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated. The residue was purified by silica gel chromatography to yield the desired product (620 mg, 87%). LCMS Anal. Calc'd for C31H26F6N2O5 620.17, found [M+H] 621.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[N+:11]([O-])=O)[CH2:6][OH:7].[CH3:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]=[C:22]=[O:23]>C(OC)(C)(C)C.[Pd]>[CH3:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:21][C:22](=[O:23])[NH:11][C:10]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1cc(CO)ccc1[N+](=O)[O-]
Reactant: Cc1ccccc1N=C=O
Agent: [Pd]
Solvent: COC(C)(C)C
Product: COc1cc(CO)ccc1NC(=O)Nc1ccccc1C
Reaction time: 0.5 h

Procedure:
15 g (81.8 mmol) of 3-methoxy-4-nitrobenzyl alcohol were hydrogenated over 1.3 g of palladium/carbon (10% strength; 50% water) in 500 mL of methyl tert-butyl ether with ice cooling. After the absorption of hydrogen was complete, the catalyst was filtered off and 10.14 mL (81.8 mmol) of 2-methylphenyl isocyanate were added to the filtrate with stirring in the course of 30 minutes. The reaction mixture was allowed to stand overnight, and the precipitated solid was filtered off with suction and washed with methyl tert-butyl ether. Yield: 20.5 g (88%).
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([NH-:7])(=[O:6])=[O:5].[C:8]([C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:19]=1[O:20][CH2:21][CH2:22][O:23][CH3:24])[N:16]=[CH:15][CH:14]=[C:13]2[O:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33](=O)[O:34]C2C=CC=CC=2)=[CH:28][CH:27]=1)#[N:9]>O1CCCC1>[C:8]([C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:19]=1[O:20][CH2:21][CH2:22][O:23][CH3:24])[N:16]=[CH:15][CH:14]=[C:13]2[O:25][C:26]1[CH:27]=[CH:28][C:29]([NH:32][C:33]([NH:7][S:4]([CH3:3])(=[O:6])=[O:5])=[O:34])=[CH:30][CH:31]=1)#[N:9]
Reactant: CS([NH-])(=O)=O
Reactant: COCCOc1cc2nccc(Oc3ccc(NC(=O)Oc4ccccc4)cc3)c2cc1C#N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCOc1cc2nccc(Oc3ccc(NC(=O)NS(C)(=O)=O)cc3)c2cc1C#N
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 74.5 %

Procedure:
After suspending sodium hydride (11 mg, 0.275 mmol) in tetrahydrofuran (8 ml) under a nitrogen atmosphere, methanesulfonylamide (31.4 mg, 0.330 mmol) was added while cooling in an ice water bath, and the mixture was stirred at room temperature for 10 minutes. Phenyl N-(4-(6-cyano-7-(2-methoxyethoxy)-4-quinolyl)oxyphenyl)carbamate (50 mg, 0.110 mmol) was added and the mixture was stirred at 60° C. for 1 hour. The insoluble portion was filtered off, and after concentration under reduced pressure, tetrahydrofuran-hexane (1:2) was added for crystallization to obtain the title compound (37.6 mg, 0.082 mmol, 75.0%) as gray crystals.