Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.C(O)(=O)C.O=[Pt]=O>[C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][NH:11]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1ccccn1
Agent: O=[Pt]=O
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NCC1CCCCN1
Yield: 80.6 %

Procedure:
A solution of 108 g (0.518 mol) of 2-[N-(tert-butoxycarbonyl)aminomethyl]pyridine in 500 mL of ethanol and 50 mL of glacial acetic acid was hydrogenated over 5 grams of PtO2 at 55 psi for 36 hours employing a Parr apparatus. The mixture was cautiously filtered through Celite® and solvent was removed at reduced pressure. The crude material was dissolved in ethyl acetate, washed with 2N aqueous NaOH, water, brine, and dried over MgSO4. Solvent was removed at reduced pressure and the resulting solid was recrystallized from ethyl acetate/hexane to provide 89.5 grams (80%) of 2-[N-(tert-butoxycarbonyl)aminomethyl]piperidine as a white solid. Mp. 93° C.
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH3:16])[N:11]([CH3:17])[C:10]=1[C:18]([NH:20][CH3:21])=[O:19])C1C=CC=CC=1.[H][H]>C(O)C.[OH-].[OH-].[Pd+2]>[OH:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH3:16])[N:11]([CH3:17])[C:10]=1[C:18]([NH:20][CH3:21])=[O:19]
Reactant: [H][H]
Reactant: CNC(=O)c1c(OCc2ccccc2)c(=O)cc(C)n1C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CNC(=O)c1c(O)c(=O)cc(C)n1C
Yield: 100.4 %

Procedure:
Pd(OH)2 on charcoal (0.2 g) was added to a solution of 3-(benzyloxy)-N,1,6-trimethyl-4-oxo-1,4-dihydropyridine-2-carboxamide (1.25 g, 4.366 mmol) in ethanol (120 ml) under nitrogen. The mixture was hydrogenated at 50 psi hydrogen for 4 hrs. The Pd(OH)2 was removed by filtration through Celite and the Celite cake was washed with ethanol (3×25 ml). The Celite cake was further stirred with ethanol (100 ml) and then filtered through Celite. The combined ethanol filtrate was evaporated to give a solid (0.86 g, quantitative yield). Melting point: >250° C. H-NMR (COCl3:DMSO-d6 [2:1]) δ:1.81 (s, 3H, Me), 2.34 (d, 3H, NHMe), 3.01 (s, 3H, NMe), 5.67 (s, 1H, CH), 7.88 (s, 1H, NH). Elemental Analysis: Calc. C 55.09; H 6.6; N 14.28. Found. C 54.67; H 6.31; N 14.12.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH3:11])[CH:4]=[CH:3]1.[CH3:12][N:13](CCN(C)C)[CH3:14].C([Li])CCC.CN(C=O)C.[NH4+].[Cl-]>C(OCC)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH3:11])[CH:4]=[C:3]1[CH2:12][NH:13][CH3:14]
Reactant: CN(C)CCN(C)C
Reactant: Cc1cccc2ccn(C)c12
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CNCc1cc2cccc(C)c2n1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.5 %

Procedure:
To a solution of 1,7-dimethylindole (2.85 g, 19.6 mmol) and TMEDA (3.3 mL, 21.6 mmol) in diethyl ether (30 mL) at −30° C. under N2 was added n-butyllithium (13.5 mL of a 1.6 M solution in hexanes, 21.6 mmol) dropwise. The resulting orange solution was heated to reflux for 1 h and then DMF (4.6 mL, 58.8 mmol) was added in one portion. The solution was stirred at room temperature overnight. Saturated aqueous NH4Cl solution was added and the mixture was then extracted with ethyl acetate (3×150 mL). The combined organics were washed with water (100 mL) and brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to provide an orange oil. Purification by flash column chromatography (silica gel, hexanes/ethyl acetate, 95:5) gave the title compound (1.57 g, 46%) as a yellow solid: 1H NMR (300 MHz, CDCl3) δ 9.83 (s, 1H), 7.54 (d, J=7.8 Hz, 1H), 7.21 (s, 1H), 7.09-7.02 (m, 2H), 4.39 (s, 3H), 2.79 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:3]=1[CH2:4][N:5]([CH3:7])[CH3:6].[Br:14]Br>C(Cl)Cl>[NH2:1][C:2]1[C:11]([Br:14])=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:3]=1[CH2:4][N:5]([CH3:7])[CH3:6]
Reactant: BrBr
Reactant: COc1ccc(N)c(CN(C)C)c1
Solvent: ClCCl
Product: COc1cc(Br)c(N)c(CN(C)C)c1

Procedure:
2-Amino-3-bromo-N,N-dimethyl-5-methoxy-benzylamine was prepared from 2-amino-N,N-dimethyl-5-methoxy-benzylamine and bromine analogous to Example 9. Proof of structure by IR-, UV- and NMR-spectra. IR-spectrum (methylenechloride): 3250 cm-1NH2 ; 3410 cm-1NH2 ; 2780 cm-1N(CH3)2 ; 2830 cm-1OCH3 ; 1590 cm-1C=C; 1600 cm-1C=C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=[C:11]([CH3:19])[CH:10]=2)[CH:5]=[CH:6][CH:7]=1.[C:20]([O-:23])(O)=O.[Na+]>C1(C)C=CC=CC=1.CCO>[CH3:19][C:11]1[CH:10]=[C:9]([NH:8][C:4]2[CH:3]=[C:2]([C:2]3[CH:3]=[CH:4][CH:5]=[C:6]([CH:20]=[O:23])[CH:7]=3)[CH:7]=[CH:6][CH:5]=2)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1
Reactant: Cc1cc(Nc2cccc(Br)c2)c2ccccc2n1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1cc(Nc2cccc(-c3cccc(C=O)c3)c2)c2ccccc2n1
Temperature: 80 °C
Yield: 68.9 %

Procedure:
To a suspension of 71 (294 mg, 0.94 mmol) in toluene (9.6 mL) under N2 were sequentially added saturated NaHCO3 (aq. 3.8 mL), a solution of 72 (199 mg, 1.33 mmol) in EtOH (6.7 mL), and PdCl2(Ph3P)3 (32 mg, 0.046 mmol). The reaction was heated at 80° C. for 21 hours before it was allowed to cool to room temperature. The reaction mixture was extracted with ethyl acetate (40 mL) and washed with water (15 mL), brine (15 mL). The ethyl acetate extracts were dried over anhydrous magnesium sulfate and concentrated. The residue was chromatographed on silica gel (dichloromethane to 20:1 dichloromethane/methanol) to give 73 as a yellow solid (219 mg, 68.9%).
Reaction SMILES: [C:1]1([CH2:7][S:8][C:9]2[N:10]=[C:11](Cl)[C:12]3[S:17][C:16]([NH2:18])=[N:15][C:13]=3[N:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:20][CH2:21][CH2:22][CH2:23][CH:24]([NH2:27])[CH2:25][OH:26].C(=O)([O-])[O-].[K+].[K+]>>[NH2:18][C:16]1[S:17][C:12]2[C:11]([NH:27][CH:24]([CH2:23][CH2:22][CH2:21][CH3:20])[CH2:25][OH:26])=[N:10][C:9]([S:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[N:14][C:13]=2[N:15]=1
Reactant: Nc1nc2nc(SCc3ccccc3)nc(Cl)c2s1
Reactant: CCCCC(N)CO
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCCC(CO)Nc1nc(SCc2ccccc2)nc2nc(N)sc12
Yield: 17.6 %

Procedure:
5-Phenylmethylthio-7-chloro-thiazolo[4,5-d]pyrimidin-2-ylamin (100 mg, 0.32 mmol), DL-2-amino-1-hexanol (295 μL, 2.3 mmol) and potassium carbonate (124 mg, 0.90 mmol) were heated for 24 hours as in Example 1. The solution was filtered and the solvent was evaporated. The crude product was flash chromatographed on silica (gradient eluent—ammonia:ethylacetate:dichloromethane, 1:69:30 to 1:99:0) resulting in 22 mg (17% yield) of the title compound as a yellow solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].Cl.N1C=CC=CC=1.[NH2:25][C:26]1[CH:32]=[CH:31][C:29]([OH:30])=[CH:28][C:27]=1[OH:33]>C(OCCO)C>[OH:33][C:27]1[CH:28]=[C:29]([OH:30])[CH:31]=[CH:32][C:26]=1[NH:25][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17]
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Reactant: Nc1ccc(O)cc1O
Agent: Cl
Solvent: CCOCCO
Solvent: c1ccncc1
Product: COc1cc2ncc(C#N)c(Nc3ccc(O)cc3O)c2cc1OC
Yield: 97.9 %

Procedure:
Using an analogous procedure to that described in Example 286, 248.7 mg (1 mmol) of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile in 12 mL of 2-ethoxyethanol and in the presence of 115.6 mg (1 mmol) of pyridine hydrochloride was reacted with 210.0 mg (1.3 mmol) of 4-aminoresorcinol to give 330.4 mg (98.0%) of the product as a deep purple solid, m.p.>250° C., mass (electrospray, m/e): M+H 337.9.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH:9]([CH3:28])[C:10]([C:16]1[CH:17]=[CH:18][C:19]2[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=2[CH:27]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[CH2:29]([O:31][C:32](=[O:41])[C:33]1[CH:38]=[CH:37][C:36]([CH2:39]Br)=[CH:35][CH:34]=1)[CH3:30].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C>[CH2:29]([O:31][C:32](=[O:41])[C:33]1[CH:38]=[CH:37][C:36]([CH2:39][O:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH:9]([CH3:28])[C:10]([OH:15])([C:16]3[CH:17]=[CH:18][C:19]4[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=4[CH:27]=3)[C:11]([F:12])([F:13])[F:14])[CH:4]=2)=[CH:35][CH:34]=1)[CH3:30]
Reactant: CC(c1cc(O)ccc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F
Reactant: CCOC(=O)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1ccc(COc2ccc(Cl)c(C(C)C(O)(c3ccc4c(c3)N(C)C(=O)CO4)C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.2 %

Procedure:
To a solution of 6-[2-(2-chloro-5-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-4-methyl-4H-benzo[1,4]oxazin-3-one (83 mg) in N,N-dimethylacetamide (1.6 ml) were added ethyl-4-(bromomethyl)benzoate (56 mg) and cesium carbonate (72 mg). The mixture was stirred for 4 h at room temperature. Ice water was added and the mixture was extracted with EtOAc. The organic phase was washed with water and dried (MgSO4). The product was purified by chromatography (SiO2, cyclohexane/EtOAc 1:0=>3:2) to give the title compound (96 mg) as colorless foam. MS (m/e, ISP neg. ion)=578.3 [M−H+].
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH2:7])=[CH:5][C:4]([CH3:8])=[N:3]1.[C:9]([O-])(=[O:11])[CH3:10].[K+].C(OC(=O)C)(=O)C>CCOC(C)=O>[CH3:1][N:2]1[C:6]([NH:7][C:9](=[O:11])[CH3:10])=[CH:5][C:4]([CH3:8])=[N:3]1
Reactant: Cc1cc(N)n(C)n1
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Product: CC(=O)Nc1cc(C)nn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.5 %

Procedure:
A suspension of 2,5-dimethylpyrazol-3-amine (1 g, 9.00 mmol), potassium acetate (0.971 g, 9.90 mmol) and acetic anhydride (1.002 mL, 9.00 mmol) in EtOAc (25 mL) was stirred at 25° C. overnight. Silica gel was added and the mixture was concentrated. The crude product was purified by flash chromatography on silica gel eluting with 0 to 5% MeOH in DCM. The solvent was evaporated to dryness to afford N-(2,5-dimethylpyrazol-3-yl)acetamide (1.400 g, 102%) as a pale yellow oil. Mass spectrum: MH+ 154 Sodium hydride (0.385 g, 9.14 mmol) was added to N-(2,5-dimethylpyrazol-3-yl)acetamide (1.4 g, 9.14 mmol) dissolved in THF (20 mL) under nitrogen. The resulting light suspension was stirred at 35° C. for 30 minutes then 2-chloro-4-iodo-5-(trifluoromethyl)pyridine (1.338 g, 4.35 mmol) was added. DMF (2 mL) was added and the mixture was stirred at 80° C. for 18 hours. The reaction mixture was cooled to room temperature, quenched with water (20 mL). Lithium hydroxide hydrate (0.548 g, 13.06 mmol) was added and the mixture was stirred at room temperature for 1.5 hours. The mixture was diluted with EtOAc and water, the phases were separated and the organic phase washed with brine, dried over magnesium sulfate and concentrated. The residue was purified by flash chromatography on silica gel (40 g) eluting with 0 to 50% EtOAc in DCM. After collection of the fractions and evaporation of the solvents, the resulting solid was triturated in petroleum ether, collected by filtration, washed with petroleum ether and dried to a constant weight to afford N-(2,5-dimethylpyrazol-3-yl)-4-iodo-5-(trifluoromethyl)pyridin-2-amine (900 mg, 54.1%) as an off-white solid.
Reaction SMILES: [F:1][C:2]1[CH:21]=[C:20]([N:22]([CH3:46])[CH:23]2[C:27]3[CH:28]=[C:29]4[C:34](=[CH:35][C:26]=3[CH2:25][CH2:24]2)[N:33]=[C:32]([CH3:36])[N:31]([CH2:37][O:38][C:39](=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41])[C:30]4=[O:45])[CH:19]=[CH:18][C:3]=1[C:4](OC1C(F)=C(F)C(F)=C(F)C=1F)=[O:5].[NH2:47][C@@H:48]([CH2:53][CH2:54][C:55]1[NH:59][N:58]=[N:57][N:56]=1)[C:49]([O:51][CH3:52])=[O:50]>>[F:1][C:2]1[CH:21]=[C:20]([N:22]([CH3:46])[CH:23]2[C:27]3[CH:28]=[C:29]4[C:34](=[CH:35][C:26]=3[CH2:25][CH2:24]2)[N:33]=[C:32]([CH3:36])[N:31]([CH2:37][O:38][C:39](=[O:44])[C:40]([CH3:43])([CH3:41])[CH3:42])[C:30]4=[O:45])[CH:19]=[CH:18][C:3]=1[C:4]([NH:47][C@@H:48]([CH2:53][CH2:54][C:55]1[NH:59][N:58]=[N:57][N:56]=1)[C:49]([O:51][CH3:52])=[O:50])=[O:5]
Reactant: Cc1nc2cc3c(cc2c(=O)n1COC(=O)C(C)(C)C)C(N(C)c1ccc(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)c(F)c1)CC3
Reactant: COC(=O)[C@@H](N)CCc1nnn[nH]1
Product: COC(=O)[C@H](CCc1nnn[nH]1)NC(=O)c1ccc(N(C)C2CCc3cc4nc(C)n(COC(=O)C(C)(C)C)c(=O)c4cc32)cc1F
Yield: 73 %

Procedure:
Using analogous procedures to those described in the second and third paragraphs of Example 12, pentafluorophenyl o-fluoro-p-[N-methyl-N-((6RS)-2-methyl-4-oxo-3-pivaloyloxymethyl-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)amino]benzoate was reacted with methyl (2S)-2-amino-4-(tetrazol-5-yl)butyrate to give methyl (2S)-2-{o-fluoro-p-[N-methyl-N-((6RS)-2-methyl-3-pivaloyloxymethyl-4-oxo-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)amino]benzamido}-4-(tetrazol-5-yl)butyrate in 73% yield which in turn was hydrolysed with aqueous sodium hydroxide solution to give (2S)-2-{o-fluoro-p-[N-methyl-N-((6RS)-2-methyl-4-oxo-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)amino]benzamido}-4-(tetrazol-5-yl)butyric acid in 81% yield, m.p. 203°-205° C.;
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([Br:20])[C:15]([O:17][CH2:18][CH3:19])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=O.[OH-].[Na+]>CO.O>[Br:20][C:14]1[C:15]([O:17][CH2:18][CH3:19])=[CH:16][C:8]2[CH2:7][CH2:6][NH:5][CH2:11][CH:10]([CH3:12])[C:9]=2[CH:13]=1
Reactant: CCOc1cc2c(cc1Br)C(C)CN(C(=O)C(F)(F)F)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCOc1cc2c(cc1Br)C(C)CNCC2
Reaction time: 8 h
Yield: 94.7 %

Procedure:
A solution of N-trifluoroacetyl-8-bromo-7-ethoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (0.010 g, 0.026 mmol) in methanol (1 mL) was treated with 15% aqueous NaOH (1 mL), and stirred overnight at 20 C. The product mixture was diluted with water (3 mL), extracted twice with EtOAc (5 mL), the combined organic phases were washed with brine (3 mL), dried with Na2SO4 and concentrated to give 0.007 g of a clear oil. 1H NMR (400 MHz, CDCl3) d 7.29 (s, 1H), 6.63 (s, 1H), 4.07 (q, J=6 Hz, 2H), 3.03 (m, 3H), 2.91 (m, 3H), 2.73 (m, 1H), 2.26 (bs, 1H), 1.46 (t, J=6 Hz, 3H), 1.32 (d, J=7 Hz, 3H). MS calculated for C15H17BrF3NO2+H: 380, observed: 380.
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[CH3:24][C:25]1[CH:26]=[C:27]([OH:32])[CH:28]=[CH:29][C:30]=1[CH3:31]>O1CCCC1>[CH3:24][C:25]1[CH:26]=[C:27]([CH:28]=[CH:29][C:30]=1[CH3:31])[O:32][CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4]
Reactant: Cc1ccc(O)cc1C
Reactant: COC(=O)C(Br)c1ccc(OCCOc2ccc(F)cc2)cc1
Solvent: C1CCOC1
Product: COC(=O)C(Oc1ccc(C)c(C)c1)c1ccc(OCCOc2ccc(F)cc2)cc1

Procedure:
As described in Example 71, methyl bromo{p-[2-(p-fluorophenoxy)ethoxy]phenyl}acetate (0.017 mole) is reacted with 3,4-dimethylphenol (0.017 mole) in 75 ml of tetrahydrofuran at 80° C. for 18 hrs to give the product as a gum.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20](Cl)[C:19]2[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=2[C:17]=1[F:34])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:35][C:36]1[CH:37]=[C:38](B2OC(C)(C)C(C)(C)O2)[S:39][CH:40]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.O.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>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20]([C:38]2[S:39][CH:40]=[C:36]([F:35])[CH:37]=2)[C:19]2[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=2[C:17]=1[F:34])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Reactant: CC1(C)OB(c2cc(F)cs2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1nc(-c2cc(F)cs2)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Temperature: 85 °C

Procedure:
To a 30 mL sealed cap glass vessel containing tert-butyl 6-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (200 mg, 0.401 mmol) and 2-(4-fluorothiophen-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (137 mg, 0.601 mmol) dissolved in DME and water (4:1) was added tetrakis(triphenylphosphine)palladium(0) (105 mg, 0.401 mmol) and potassium phosphate, tribasic (212 mg, 1 mmol). The cap was sealed, and the reaction mixture was heated at 85° C. for 4 hours and then cooled to room temperature. The mixture was diluted with water and extracted with EtOAc (2×25 mL). The organic layers were combined, dried over sodium sulfate, and evaporated to give the intermediate, tert-butyl 6-(((1R,2S)-2-((tert-butoxycarbonyl)amino)cyclohexyl)amino)-7-fluoro-4-(4-fluorothiophen-2-yl)-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate. The intermediate was dissolved in TFA (5 mL) and stirred at room temperature for 2 hours. The mixture was evaporated and purified by preparative HPLC, eluting with a gradient of 15-50% ACN (0.035% TFA) and H2O (0.05% TFA). The pure fractions were combined, evaporated to minimal volume, and lyophilized to give a TFA salt of the title compound as a white solid (112 mg, 77%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.29-1.54 (m, 2H), 1.60 (d, J=12.88 Hz, 2H), 1.66-1.81 (m, 2H), 1.83-1.99 (m, 2H), 3.81 (br s, 1H), 4.24 (br s, 1H), 4.45 (d, J=2.27 Hz, 2H), 7.14 (d, J=5.31 Hz, 1H), 7.31 (t, J=1.39 Hz, 1H), 7.79 (br s, 3H), 8.62 (s, 1H), 8.97 (d, J=1.77 Hz, 1H). ESI-MS m/z [M+H]+ calc'd for C17H18F2N4OS, 365. found, 365.
Reaction SMILES: [Mg].[CH:2]1([C:5]([C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=2)=[CH:6][CH:7]=[CH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:10]=2)[CH2:4][CH2:3]1.C(OCC)(=O)C.Cl>CO>[CH:2]1([CH:5]([C:23]2[CH:24]=[CH:25][C:26]([O:29][C:30]([F:33])([F:31])[F:32])=[CH:27][CH:28]=2)[CH:6]=[CH:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:10]=2)[CH2:4][CH2:3]1
Reactant: Fc1ccc(C=CC=C(c2ccc(OC(F)(F)F)cc2)C2CC2)cc1Oc1ccccc1
Agent: Cl
Agent: [Mg]
Solvent: CO
Solvent: CCOC(C)=O
Product: Fc1ccc(CC=CC(c2ccc(OC(F)(F)F)cc2)C2CC2)cc1Oc1ccccc1
Yield: 83.1 %

Procedure:
A stirred mixture of 1.64 grams (0.068 mole) of magnesium turnings in 200 mL of methanol was warmed to reflux, and a solution of 3.0 grams (0.0068 mole) of 1-cyclopropyl-1-(4-trifluoromethoxyphenyl)-4-(4-fluoro-3-phenoxyphenyl)-1,3-butadiene was added dropwise. Upon completion of addition the reaction mixture was heated at reflux for one hour. The reaction mixture was cooled and stirred with ethyl acetate and aqueous 3N hydrochloric acid. The mixture was filtered, the organic layer was separated from the filtrate, and it was washed in turn with aqueous 1N hydrochloric acid and water. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure yielding 2.5 grams of 1-cyclopropyl-1-(4-trifluoromethoxyphenyl)-4-(4-fluoro-3-phenoxyphenyl)-2-butene.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[N:12]=[C:13]([C:24]2[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=2[F:31])[S:14][C:15]=1[NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:10].F[C:33]1(C2N(C)N=CC=2[N+]([O-])=O)[CH2:39][CH2:38][CH:37]([NH:40][C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44])[CH:36]([OH:48])[CH2:35][CH2:34]1>>[C:19]([O:18][C:17]([NH:16][C:15]1[S:14][C:13]([C:24]2[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=2[F:31])=[N:12][C:11]=1[C:9]([NH:8][C:3]1[CH:4]=[N:5][N:6]([CH3:7])[C:2]=1[C:33]12[O:48][CH:36]([CH2:35][CH2:34]1)[CH:37]([NH:40][C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44])[CH2:38][CH2:39]2)=[O:10])=[O:23])([CH3:22])([CH3:21])[CH3:20]
Reactant: Cn1ncc([N+](=O)[O-])c1C1(F)CCC(O)C(NC(=O)OC(C)(C)C)CC1
Reactant: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2NC(=O)OC(C)(C)C)c1Cl
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2NC(=O)OC(C)(C)C)c1C12CCC(NC(=O)OC(C)(C)C)C(CC1)O2

Procedure:
Following the procedure for Intermediate 1 starting from tert-butyl N-(5-fluoro-2-hydroxy-5-(2-methyl-4-nitro-pyrazol-3-yl)cycloheptyl)carbamate gave tert-butyl N-(5-[4-[[5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carbonyl]amino]-2-methyl-pyrazol-3-yl]-8-oxabicyclo[3.2.1]octan-2-yl]carbamate as a pale pink solid (172 mg, 17% over two steps). 1H NMR (400 MHz, CDCl3) δ 10.47 (s, 1H), 10.45 (s, 1H), 8.29 (s, 1H), 7.35-7.27 (m, 1H), 7.18-7.08 (m, 2H), 4.76 (br s, 1H), 4.29 (br s, 1H), 4.04 (br s, 1H), 3.85 (s, 3H), 2.38-2.33 (m, 1H), 2.19-1.86 (m, 7H), 1.55 (s, 9H), 1.48 (s, 9H).
Reaction SMILES: O1CCCC1.[O:6]([CH2:14][C@H:15]([O:25][CH2:26][O:27][CH3:28])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][CH3:24])[Si](C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O>[CH3:28][O:27][CH2:26][O:25][C@H:15]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][CH3:24])[CH2:14][OH:6]
Reactant: COCO[C@@H](CO[Si](C)(C)C(C)(C)C)Cc1ccccc1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: COCO[C@@H](CO)Cc1ccccc1OC
Reaction time: 2 h
Yield: 103.3 %

Procedure:
Under ice-cooling, to a tetrahydrofuran solution of (R)-1-t-butyldimethylsiloxy-2-methoxymethoxy-3-(2-methoxyphenyl)propane (2.2 g) was added a solution of n tetrabutylammoniumfluoride (1 mol/l, 6.46 ml) in tetrahydrofuranand stirred for 2 hours successively. After tetrahydrofuran wasevaporated in vacuo, water was added, extracted with ethyl acetate,and dried over magnesium sulfate. The solvent was evaporated invacuo, the gained crude product was purified by silica gel columnchromatography, and eluted with a mixed solvent of hexane andethyl acetate (1:1, v/v). The fractions containing the desiredproduct were combined and evaporated in vacuo to obtain (R)-2-methoxymethoxy-3-(2-methoxyphenyl)-1-propanol(1.51 g).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:3]=1[C:4]([O:6]CC)=O.[C:14](#[N:16])[CH3:15].[H-].[Na+].CCOCC>O1CCCC1>[Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:3]=1[C:4]([CH2:15][C:14]#[N:16])=[O:6]
Reactant: CCOC(=O)c1ccc(Cl)cc1Cl
Reactant: CC#N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: N#CCC(=O)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Yield: 28.1 %

Procedure:
A mixture of 43.8 g of ethyl 2,4-dichloro-benzoate and 8.2 g of anhydrous acetonitrile is added dropwise to a suspension of 6.1 g of 80% strength sodium hydride in 100 ml of anhydrous tetrahydrofuran in the course of about 1 hour under reflux. The mixture is heated at the boiling point under reflux for a further hour and cooled to room temperature and 150 ml of ether are added. The precipitate is filtered off with suction and dissolved in 50 ml of ice-water and the solution is acidified to pH=6 with 10% strength hydrochloric acid. The precipitate is filtered off cold with suction, rinsed with ice-water and dried in vacuo at 40° C. 12 g of 2,4-dichlorobenzoylacetonitrile of melting point 96°-98° C. are obtained.