Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][N:11]([CH3:13])[CH3:12])[N:5]=[C:4]2[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:15](=[O:18])[NH:16][CH2:17][C:3]=12.O.C(=O)([O-])[O-].[K+].[K+].[CH3:34][C:35]([O:38][C:39]([C:41]1[CH:42]=[C:43]([F:51])[C:44]([CH3:50])=[C:45](B(O)O)[CH:46]=1)=[O:40])([CH3:37])[CH3:36]>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>[F:26][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]([F:25])[C:19]=1[N:14]1[C:4]2[N:5]=[C:6]([NH:8][CH2:9][CH2:10][N:11]([CH3:13])[CH3:12])[N:7]=[C:2]([C:45]3[CH:46]=[C:41]([CH:42]=[C:43]([F:51])[C:44]=3[CH3:50])[C:39]([O:38][C:35]([CH3:34])([CH3:36])[CH3:37])=[O:40])[C:3]=2[CH2:17][NH:16][C:15]1=[O:18]
Reactant: Cc1c(F)cc(C(=O)OC(C)(C)C)cc1B(O)O
Reactant: CN(C)CCNc1nc(Cl)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
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: O
Solvent: C1COCCO1
Product: Cc1c(F)cc(C(=O)OC(C)(C)C)cc1-c1nc(NCCN(C)C)nc2c1CNC(=O)N2c1c(F)cccc1F
Yield: 93.3 %

Procedure:
To a solution of 5-chloro-1-(2,6-difluorophenyl)-7-{[2-(dimethylamino)ethyl]amino}-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (200 mg, 0.52 mmol) in dioxane (15 mL)/water (5 mL) were added potassium carbonate (433 mg, 3.14 mmol), tetrakis(triphenylphosphine)palladium(0) (31 mg, 0.027 mmol) and (5-{[(1,1-dimethylethyl)oxy]carbonyl}-3-fluoro-2-methylphenyl)boronic acid (159 mg, 0.63 mmol). The reaction mixture was bubbled with N2 for 10 mins, then microwaved at 150° C. for 30 mins. The reaction mixture was concentrated. To the concentrated mixture were added DMSO (2 mL), H2O (0.5 mL) and AcOH (0.05 mL). Separation via a HPLC then provided the title compound as a white solid (270 mg, 88%). LC-MS m/z 587 (M+H)+.
Reaction SMILES: [CH3:1][C@:2]1([C:19]([O-:21])=O)[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1.[Li+].Cl.[NH2:24][C:25]1([C:28]2[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=2)[CH2:27][CH2:26]1>>[CH3:1][C@:2]1([C:19]([NH:24][C:25]2([C:28]3[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=3)[CH2:27][CH2:26]2)=[O:21])[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=1
Reactant: C[C@]1(C(=O)[O-])CCCCN1Cc1ccc(C(F)(F)F)cc1
Reactant: COC(=O)c1ccc(C2(N)CC2)cc1
Agent: Cl
Agent: [Li+]
Product: COC(=O)c1ccc(C2(NC(=O)[C@@]3(C)CCCCN3Cc3ccc(C(F)(F)F)cc3)CC2)cc1
Yield: 16.2 %

Procedure:
The title compound (D157) (5 mg) was prepared according to the general procedure for amides preparation (Method B) starting from lithium (R)-2-methyl-1-(4-(trifluoromethyl)benzyl)piperidine-2-carboxylate (D112) (20 mg) and methyl 4-(1-aminocyclopropyl)benzoate hydrochloride (17.2 mg).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[S:10]([NH2:13])(=[O:12])=[O:11].[CH:14]1([N:17]2[C:21](=[O:22])[N:20]([C:23](OC3C=CC=CC=3)=[O:24])[N:19]=[C:18]2[O:32][CH2:33][CH3:34])[CH2:16][CH2:15]1.N12CCCN=C1CCCCC2>C(#N)C>[CH:14]1([N:17]2[C:21](=[O:22])[N:20]([C:23]([NH:13][S:10]([C:3]3[C:4]([O:8][CH3:9])=[CH:5][CH:6]=[CH:7][C:2]=3[I:1])(=[O:12])=[O:11])=[O:24])[N:19]=[C:18]2[O:32][CH2:33][CH3:34])[CH2:15][CH2:16]1
Reactant: COc1cccc(I)c1S(N)(=O)=O
Reactant: CCOc1nn(C(=O)Oc2ccccc2)c(=O)n1C1CC1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCOc1nn(C(=O)NS(=O)(=O)c2c(I)cccc2OC)c(=O)n1C1CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 250 mg (0.80 mmol) of 2-iodo-6-methoxybenzenesulfonamide in 3 ml of acetonitrile is admixed at room temperature first with 254.08 mg (0.88 mmol) of 4-cyclopropyl-3-ethoxy-5-oxo-1-phenyloxycarbonyl-4,5-dihydro-1H-1,2,4-triazole and then slowly with 0.24 ml (1.60 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene. After 60 min of stirring at room temperature the solution is adjusted slowly to a pH of 1 using 2 N salt solution. The precipitated solid is filtered off with suction, washed with diisopropyl ether and acetonitrile, and dried. This gives 267 mg (62% of theory) of 4-cyclopropyl-3-ethoxy-N-[(2-iodo-6-methoxyphenyl)sulfonyl]-5-oxo-4,5-dihydro-1H-1,2,4-triazole-1-carboxamide.
Reaction SMILES: Cl.[C:2]([O:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)([CH3:5])([CH3:4])[CH3:3].C(N(CC)CC)C.[O:20]=[C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]([CH2:31][C:32]2[CH:37]=[CH:36][N:35]=[C:34]([C:38](O)=[O:39])[CH:33]=2)=[N:23][NH:22]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[C:2]([O:6][CH:7]1[CH2:12][CH2:11][N:10]([C:38]([C:34]2[CH:33]=[C:32]([CH2:31][C:24]3[C:25]4[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:21](=[O:20])[NH:22][N:23]=3)[CH:37]=[CH:36][N:35]=2)=[O:39])[CH2:9][CH2:8]1)([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC1CCNCC1
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC1CCN(C(=O)c2cc(Cc3n[nH]c(=O)c4ccccc34)ccn2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 55.6 %

Procedure:
A solution of 4-tert-butoxypiperidine hydrochloride (227 mg, 1.17 mmol) and triethylamine (0.327 mL, 2.35 mmol) in N,N-dimethlformamide (3 mL) was added in one portion to a stirred solution of 4-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)picolinic acid (5) (300 mg, 1.07 mmol), Triethylamine (0.327 mL, 2.35 mmol) and O-Benzotriazol-1-yl-N,N,N′,N′-tetra-methyluronium hexafluorophosphate (607 mg, 1.60 mmol) in N,N-dimethlformamide (3 mL) at 25° C. The resulting solution was stirred at 25° C. for 4 hours, then The crude mixture was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness and lyophilised to afford the desired compound as a solid (250 mg, 55.7% yield); 1H NMR (400.132 MHz, DMSO) δ 1.15 (9H, s), 1.25-1.40 (2H, m), 1.56-1.63 (1H, m), 1.71-1.79 (1H, m), 3.08-3.23 (2H, m), 3.44-3.50 (1H, m), 3.71-3.78 (1H, m), 4.01-4.08 (1H, m), 4.40 (2H, s), 7.39 (1H, dd), 7.48-7.49 (1H, m), 7.83-7.87 (1H, m), 7.90 (1H, td), 7.94-7.97 (1H, m), 8.28 (1H, dd), 8.46-8.48 (1H, m), 12.60 (1H, s); m/z (LC-MS, ESI+), RT=1.67 (M+H 421.5).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]3[CH:31]=[CH:30][C:17]([C:18]([NH:20][CH2:21][CH2:22][C:23]([O:25]C(C)(C)C)=[O:24])=[O:19])=[CH:16][CH:15]=3)[N:11]=[C:10]([C:32]3[CH:37]=[C:36]([Cl:38])[CH:35]=[C:34]([Cl:39])[CH:33]=3)[CH:9]=2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]3[CH:15]=[CH:16][C:17]([C:18]([NH:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[O:19])=[CH:30][CH:31]=3)[N:11]=[C:10]([C:32]3[CH:33]=[C:34]([Cl:39])[CH:35]=[C:36]([Cl:38])[CH:37]=3)[CH:9]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)CCNC(=O)c1ccc(Cn2nc(-c3cc(Cl)cc(Cl)c3)cc2-c2ccc(Br)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CCNC(=O)c1ccc(Cn2nc(-c3cc(Cl)cc(Cl)c3)cc2-c2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the intermediate from step F (30 mg, 0.047 mmol) in DCM (2 mL) was added trifluroacetic acid (2 mL). The reaction was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo and lyophilized from acetonitrile-water to give the title compound. 1H NMR (DMSO, 500 MHz): δ 8.49(t, J=5.5 Hz, 1H), 7.89 (d, J=1.8 Hz, 2H), 7.75 (d, J=8.2 Hz, 2H), 7.7 (d, J=8.5 Hz, 2H), 7.43 (d, J=8.4 Hz, 2H), 7.22 (s, 1H), 7.11 (d, J=8.2 Hz, 2H), 5.5 (s, 2H), 3.45 (q, J=7.1 Hz, 2H), 2.49 (t, J=6.8 Hz, 2H). LC-MS: 2.59 min; (M+H)=571.9.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH:13]([CH2:19]C=C)[C:14]([O:16]CC)=O)[C:4](C=C)=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[C:33]([CH:34]([CH3:36])[CH3:35])=[C:32]([NH2:37])[CH:31]=[N:30]2)=[CH:25][CH:24]=1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([N:29]2[C:33]([CH:34]([CH3:35])[CH3:36])=[C:32]([NH:37][C:14](=[O:16])[C@@H:13]([N:3]3[CH:4]=[C:5]([C:7]([F:8])([F:9])[F:10])[N:6]=[C:2]3[CH3:1])[CH3:19])[CH:31]=[N:30]2)=[CH:27][CH:28]=1
Reactant: CC(C)c1c(N)cnn1-c1ccc(Cl)cc1
Reactant: C=CCC(C(=O)OCC)n1c(C)nc(C(F)(F)F)c1C=C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc(C(F)(F)F)cn1[C@@H](C)C(=O)Nc1cnn(-c2ccc(Cl)cc2)c1C(C)C
Reaction time: 0.58 h

Procedure:
To a solution of the acid intermediate from step d (23.6 mg, 0.1 mmol) and 1-(4-chlorophenyl)-5-isopropyl-1H-pyrazol-4-amine (16.6 mg, 0.064 mmol) in DMF (0.5 mL) was added Et3N (20 μL, 0.13 mmol) and HATU (31.6 mg, 0.083 mmol). After stirring 35 min, the slurry was concentrated under reduced pressure and the residue was purified by reverse phase HPLC (C18 column, acetonitrile-H2O with 0.1% TFA as eluent). The residue was neutralized and salted with HCL to provide the titled compound hydrochloride salt as a colorless solid (12.3 mg). 1H NMR (400 MHz, CD3OD) δ 8.28 (d, J=1.6 Hz, 1H), 7.63 (s, 1H), 7.57 (ddd, J=9.7, 5.1, 3.1 Hz, 2H), 7.41 (ddd, J=9.7, 5.0, 3.1 Hz, 2H), 5.38 (q, J=7.0 Hz, 1H), 3.03 (hept, J=7.0 Hz, 1H), 2.65 (s, 3H), 1.91 (d, J=7.0 Hz, 3H), 1.23 (d, J=7.1 Hz, 3H), 1.22 (d, J=7.0 Hz, 3H); MS: (ES) m/z calculated for C20H22ClF3N5O [M+H]+ 440.1, found 439.9. Retention time on chiral HPLC: 5.9 min (RegisPack cat#783104, 25 cm×4.6 mm, 5 micron; eluent: 0.1% diethylamine/IPA, 1.0 ml/min). The er is determined to be 20:1 with the (R)-enantiomer having a retentime of 3.4 min. Absolute configuration of the (R)-enantiomer was confirmed by an independent synthesis from methyl (L)-lactate.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[C:19]([C:20](O)=[O:21])=[CH:18][C:12]2[NH:13][C:14](=[O:17])[CH2:15][O:16][C:11]=2[C:10]=1[F:23].ClC(OCC(C)C)=O>C1COCC1>[F:8][C:9]1[C:19]([CH2:20][OH:21])=[CH:18][C:12]2[NH:13][C:14](=[O:17])[CH2:15][O:16][C:11]=2[C:10]=1[F:23]
Reactant: O=C1COc2c(cc(C(=O)O)c(F)c2F)N1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1COc2c(cc(CO)c(F)c2F)N1
Reaction time: 2 h
Yield: 34 %

Procedure:
Triethylamine (2.4 mL, 17.3 mmol) was added to a suspension of 7,8-difluoro-4H-benzo[1,4]oxazine-3-one-6-carboxylic acid (3.6 g, 15.7 mmol) in anhydrous THF (250 mL). Isobutyl chloroformate (2.2 mL, 17.3 mmol) was added to the mixture at ice cold temperature over 0.5 hour. Stirring was continued for further 2 hours at room temperature. It was then cooled in ice and the solid was removed by filtration. The filtrate was added to a cold solution of sodium borohydride (3.2 g) in water. The mixture was stirred in cold for 1 hour before it was concentrated in vacuo to half and acidified with 2M hydrochloric acid. The resulting solid precipitate was collected by filtration and dried to give the title compound (1.15 g, 22%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.[Br-].[Mg+2].[CH2:10]=[CH2:11].[Br-]>O1CCCC1.CO>[C:10]([C:4]1([OH:7])[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)#[CH:11]
Reactant: C=C
Reactant: O=C1CCOCC1
Agent: [Br-]
Agent: [Mg+2]
Solvent: C1CCOC1
Solvent: CO
Product: C#CC1(O)CCOCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.2 %

Procedure:
A solution of tetrahydro-4H-pyran-4-one (1.25 g, 12.5 mmol) in tetrahydrofuran (10 mL) was cooled to 0° C. and then treated with a 0.5M solution of ethylene magnesium bromide in tetrahydrofuran (40 mL, 20 mmol). The mixture was stirred at 0° C. for 2 h and at 25° C. for 4 h. The resulting mixture was cooled to 0° C. and then diluted with methanol (10 ml). The solvents were concentrated in vacuo, and the residue was extracted with a saturated aqueous ammonium chloride solution and ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was dried in vacuo to afford solid 4-ethynyl-tetrahydro-pyran-4-ol (1.2 g, 95.2%).
Reaction SMILES: Br[Mg][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:5][CH:4]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:29]([CH:30]=[O:31])=[C:28]([CH:32]([CH3:34])[CH3:33])[CH:27]=[C:26]3[C:21]=2[C:22](=[O:37])[CH2:23][C:24]([CH3:36])([CH3:35])[O:25]3)=[CH:16][CH:15]=1.C(=O)(O)[O-].[Na+]>O1CCCC1>[C:9]([C:6]1[CH:7]=[CH:8][C:3]([CH:30]([OH:31])[C:29]2[C:20]([C:17]3[CH:16]=[CH:15][C:14]([F:13])=[CH:19][CH:18]=3)=[C:21]3[C:26](=[CH:27][C:28]=2[CH:32]([CH3:34])[CH3:33])[O:25][C:24]([CH3:35])([CH3:36])[CH2:23][C:22]3=[O:37])=[CH:4][CH:5]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1C=O)C(=O)CC(C)(C)O2
Reactant: CC(C)(C)c1ccc([Mg]Br)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1C(O)c1ccc(C(C)(C)C)cc1)C(=O)CC(C)(C)O2
Reaction time: 0.75 h

Procedure:
At −78° C., 2.12 ml (1.06 mmol) of a freshly prepared 0.5 M solution of bromo(4-tert-butylphenyl)magnesium in tetrahydrofuran are slowly added dropwise to a solution of 300 mg (880 μmol) of 5-(4-fluorophenyl)-7-isopropyl-2,2-dimethyl-4-oxochroman-6-carbaldehyde (Example 20A) in 7 ml of tetrahydrofuran. The mixture is then allowed to thaw slowly to −20° C. and stirred at this temperature for 45 min. 10% strength sodium bicarbonate solution is then added, the mixture is extracted three times with ethyl acetate and the combined organic phases are washed with saturated sodium chloride solution. The organic phases are dried over magnesium sulfate, the solvent is then removed under reduced pressure and the residue is purified by column chromatography on silica gel (mobile phase: gradient cyclohexane→cyclohexane/ethyl acetate 10:1).
Reaction SMILES: C(N(CC)C(C)C)(C)C.O[C@@H:11]1[CH2:15][CH2:14][O:13][C:12]1=[O:16].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[Cl:32][C:33]1[C:41]([F:42])=[CH:40][CH:39]=[C:38]2[C:34]=1[CH2:35][CH2:36][NH:37]2>C(Cl)Cl>[Cl:32][C:33]1[C:41]([F:42])=[CH:40][CH:39]=[C:38]2[C:34]=1[CH2:35][CH2:36][N:37]2[C@H:11]1[CH2:15][CH2:14][O:13][C:12]1=[O:16]
Reactant: O=C1OCC[C@H]1O
Reactant: Fc1ccc2c(c1Cl)CCN2
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C1OCC[C@@H]1N1CCc2c1ccc(F)c2Cl
Temperature: -40 °C
Reaction time: 1 h
Yield: 91.4 %

Procedure:
Prepared using general procedure 57. Under an N2 atmosphere at −40° C., N,N-diisopropylethylamine (34.1 mL, 196 mmol) was added dropwise to a solution of solution of (R)-dihydro-3-hydroxyfuran-2(3H)-one (10.0 g, 98 mmol) in CH2Cl2 (100 mL). Trifluoromethanesulfonic anhydride (17.3 mL, 103 mmol) was added dropwise to this solution maintaining the internal temperature of the reaction mixture below −40° C. Upon completion of addition, the mixture was stirred at −40° C. for 1 h. A solution of 4-chloro-5-fluoroindoline (27.6, 147 mmol) in CH2Cl2 (40 mL) was added dropwise to this solution maintaining the internal temperature of the reaction mixture below −40° C. The reaction was allowed to warm up to −20° C. and was kept at this temperature for 48 h. The reaction mixture was washed with saturated aqueous sodium bicarbonate (2×), brine, dried over magnesium sulfate, and concentrated. Purification via silica gel chromatography using 0-40% ethyl acetate in hexane gave (S)-3-(4-chloro-5-fluoroindolin-1-yl)-dihydrofuran-2(3H)-one as a white solid (22.9 g, 90%). 1H NMR (400 MHz, DMSO-d6) δ 7.07-7.02 (m, 1H), 6.50 (dd, J=3.6, 8.6 Hz, 1H), 4.88 (dd, J=9.0, 11.4 Hz, 1H), 4.44-4.39 (m, 1H), 4.29-4.22 (m, 1H), 3.60-3.54 (m, 1H), 3.28 (dd, J=8.6, 17.8 Hz, 1H), 3.07-2.92 (m, 2H), 2.43-2.28 (m, 2H). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=256.1; tR=1.54 min.
Reaction SMILES: [CH2:1]([N:3]([C:29](=O)[C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([F:37])[CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].Cl[CH2:40][C:41]([N:43]1[CH2:47][CH2:46][CH2:45][CH2:44]1)=O>>[CH2:1]([N:3]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:40][CH2:41][N:43]2[CH2:47][CH2:46][CH2:45][CH2:44]2)=[C:32]([F:37])[CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: O=C(CCl)N1CCCC1
Reactant: CCN(C(=O)c1ccc(O)c(F)c1)c1cc(OC)ccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCN(Cc1ccc(OCCN2CCCC2)c(F)c1)c1cc(OC)ccc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 13.5 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(3-fluoro-4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and 2-chloro-1-pyrrolidin-1-ylethanone (11 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (2.7 mg) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Br:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[C:3]=1[CH3:16].[Br:17]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([Br:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[C:3]=1[CH2:16][Br:17]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1c(Br)cc(Br)nc1-c1ccccc1Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ccccc1-c1nc(Br)cc(Br)c1CBr
Reaction time: 6 h

Procedure:
To a suspension of 6.3 g of 4,6-dibromo-2-(2-chlorophenyl)-3-methylpyridine (COMPOUND W-1) in 75 mL of CCl4 was added 3.7 g of N-bromosuccinimide and 420 mg of benzoyl peroxide. The mixture was heated to reflux and stirred at this temperature for 6 h, then cooled and concentrated. The residue was dissolved in 150 mL of 1:1 hexanes-Et2O and filtered through a pad of silica gel, then purified in two batches by flash chromatography on Biotage 40M columns, eluting with a gradient system of 99:1 to 97:3 hexanes-Et2O, to yield the title compound as a white solid.
Reaction SMILES: [F:1][N:2]([F:20])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11]C(=O)C2C=CC=CC=2)=[CH:7][CH:6]=1.Cl>CO>[F:1][N:2]([F:20])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1
Reactant: O=C(Oc1ccc(CCN(F)F)cc1)c1ccccc1
Agent: Cl
Solvent: CO
Product: Oc1ccc(CCN(F)F)cc1
Yield: 49.3 %

Procedure:
N,N-Difluoro-O-benzoyltyramine (130 mg.) in methanol saturated with HCl was heated at 60° C. for 3 hours. The title compound (40 mg, 40%), isolated by preparative layer chromatography on silica gel, was a liquid at room temperature, and exhibited 1H n.m.r. signals, (CDCl3) at δ 3.0 (2H, t, J=8 Hz, Ar--CH2 --CH2 --), δ 3.6 (2H, tt, JHH =8 Hz, JHF =27 Hz, --CH2CH2NF2), δ 4.9 (1H, bs, exchangeable with D2O, --OH) and δ 6.8 (4H, m, aromatic protons); 19F n.m.r. signals (CDCl3) at φ*-55.3 (t, JHF =27 Hz, --CH2NF2). The mass spectrum had a molecular ion at m/e 173 [Accurate mass: M(173)=173.0653; calc. for C8H9NF2O=173.0652].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([CH2:15][CH3:16])([CH2:13][CH3:14])[C:6]=2[CH:17]=1.[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21](I)[C:20]=1[Cl:26]>>[Cl:18][C:19]1[C:20]([Cl:26])=[CH:21][CH:22]=[CH:23][C:24]=1[NH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([CH2:15][CH3:16])([CH2:13][CH3:14])[C:6]=2[CH:17]=1
Reactant: Clc1cccc(I)c1Cl
Reactant: CCC1(CC)OC(=O)N(C)c2ccc(N)cc21
Product: CCC1(CC)OC(=O)N(C)c2ccc(Nc3cccc(Cl)c3Cl)cc21

Procedure:
Prepared from 6-amino-4,4-diethyl-1-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one and 1,2-dichloro-3-iodobenzene according to the coupling procedure described in example 2. 1H NMR (DMSO-d6): δ 7.83 (s, 1H), 7.17 (m, 2H), 7.06 (d, J=8.7 Hz, 1H), 7.03 (m, 2H), 6.94 (dd, J=8.3, 1.4 Hz, 1H), 3.28 (s, 3H), 1.97 (m, 4H), 0.81 (t, J=7.3 Hz, 6H); MS (ESI) m/z [M+H]+ (379/381/383); Anal. calcd for C19H20Cl2N2O2: C, 60.17; H, 5.32; N, 7.39. Found: C, 59.80; H, 4.96; N, 7.13.
Reaction SMILES: C([O:3][CH:4](OCC)[C:5]1[NH:6][C:7]([CH:28](OCC)[O:29]CC)=[C:8]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])[C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])C.Cl>CC(C)=O>[CH:4]([C:5]1[NH:6][C:7]([CH:28]=[O:29])=[C:8]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])[C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:3]
Reactant: CCOC(=O)C1=C(C(OCC)OCC)NC(C(OCC)OCC)=C(C(=O)OCC)C1c1ccccc1Cl
Agent: Cl
Solvent: CC(C)=O
Product: CCOC(=O)C1=C(C=O)NC(C=O)=C(C(=O)OCC)C1c1ccccc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 109.5 %

Procedure:
To a solution of diethyl 2,6-bis(diethoxymethyl)-4-(2-chlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylate (1.7 g) in acetone (17 ml) was added 6N-hydrochloric acid (1.5 ml) and stirred at room temperature for 3 hours. After removing the solvent, the residue was extracted with diethyl ether and the extract was washed with water and dried. The solvent was removed from the extract to give diethyl 2,6-diformyl-4-(2-chlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylate (1.35 g). The product was recrystallized from diethyl ether to give pure yellowish granules, m.p. 85° to 86° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:22])=[CH:4][C:5]([F:21])=[C:6]([C@:8]2([CH3:20])[C:14]([F:16])([F:15])[C:13]([CH3:18])([CH3:17])[O:12][CH2:11][C:10](=[S:19])[NH:9]2)[CH:7]=1.[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([C:30](O)=[O:31])=[N:28][CH:29]=1>>[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]([NH:1][C:2]2[CH:7]=[C:6]([C@:8]3([CH3:20])[C:14]([F:15])([F:16])[C:13]([CH3:17])([CH3:18])[O:12][CH2:11][C:10](=[S:19])[NH:9]3)[C:5]([F:21])=[CH:4][C:3]=2[F:22])=[O:31])=[N:28][CH:29]=1
Reactant: CC1(C)OCC(=S)N[C@](C)(c2cc(N)c(F)cc2F)C1(F)F
Reactant: O=C(O)c1ccc(Cl)cn1
Product: CC1(C)OCC(=S)N[C@](C)(c2cc(NC(=O)c3ccc(Cl)cn3)c(F)cc2F)C1(F)F
Yield: 91 %

Procedure:
The compound was prepared in an analogous manner as described for intermediate B14A from (R)-5-(5-amino-2,4-difluorophenyl)-6,6-difluoro-5,7,7-trimethyl-[1,4]oxazepane-3-thione (intermediate A17C) (70 mg, 0.208 mmol) and commercially available 5-chloro-pyridine-2-carboxylic acid [CAS No. 86873-60-1] (49 mg, 0.312 mmol). The compound was obtained as a white solid (90 mg, 91%). MS (ISP): m/z=476.1 [(M+H)+] and 478.1 [(M+2+H)+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8](C)[C:9](=O)OC(C)(C)C)=[CH:5][C:4]=1[N:19]([CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)[S:20]([CH3:23])(=[O:22])=[O:21].Cl.O1CCOCC1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][NH:8][CH3:9])=[CH:5][C:4]=1[N:19]([CH2:24][CH2:25][N:26]1[CH2:27][CH2:28][O:29][CH2:30][CH2:31]1)[S:20]([CH3:23])(=[O:22])=[O:21]
Reactant: COc1ccc(CN(C)C(=O)OC(C)(C)C)cc1N(CCN1CCOCC1)S(C)(=O)=O
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CNCc1ccc(OC)c(N(CCN2CCOCC2)S(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
tert-Butyl 4-methoxy-3-(N-(2-morpholinoethyl)methylsulfonamido)benzyl-(methyl)carbamate (114 mg, 0.249 mmol) was dissolved in dry DCM (6 ml), and HCl 4M in dioxane (500 μl, 2.000 mmol) was added. The reaction was stirred at RT for 24 hours. The solvent was evaporated under vacuum and N-(2-methoxy-5-((methylamino)methyl)phenyl)-N-(2-morpholinoethyl)methanesulfonamide was obtained as hydrochloride salt (89 mg, 0.249 mmol, 100% yield, MS/ESI+ 358.1 [MH]+) that was used in the next step without further purification.