Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[CH:15]([C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:18]=1[C:27]1[CH:28]=[CH:29][C:30]([C:33]([NH:35][CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])=[O:34])=[N:31][CH:32]=1)=O.[Cl:43][C:44]1[CH:45]=[C:46]([CH:48]=[CH:49][C:50]=1[I:51])[NH2:47].CC(O)=O>CCOC(C)=O.ClCCCl>[Cl:43][C:44]1[CH:45]=[C:46]([NH:47][CH2:15][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:25])([F:24])[F:26])=[CH:19][C:18]=2[C:27]2[CH:28]=[CH:29][C:30]([C:33]([NH:35][CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])=[O:34])=[N:31][CH:32]=2)[CH:48]=[CH:49][C:50]=1[I:51]
Reactant: Nc1ccc(I)c(Cl)c1
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2cc(C(F)(F)F)ccc2C=O)cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCOC(=O)CCNC(=O)c1ccc(-c2cc(C(F)(F)F)ccc2CNc2ccc(I)c(Cl)c2)cn1
Temperature: 25 °C

Procedure:
Solid NaBH(OAc)3 (4.2 g, 19.8 mmol) was added to a DCE solution (45 mL) of ethyl 3-(5-(2-formyl-5-(trifluoromethyl)phenyl)picolinamido)propanoate, prepared as described in Example 22, (3.9 g, 9.9 mmol), 3-chloro-4-iodoaniline (3.0 g, 11.9 mmol), and AcOH (2.8 mL, 49.4 mmol) and the resulting mixture was stirred at room temperature. After 16 h the resulting mixture diluted with EtOAc washed with water and brine, dried (Na2SO4), dry-packed onto silica gel and purified via column chromatography to yield the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([N:14]([C:19]([C:21]2[C:22]([NH:31][CH2:32][CH2:33][CH2:34][O:35][CH3:36])=[N:23][C:24]([C:27]([CH3:30])([CH3:29])[CH3:28])=[N:25][CH:26]=2)=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:11][C@@H:10]([C:37]([OH:39])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:40][O:41][CH2:42][C@H:43]1[CH2:47][CH2:46][CH2:45][NH:44]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.C(N(CC)CC)C>[C:27]([C:24]1[N:23]=[C:22]([NH:31][CH2:32][CH2:33][CH2:34][O:35][CH3:36])[C:21]([C:19]([N:14]([CH2:15][CH:16]([CH3:17])[CH3:18])[C@H:12]2[CH2:11][C@@H:10]([C:37]([N:44]3[CH2:45][CH2:46][CH2:47][C@@H:43]3[CH2:42][O:41][CH3:40])=[O:39])[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13]2)=[O:20])=[CH:26][N:25]=1)([CH3:29])([CH3:28])[CH3:30]
Reactant: COCCCNc1nc(C(C)(C)C)ncc1C(=O)N(CC(C)C)[C@H]1C[C@@H](C(=O)O)CN(C(=O)OC(C)(C)C)C1
Reactant: COC[C@H]1CCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCCCNc1nc(C(C)(C)C)ncc1C(=O)N(CC(C)C)[C@H]1C[C@@H](C(=O)N2CCC[C@@H]2COC)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 75.8 %

Procedure:
(3R,5S)-1-(tert-Butoxycarbonyl)-5-[({2-tert-butyl-4-[(3-methoxypropyl)amino]pyrimidin-5-yl}carbonyl)(isobutyl)amino]piperidine-3-carboxylic acid (102 mg), (2R)-2-(methoxymethyl)pyrrolidine (64 mg), HOBt (20 mg) and triethylamine (104 μl) were dissolved in DMF (5 ml), WSC.HCl (107 mg) was added, and the mixture was stirred at room temperature for 18 hr. The reaction mixture was concentrated under reduced pressure, and diluted with saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (0:1-1:0) was concentrated under reduced pressure to give the object compound (91 mg).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:3]=1[O:4][C:5]1[CH2:9][N:8]([C@@H:10]([CH2:14][CH2:15][CH3:16])[C:11]([OH:13])=O)[C:7](=[O:17])[CH:6]=1.[CH3:23][C:24]1([CH3:36])[O:28][C@H:27]([CH2:29][N:30]2[CH:34]=[CH:33][C:32]([NH2:35])=[N:31]2)[CH2:26][O:25]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C>[CH3:23][C:24]1([CH3:36])[O:28][C@H:27]([CH2:29][N:30]2[CH:34]=[CH:33][C:32]([NH:35][C:11](=[O:13])[C@@H:10]([N:8]3[CH2:9][C:5]([O:4][C:3]4[C:18]([F:22])=[CH:19][CH:20]=[CH:21][C:2]=4[F:1])=[CH:6][C:7]3=[O:17])[CH2:14][CH2:15][CH3:16])=[N:31]2)[CH2:26][O:25]1
Reactant: CCC[C@@H](C(=O)O)N1CC(Oc2c(F)cccc2F)=CC1=O
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCC[C@@H](C(=O)Nc1ccn(C[C@@H]2COC(C)(C)O2)n1)N1CC(Oc2c(F)cccc2F)=CC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.3 %

Procedure:
To a solution of (S)-2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-pentanoic acid (0.086 g, 0.28 mmol) in dry N,N-dimethylformamide (5 mL) was added 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-ylamine (prepared as in Example 49, 0.068 g, 0.34 mmol), and benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (0.183 g, 0.41 mmol). To this mixture was added N,N-diisopropylethylamine (0.109 g, 0.85 mmol) and the resulting mixture stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with an ammonium chloride solution, a saturated sodium bicarbonate solution, saturated sodium chloride solution and then dried over magnesium sulfate. The solvents were evaporated and the residue was purified by AnaLogix flash chromatography (Teledyne Isco RediSep Flash Column 12 g, 100% ethyl acetate) which afforded (S)-2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-amide (0.102 g, 75%) as a light yellow solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 0.91 (t, J=7.2 Hz, 3H), 1.10-1.43 (m, 2H), 1.25 (s, 3H), 1.30 (s, 3H), 1.77 (q, J=7.7 Hz, 2H), 3.73 (dd, J=8.5, 6.0 Hz, 1H), 4.00 (dd, J=8.5, 6.3 Hz, 1H), 4.04-4.20 (m, 2H), 4.24-4.41 (m, 2H), 4.61 (d, J=18.7 Hz, 1H), 4.79 (t, J=7.7 Hz, 1H), 5.03 (s, 1H), 6.44 (d, J=2.1 Hz, 1H), 7.27-7.51 (m, 3H), 7.60 (d, J=2.1 Hz, 1H), 10.75 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([C:11]2[CH:12]=[N:13][C:14]3[N:15]([C:17]([C:20]4([C:23]5[CH:24]=[C:25]6[C:30](=[CH:31][CH:32]=5)[N:29]=[CH:28][CH:27]=[CH:26]6)[CH2:22][CH2:21]4)=[CH:18][N:19]=3)[CH:16]=2)[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[CH3:33][O:34][CH2:35][CH:36]([NH2:38])[CH3:37].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=C[C:49]=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[F:1][C:2]1[CH:10]=[C:9]([C:11]2[CH:12]=[N:13][C:14]3[N:15]([C:17]([C:20]4([C:23]5[CH:24]=[C:25]6[C:30](=[CH:31][CH:32]=5)[N:29]=[CH:28][CH:27]=[CH:26]6)[CH2:21][CH2:22]4)=[CH:18][N:19]=3)[CH:16]=2)[CH:8]=[CH:7][C:3]=1[C:4]([NH:38][CH:36]([CH3:37])[CH2:35][O:34][CH2:33][CH3:49])=[O:5]
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: O=C(O)c1ccc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3c2)cc1F
Reactant: COCC(C)N
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOCC(C)NC(=O)c1ccc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3c2)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzoic acid (19 mg, 0.045 mmol), 1-methoxypropan-2-amine (8 mg, 0.090 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (40 mg, 0.090 mmol), and N,N-diisopropylethylamine (31 μL, 0.18 mmol) in N,N-dimethylformamide (0.5 mL) was stirred at RT for 2 h. The reaction mixture was purified by RP-HPLC (pH 10) to afford the desired product. LCMS: (M+H)=496.1
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Cl:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[N:16]([S:19]([C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=3)(=[O:21])=[O:20])[CH:17]=[CH:18][C:11]=12.[Sn:29](Cl)([CH2:38][CH2:39][CH2:40][CH3:41])([CH2:34][CH2:35][CH2:36][CH3:37])[CH2:30][CH2:31][CH2:32][CH3:33].O>C1COCC1.CCOC(C)=O>[Cl:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[N:16]([S:19]([C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=3)(=[O:21])=[O:20])[C:17]([Sn:29]([CH2:34][CH2:35][CH2:36][CH3:37])([CH2:38][CH2:39][CH2:40][CH3:41])[CH2:30][CH2:31][CH2:32][CH3:33])=[CH:18][C:11]=12
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)ccnc32)cc1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCC[Sn](CCCC)(CCCC)c1cc2c(Cl)ccnc2n1S(=O)(=O)c1ccc(C)cc1
Temperature: -78 °C
Yield: 79 %

Procedure:
Add LDA (1.5 equiv., 0.74 mL, 1.47 mmol) dropwise in the space of 5 min to azaindole 25 (0.3 g, 0.98 mmol) in THF (15 mL), stirred at −78° C., under N2. After stirring the reaction medium for 0.5 h, add Bu3SnCl dropwise (475 mg, 400 μL, 1.47 mmol) and stir the reaction medium for a further 0.5 h. Then allow the reaction medium to return to room temperature, stop the reaction with H2O, dilute with EtOAc (200 mL), wash with brine, dry (MgSO4) and concentrate. The residue is submitted to flash chromatography to give 26 (0.46 g, 79%) as a colorless oil: 1H NMR (CDCl3) δ 8.15 (d, 1H, J=5.1 Hz), 7.97 (dd, 2H, J=8.0, 1.5 Hz), 7.27 (d, 2H, J=8.4 Hz), 7.09 (d, 1H, J=5.2 Hz), 6.75 (s, 1H), 2.36 (s, 3H), 1.65-1.20 (m, 12H), 0.93 (t, 9H), TLC (EtOAc at 40%/heptane) Rf=0.65.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([F:12])[C:3]=1[C:13]1[S:17][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22](=[O:25])[NH:21][N:20]=2)=[C:15]([C:26]([NH2:28])=[O:27])[CH:14]=1.[C:29]([O-])([O-])=O.[K+].[K+].IC.O>CN(C=O)C>[F:12][C:4]1[CH:5]=[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])[CH:7]=[C:2]([F:1])[C:3]=1[C:13]1[S:17][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22](=[O:25])[N:21]([CH3:29])[N:20]=2)=[C:15]([C:26]([NH2:28])=[O:27])[CH:14]=1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3ccc(=O)[nH]n3)s2)c(F)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1nc(Nc2sc(-c3c(F)cc(C(C)(C)O)cc3F)cc2C(N)=O)ccc1=O
Temperature: 25 °C

Procedure:
5-[2,6-Difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-2-[(6-oxo-1,6-dihydropyridazin-3-yl)amino]thiophene-3-carboxamide (Example 578 Step 3) (50 mg, 0.123 mmol), K2CO3 (18.70 mg, 0.135 mmol) and iodomethane (8.08 μL, 0.129 mmol) were stirred in DMF (1 mL) at 80° C. overnight. The reaction mixture was cooled to room temperature, water was added and the products extracted into EtOAc (2×). The combined organic extracts were washed with brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue twice by silica gel column chromatography (0-10% MeOH—CHCl3) followed by mass-triggered reverse phase HPLC gave the title compound as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:24]=[CH:23][CH:22]=[CH:21][C:4]=1[O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[S:13][C:14]([C:17]([O:19]C)=[O:18])=[CH:15][N:16]=2)[CH2:8][CH2:7]1.[OH-].[Na+].Cl>C1COCC1.CO>[F:25][C:2]([F:1])([F:26])[C:3]1[CH:24]=[CH:23][CH:22]=[CH:21][C:4]=1[O:5][CH:6]1[CH2:7][CH2:8][N:9]([C:12]2[S:13][C:14]([C:17]([OH:19])=[O:18])=[CH:15][N:16]=2)[CH2:10][CH2:11]1
Reactant: COC(=O)c1cnc(N2CCC(Oc3ccccc3C(F)(F)F)CC2)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cnc(N2CCC(Oc3ccccc3C(F)(F)F)CC2)s1
Temperature: 80 °C

Procedure:
A mixture of methyl 2-{4-[2-(trifluoromethyl)phenoxy]piperidin-1-yl}-1,3-thiazole-5-carboxylate (16 g, 41.4 mmol) and 1 N NaOH (85 mL, 85 mmol) in THF/MeOH (1:1) (v/v) (300 mL) was heated at 80° C. bath for 1 h. Volatile solvents were removed in vacuo. The residue was diluted with H2O, acidified with 1 N HCl (2.2 equiv) and extracted with EtOAc. The EtOAc extract was washed with H2O, dried (Na2SO4) and concentrated to give the title compound as a white solid.
Reaction SMILES: [C:1]1([C:7]([C:9]2[N:17](S(C3C=CC=CC=3)(=O)=O)[C:12]3=[CH:13][N:14]=[CH:15][CH:16]=[C:11]3[CH:10]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:27].[CH2:28]([O:35][NH2:36])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.N1C=CC=CC=1.[NH4+].[Cl-]>ClCCCl>[ClH:27].[CH2:28]([O:35][N:36]=[C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:9]1[NH:17][C:12]2=[CH:13][N:14]=[CH:15][CH:16]=[C:11]2[CH:10]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: NOCc1ccccc1
Reactant: O=C(c1ccccc1)c1cc2ccncc2n1S(=O)(=O)c1ccccc1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCCl
Solvent: c1ccncc1
Product: c1ccc(CON=C(c2ccccc2)c2cc3ccncc3[nH]2)cc1
Temperature: 60 °C
Reaction time: 24 h
Yield: 42 %

Procedure:
A mixture of phenyl[1-(phenylsulfonyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]methanone (Reference Example 13) (200 mg, 0.55 mmol), O-benzylhydroxylamine hydrochloride (97 mg, 0.92 mmol) and pyridine (74 μL, 0.92 mmol) in 1,2-dichloroethane (8 mL) was heated at 60° C. After 24 h, saturated NH4Cl (10 mL) was added and the mixture was extracted with EtOAc (2×25 mL). The combined extracts were washed with saturated NaCl (20 mL), dried (Na2SO4) and concentrated under reduced pressure. Purification by column chromatography (silica gel, 1:1 hexanes/EtOAc) gave phenyl(1H-pyrrolo[2,3-c]pyridin-2-yl)methanone O-benzyloxime hydrochloride (84 mg, 47%) as a mixture of isomers: mp 153-155° C.; 1H NMR (500 MHz, DMSO-d6) δ 5.35-5.40 (2H, m), 6.66 (0.5H, s), 7.12 (0.5H, s), 7.34-7.56 (10H, m), 8.07 (0.5H, d, J=6.3 Hz), 8.19 (0.5H, d, J=6.3 Hz), 8.29 (0.5H, d, J=6.3 Hz), 8.34 (0.5H, d, J=6.3 Hz), 8.99 (0.5H, s), 9.17 (0.5H, s), 13.04 (0.5H, s), 13.14 (0.5H, s), 15.14 (1H, br s); ESI MS m/z 328 [C21H17N3O+H]+; HPLC (Method A) 98.3% (AUC), tR=19.1 and 19.3 min.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][N:6]=2)[CH2:3][CH2:2]1.CI.[C:16](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:1]1([N:4]([CH3:16])[C:5]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][N:6]=2)[CH2:3][CH2:2]1
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1ccc(NC2CC2)nc1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN(c1ccc([N+](=O)[O-])cn1)C1CC1
Temperature: 200 °C

Procedure:
The intermediate, cyclopropyl-(5-nitro-pyridin-2-yl)-amine, from the above procedure, was methylated with methyl iodide. To a 2 mL microwave vial was added cyclopropyl-(5-nitro-pyridin-2-yl)-amine (146 mg, 0.812 mmol), DMF (2 mL), potassium carbonate (224 mg, 1.62 mmol), and the MeI (56 μl, 0.893 mmol). The mixture was heated by microwave for two 10 min increments at 200° C. using a Personal Chemistry, Emrys Optimizer. Then followed addition of another portion of MeI (56 μL, 0.893 mmol) microwave at 200° C. for 10 min and then conventional heating at 70° C. for 15 hr. At the end of this period a third addition of MeI (56 μL, 0.893 mmol) took place and the mixture was heated by microwave once more for 10 min at 200° C. The reaction mixture was then concentrated to dryness, suspended in ethyl acetate (100 mL) and washed with water (100 mL) two times and one time with brine. The aqueous layers were combined and extracted once with ethyl acetate (50 mL). The combined organic layer was washed once with brine (100 mL), concentrated, supported onto silica gel, and purified by flash chromatography using the Analogix system with a 12 g Silicycle silica gel column with increasing concentrations of ethyl acetate in hexanes (20 mL/min, equilibrate with 0%, 0 to 5 min: 0%; 5 to 25 min: 0 to 30%; 25-45 min: 30%). The appropriate fractions were collected and dried to afford 90 mg of cyclopropyl-methyl-(5-nitro-pyridin-2-yl)-amine, a yellow solid (yield 57%). LCMS calcd. for C9H11N3O2 (m/e) 193, observed 194 (M+H). This intermediate nitropyridyl compound was then reduced, as described in the preparation of cyclopentyl-pyridine-2,5-diamine above, to afford N2-cyclopropyl-N2-methyl pyridine-2,5-diamine. LCMS calcd. for C9H13N3 (m/e) 163, observed 164 (M+H).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH:8]([OH:11])[CH2:9][OH:10])[CH:5]=[CH:4][CH:3]=1.[NH2:12][C:13]1[S:14][C:15]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[F:27])=[CH:16][C:17]=1[C:18]([NH2:20])=[O:19]>>[OH:11][CH:8]([C:6]1[N:7]=[C:2]([NH:12][C:13]2[S:14][C:15]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])=[CH:16][C:17]=2[C:18]([NH2:20])=[O:19])[CH:3]=[CH:4][CH:5]=1)[CH2:9][OH:10]
Reactant: OCC(O)c1cccc(Br)n1
Reactant: NC(=O)c1cc(-c2ccccc2F)sc1N
Product: NC(=O)c1cc(-c2ccccc2F)sc1Nc1cccc(C(O)CO)n1

Procedure:
The title compound was prepared according to the general procedure in Example 1 using 1-(6-bromopyridin-2-yl)ethane-1,2-diol (71 mg, 0.33 mmol) and 2-amino-5-(2-fluorophenyl)thiophene-3-carboxamide (78 mg, 0.33 mmol) as the starting materials.
Reaction SMILES: Cl.Cl.[N:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]([OH:18])=O)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[CH2:19](N(CC)CC)[CH3:20].C1C=CC2N(O)N=NC=2C=1.C(N=C=NC(C)C)(C)C.C([N:47]1[CH2:52][CH2:51][CH:50]([CH2:53][C:54]([OH:56])=[O:55])[CH2:49][CH2:48]1)C>CN(C)C=O>[N:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:10][CH2:11][N:12]([CH2:15][C:16]([N:47]3[CH2:48][CH2:49][CH:50]([CH2:53][C:54]([O:56][CH2:19][CH3:20])=[O:55])[CH2:51][CH2:52]3)=[O:18])[CH2:13][CH2:14]2)=[CH:7][CH:8]=1
Reactant: CCN(CC)CC
Reactant: CCN1CCC(CC(=O)O)CC1
Reactant: O=C(O)CN1CCN(c2ccncc2)CC1
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCOC(=O)CC1CCN(C(=O)CN2CCN(c3ccncc3)CC2)CC1
Reaction time: 0.08 h

Procedure:
A solution containing 1-(4-pyridyl)-4-carboxymethylpiperazine dihydrochloride 1/4H2O(400 mg, 1.33 mMoles), triethylamine (0.4 ml, 2.66 mMoles) and HOBT (0.2 g, 1.46 mMoles) in dry dimethylformamide (20 ml) was treated with diisopropylcarbodiimide (0.23 ml, 1.46 mMoles) and the mixture was stirred for 5 minutes. Ethyl 4-carboxymethylpiperidine was added and the mixture was stirred for a further 4 hours. The mixture was concentrated to half volume under reduced pressure and then poured into water (50 ml) and extracted with ethyl acetate (3×20 ml) and dichloromethane (3×20 ml). The combined organic extracts were concentrated under reduced pressure and the residue was purified by chromatography (flash column made with grade III alumina and eluted with a gradient of 0-1% methanol in dichloromethane) to give the title compound (130 mg) as a colourless oil; NMR (d6DMSO): 0.9-1.1 (m,2H), 1.2 (t,3H), 1.65 (d,2H), 1.8-2.0 (m,1H), 2.2 (d,2H), 2.5 (m,2H), 2.9-3.4 (m,10H), 4.0 (q,2H+m,1H), 4.3 (d,1H), 6.8 (d,2H), 8.15 (d,2H); m/e 375 (M+H)+.
Reaction SMILES: C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[Br:19][C:20]1[CH:21]=[N:22][C:23]([O:29][CH3:30])=[C:24]([CH:28]=1)[C:25]([OH:27])=O.[F:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][NH2:39])=[CH:34][CH:33]=1.CCN(CC)CC>C(Cl)Cl.O>[Br:19][C:20]1[CH:21]=[N:22][C:23]([O:29][CH3:30])=[C:24]([CH:28]=1)[C:25]([NH:39][CH2:38][C:35]1[CH:36]=[CH:37][C:32]([F:31])=[CH:33][CH:34]=1)=[O:27]
Reactant: NCc1ccc(F)cc1
Reactant: COc1ncc(Br)cc1C(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ncc(Br)cc1C(=O)NCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.4 %

Procedure:
T3P (8.2 g, 25.8 mmol) was added to a solution of 5-bromo-2-methoxynicotinic acid (3 g, 12.9 mmol), (4-fluorophenyl)methanamine (1.6 g, 12.9 mmol) and Et3N (3.9 g, 38.7 mmol) in DCM (50 mL) at 0° C. The mixture was stirred at RT for 1 h. Water (50 mL) was added and the mixture was extracted with DCM. The organic layer was washed with brine and dried over Na2SO4. After being concentrated, the residue was purified by column chromatography (PE:EtOAc=4:1) to give the product of 5-bromo-N-(4-fluorobenzyl)-2-methoxynicotinamide (4.0 g, yield: 91%). 1H-NMR (CDCl3, 400 MHz) δ 8.64 (d, J=2.4 Hz, 1H), 8.31 (d, J=2.4 Hz, 1H), 8.17 (s, 1H), 7.32 (dd, J=5.2, 8.4 Hz, 2H), 7.04 (t, J=8.8 Hz, 2H), 4.63 (d, J=6.0 Hz, 2H), 4.05 (s, 3H). MS (M+H)+: 339/341
Reaction SMILES: [CH3:1][C@H:2]([OH:6])[CH2:3][C:4]#[CH:5].[F:7][C:8]1[C:9](I)=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])/[C:11]/2=[CH:18]\[C:19]1[NH:20][CH:21]=[CH:22][C:23]=1[O:24][CH3:25]>CN(C=O)C.CCN(CC)CC.CCOC(C)=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.[Cu]I>[F:7][C:8]1[C:9]([C:5]#[C:4][CH2:3][C@@H:2]([OH:6])[CH3:1])=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])/[C:11]/2=[CH:18]\[C:19]1[NH:20][CH:21]=[CH:22][C:23]=1[O:24][CH3:25]
Reactant: C#CC[C@H](C)O
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(C#CC[C@H](C)O)c21

Procedure:
Using Method C above, (S)-pent-4-yn-2-ol (44 mg, 0.52 mmol) (see below) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (50 mg, 0.13 mmol) (Starting Material 6) using (Ph3P)4Pd (15 mg, 0.01 mmol) and CuI (2 mg) in a mixture of DMF (5 mL) and Et3N (5 mL) as a solvent at 80° C. for 7 hrs. Upon completion, the reaction mixture was diluted with EtOAc and extracted with H2O. The organic layer was dried over Na2SO4 and concentrated. (S)-(Z)-1,3-Dihydro-5-fluoro-4-(4-hydroxy-1-pentynyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one was obtained after silica gel column chromatography with a 0-70% EtOAc in hexanes gradient and trituration with Et2O. (Yield 30 mg, 65%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH2:19][CH2:18][C@@H:17]([NH:26][C:27](=[O:40])[CH2:28][C:29]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])([CH3:31])[CH3:30])[C:16]2=[O:41])=[CH:10][CH:9]=1.[CH3:42][N:43]=[C:44]=[O:45].N12CCCN=C1CCCCC2>C(Cl)Cl>[CH3:42][NH:43][C:44]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[CH:10][C:11]([CH2:14][N:15]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH2:19][CH2:18][C@@H:17]([NH:26][C:27](=[O:40])[CH2:28][C:29]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])([CH3:31])[CH3:30])[C:16]2=[O:41])=[CH:12][CH:13]=1)=[O:45]
Reactant: CN=C=O
Reactant: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3O)cc2)C1=O)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CNC(=O)Oc1ccccc1-c1ccc(CN2C(=O)[C@H](NC(=O)CC(C)(C)NC(=O)OC(C)(C)C)CCc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 118.8 %

Procedure:
A solution of 100 mg (approx. 0.2 mmol) of the crude intermediate obtained in Step G in 5 mL of methylene chloride was treated with 1.0 mL of methyl isocyanate (17 mmol) and 0.1 mL of 1,8-diazabicyclo[5.4.0]undec-7-ene under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 10 minutes and then evaporated under vacuum to give 146 mg of crude product. 1H NMR (400 MHz, CDCl3): δ 1.32 (s, 3H), 1.33 (s, 3H), 1.39 (s, 9H), 2.12 (m, 1H), 2.33 (m, 1H), 2.52 (dd, 1H), 2.57 (m, 2H), 2.59 (s, 3H), 4.38 (dd, 1H), 4.8 (d, 1H), 5.26 (d, 1H), 7.10 (d, 1H), 7.36 (m, 11H).