Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH:56]1[CH2:61][CH2:60][S:59](=[O:63])(=[O:62])[CH2:58][CH2:57]1>CN(C=O)C>[O:62]=[S:59]1(=[O:63])[CH2:60][CH2:61][N:56]([C:19]([C:18]2[CH:17]=[N:16][C:15]([O:14][CH2:13][C:12]3[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[N:9][O:10][C:11]=3[CH3:24])=[CH:23][CH:22]=2)=[O:21])[CH2:57][CH2:58]1
Reactant: Cc1onc(-c2ccc(F)cc2)c1COc1ccc(C(=O)O)cn1
Reactant: O=S1(=O)CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1onc(-c2ccc(F)cc2)c1COc1ccc(C(=O)N2CCS(=O)(=O)CC2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.5 %

Procedure:
To a solution of 6-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid (99 mg, 0.33 mmol (69 mg, 0.2 mmol)) in DMF (300 μL) were added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (71 mg, 0.22 mmol), N,N-diisopropyl ethyl amine (171 μL, 1.0 mmol) and thiomorpholine-S,S-dioxide (17.3 μL, 0.22 mmol). The resulting reaction mixture was stirred for 1 h at room temperature. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 1:1) afforded the title compound (73 mg, 55%) as a white solid. MS: m/e=446.1 [M+H]+.
Reaction SMILES: N1C2C(=NC=CC=2)N([N:10]2[C:14](/[CH:15]=[C:16]3\[C:17](=[O:26])[NH:18][C:19]4[C:24]\3=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)=[C:13]([CH3:27])[C:12]([C:28]([O-])=[O:29])=[C:11]2[CH3:31])N=1.CN([CH:35]=[O:36])C>>[O:36]=[C:35]1[CH2:16][CH2:15][CH:14]([NH:10][C:28]([C:12]2[C:13]([CH3:27])=[C:14](/[CH:15]=[C:16]3\[C:17](=[O:26])[NH:18][C:19]4[C:24]\3=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[NH:10][C:11]=2[CH3:31])=[O:29])[CH2:13][CH2:12]1
Reactant: Cc1c(C(=O)[O-])c(C)n(-n2nnc3cccnc32)c1/C=C1\C(=O)Nc2ccc(F)cc21
Reactant: CN(C)C=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)NC1CCC(=O)CC1
Temperature: 25 °C
Yield: 26 %

Procedure:
To the solution of (Z)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl-5-[(5-fluoro-2-oxoindolin-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxylate (A4) (0.2 g, 0.48 mmol) in 25 mL of DMF solution was added compound 7b (0.13 g, 0.58=01), the reaction mixture was stirred at room temperature for several hours. LC/MS detection was applied to determine completion of the reaction. DMF was evaporated under reduced pressure and the residue was precipitated with 5% diethylamine/methanol (25 mL) under sonication. The solid was collected by filtration and washed with methanol (5 mL*2), dried under vacuum to provide the title compound (50 mg, 26% yield) as orange solid. 1H NMR (300 MHz, DMSO-d6): δ=13.68 (s, 1H), 10.89 (s, 1H), 7.70-7.78 (m, 3H), 6.82-6.93 (m, 2H), 4.21-4.28 (m, 1H), 2.41-2.49 (m, 8H), 2.28-2.31 (m, 2H), 2.07-2.13 (m, 2H), 1.76-1.80 (m, 2H). LC/MS: 394.3 [M−H]+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:12][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15](O)=[O:16].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[NH2:12][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([NH:11][C:8]1[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:10][CH:9]=1)=[O:16]
Reactant: CC(C)(C)c1ccc(N)cc1
Reactant: Nc1ccccc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1ccc(NC(=O)c2ccccc2N)cc1
Temperature: 50 °C

Procedure:
A mixture of 4-tert-butyl-phenylamine (5.8 mL, 36.5 mmol), 2-amino-benzoic acid (5.0 g, 36.5 mmol), TBTU (12.9 g, 40.2 mmol) and DIEA (6.7 mL, 40.2 mmol) in 5 mL of DMF was heated (50° C.) for 12 h in a sealed tube. The mixture was diluted with EtOAc and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (SiO2, 20% EtOAc/hexane) and crystallized from EtOH:H2O (3:1) to afford a yellow solid. MS (ES+): 269.4. (M+H)+. Calc'd for C17H20N2O-268.35.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][CH:6]1[CH2:8][CH2:9]SC)=[O:4].O[O:21][S:22]([O-:24])=O.[K+].[CH3:26]O>O>[CH3:1][O:2][C:3]([C:5]1([NH:12][C:13]([O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:14])[CH2:7][CH:6]1[CH2:8][CH2:9][S:22]([CH3:26])(=[O:24])=[O:21])=[O:4]
Reactant: O=S([O-])OO
Reactant: COC(=O)C1(NC(=O)OC(C)(C)C)CC1CCSC
Reactant: CO
Agent: [K+]
Solvent: O
Product: COC(=O)C1(NC(=O)OC(C)(C)C)CC1CCS(C)(=O)=O
Reaction time: 2 h
Yield: 71 %

Procedure:
A solution of 1-tert-butoxycarbonylamino-2-(2-methylsulfanylethyl)-cyclopropanecarboxylic acid methyl ester (0.63 g, 2.2 mmol) in 10 mL MeOH was added slowly to a suspension of Oxone (2.0 g, 3.3 mmol) in 10 mL H2O at rt. After 2 h at rt, the solvent was removed in vacuo and the residue was taken up in EtOAc and H2O (15 mL each). The aqueous layer was extracted with 3×10 mL EtOAc. The combined organics were washed with brine and dried over anhydrous MgSO4. Following concentration in vacuo, the residue was purified by column chromatography on SiO2 (0→65% EtOAc/hexanes) to produce 1-tert-butoxycarbonylamino-2-(2-methanesulfonylethyl)-cyclopropanecarboxylic acid methyl ester (0.50 g, 71%) as a colorless film. LCMS found 222.0 [(M-Boc)+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:16][CH2:15][C:14]([CH2:20][CH2:21][O:22][CH3:23])([C:17](O)=[O:18])[CH2:13][CH2:12]1)(=[O:10])=[O:9].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[CH2:48]([O:50][C:51](=[O:60])[CH2:52][C:53]1[CH:58]=[CH:57][C:56]([NH2:59])=[CH:55][CH:54]=1)[CH3:49].CN1CCOCC1>C1COCC1>[CH2:48]([O:50][C:51](=[O:60])[CH2:52][C:53]1[CH:54]=[CH:55][C:56]([NH:59][C:17]([C:14]2([CH2:20][CH2:21][O:22][CH3:23])[CH2:13][CH2:12][N:11]([S:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])(=[O:9])=[O:10])[CH2:16][CH2:15]2)=[O:18])=[CH:57][CH:58]=1)[CH3:49]
Reactant: COCCC1(C(=O)O)CCN(S(=O)(=O)c2ccccc2Cl)CC1
Reactant: CCOC(=O)Cc1ccc(N)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CCOC(=O)Cc1ccc(NC(=O)C2(CCOC)CCN(S(=O)(=O)c3ccccc3Cl)CC2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 60.6 %

Procedure:
1-(2-Chloro-benzenesulfonyl)-4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid (2.82 g) were dissolved in THF (30 ml) under an argon atmosphere at RT and then sequentially treated with O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (3.26 g), (4-amino-phenyl)-acetic acid ethyl ester (1.536 g) and N-methyl morpholine (1.04 ml). The reaction mixture was stirred 12 h at RT, and 1 h at reflux to complete the reaction. The mixture was partitioned between AcOEt and 1N HCl/water, the layers were separated; the organic layer was dried over sodium sulphate and then removed in vacuo. The residue was purified by chromatography on silica gel (CH2Cl2/AcOEt, 19/1 to 9/1) to give the desired (4-{[1-(2-chloro-benzenesulfonyl)-4-(2-methoxy-ethyl)-piperidine-4-carbonyl]-amino}-phenyl)-acetic acid ethyl ester (2.47 g) which was directly used in the next step.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:35])[C:15](=[O:34])[CH2:16][O:17][C:18]2[N:23]=[C:22]([CH3:24])[C:21]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[C:20]([CH3:33])[N:19]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1>CO.[Pd]>[CH3:24][C:22]1[C:21]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:29])[CH3:30])=[C:20]([CH3:33])[N:19]=[C:18]([O:17][CH2:16][C:15]([N:14]([CH3:35])[CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[O:34])[N:23]=1
Reactant: Cc1nc(OCC(=O)N(C)C2CCN(Cc3ccccc3)CC2)nc(C)c1NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: Cc1nc(OCC(=O)N(C)C2CCNCC2)nc(C)c1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.3 %

Procedure:
Pd—C (371 mg) was added to a solution of Compound 30 (3.7 g) in methanol (111 ml) and then, hydrogenation was carried out by stirring the mixture at atmospheric pressure and room temperature overnight. Subsequently, the catalyst was removed by filtration and the filtrate was concentrated under reduced pressure to give 2.9 g (96% yield) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14](SC)=[NH:15])=[CH:9][C:8]=2[O:18][CH3:19])[CH:6]=1.[Cl:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]([C:29]1[CH:34]=[C:33]([F:35])[C:32]([F:36])=[C:31]([F:37])[CH:30]=1)[C:26](O)=O.[NH2:38][NH2:39]>>[Cl:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]([C:26]1[NH:39][N:38]=[C:14]([NH:13][C:10]2[CH:11]=[CH:12][C:7]([N:5]3[CH:6]=[C:2]([Cl:1])[N:3]=[CH:4]3)=[C:8]([O:18][CH3:19])[CH:9]=2)[N:15]=1)[C:29]1[CH:34]=[C:33]([F:35])[C:32]([F:36])=[C:31]([F:37])[CH:30]=1
Reactant: O=C(O)C(CCCCCl)c1cc(F)c(F)c(F)c1
Reactant: COc1cc(NC(=N)SC)ccc1-n1cnc(Cl)c1
Reactant: NN
Product: COc1cc(Nc2n[nH]c(C(CCCCCl)c3cc(F)c(F)c(F)c3)n2)ccc1-n1cnc(Cl)c1
Yield: 100 %

Procedure:
Methyl 4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylcarbamimidothioate (1.5 g, 5.05 mmol, from preparation A) and 6-chloro-2-(3,4,5-trifluorophenyl)hexanoic acid (1.419 g, 5.05 mmol, from preparation AN) were coupled and then reacted with hydrazine (0.635 mL, 20.23 mmol) using a procedure analogous to Step A of Example 13. The crude product, 5-(5-chloro-1-(3,4,5-trifluorophenyl)pentyl)-N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-1H-1,2,4-triazol-3-amine (2.77 g, 100% yield), was used in the subsequent step without purification. LC-MS (M+H)+ 525.3.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:9]([Mg]Cl)([CH3:12])([CH3:11])[CH3:10].C(OCC)C>C1COCC1.[Cl-].[Na+].O.[Cu](I)I>[C:9]([C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: Clc1cccnc1Cl
Reactant: CC(C)(C)[Mg]Cl
Agent: I[Cu]I
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)c1ncccc1Cl
Temperature: 0 °C

Procedure:
2,3-Dichloropyridine (1.0 g, 6.8 mmol) and copper iodide (0.065 g, 0.341 mmol) were dissolved in THF (6 mL). The mixture was degassed three times then cooled to 0° C. with an ice bath. Then tert-butyl(chloro)magnesium in diethylether (5.10 mL, 10.2 mmol) was added dropwise to the reaction mixture under a nitrogen atmosphere keeping the temperature at 0° C. with an ice bath. When the addition was complete, it was left to warm up to room temperature for 16 hours. Brine was slowly added to the reaction mixture (20 mL) and the product extracted with TBME (20 mL). The organic layer was then dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting crude was purified by silica gel chromatography eluting with 0 to 5% EtOAc in heptane to yield the title compound as a yellow oil (0.108 g, 0.6392 mmol).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:7]=[C:6]([Cl:8])[S:5][C:4]=1[S:9]([NH2:12])(=[O:11])=[O:10].[CH3:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][N:19]=[C:20]=S>>[Cl:8][C:6]1[S:5][C:4]2[S:9](=[O:10])(=[O:11])[N:12]=[C:20]([NH:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH3:13])[NH:2][C:3]=2[CH:7]=1
Reactant: Nc1cc(Cl)sc1S(N)(=O)=O
Reactant: CCCCCCN=C=S
Agent: Cl
Product: CCCCCCNC1=NS(=O)(=O)c2sc(Cl)cc2N1

Procedure:
The title compound was prepared from 3-amino-5-chlorothiophene-2-sulfonamide hydrochloride and n-hexyl isothiocyanate by a procedure analogous to the procedure described in example 3Bc-d; mp 207°-209° C.; 1H-NMR (DMSO-d6): δ 0.87 (distorted t, 3H), 1.28 (m, 6H), 1.51 (m, 2H), 3.17 (q, 2H), 7.05 (s, 1H), 7.30 (br. s, 1H), 11.01 (s, 1H).
Reaction SMILES: O[Li].O.C([O:6][C:7](=[O:25])[CH2:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]2=[O:24])=[CH:14][CH:13]=1)=[O:10])C>CO.C1COCC1.O>[O:24]=[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][N:18]1[C:15]1[CH:14]=[CH:13][C:12]([NH:11][C:9](=[O:10])[CH2:8][C:7]([OH:25])=[O:6])=[CH:17][CH:16]=1
Reactant: CCOC(=O)CC(=O)Nc1ccc(-n2ccccc2=O)cc1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)CC(=O)Nc1ccc(-n2ccccc2=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.5 %

Procedure:
LiOH.H2O (56 mg, 1.3 mmol) was added to a solution of N-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-malonamic acid ethyl ester (200 mg, 0.6 mmol) in methanol (0.5 mL), THF (1 mL) and H2O (0.5 mL) and the resulting mixture was stirred for 1 hour at room temperature then concentrated. The residue was diluted with water and acidified with concentrated HCl. The resulting precipitate was isolated by filtration to afford 156 mg (86%) of N-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-malonamic acid. 1H NMR: (DMSO-d6): δ 12.8 (s, 1H), 10.3 (s, 1H), 7.78-7.6 (m, 3H), 7.5 (t, 1H), 7.4-7.3 (m, 2H), 6.5 (d, 1H), 6.38 (t, 1H), 3.4 (d, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:20][C:21]4[NH:22][C:23](=O)NC[C:26]=4[N:27]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].CI.[CH3:40][N:41]([CH:43]=[O:44])[CH3:42]>>[C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:19]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:20][C:40]4[N:41]([CH3:42])[C:43](=[O:44])[N:22]([CH3:23])[CH2:21][C:26]=4[N:27]=3)=[CH:16][CH:17]=2)[CH2:9][CH2:10][CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=O)NC4)cc2)CCC1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: CN1Cc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc2N(C)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
To a solution of tert-butyl(1-(4-(2-oxo-7-phenyl-1,2,3,4-tetrahydropyrido[3,2-d]pyrimidin-6-yl)phenyl)cyclobutyl)carbamate (46 mg, 0.10 mmol) in dry DMF (1 ml) at −78 C was added sodium hydride (3.9 mg, 0.10 mmol) and methyliodide (6.1 μl, 0.10 mmol) under nitrogen. The bath was removed and the resulting mixture was stirred for 1 h at room temperature. The mixture was cooled down to −78 C. Sodium hydride (3.9 mg, 0.10 mmol) and methyliodide (6.10, μl, 0.10 mmol) were added under nitrogen. The bath was removed and the resulting mixture was stirred for 1 h at room temperature. Water was added and the mixture was extracted with EtOAc (3×10 ml). The combined organic phases were dried over Na2SO4 and concentrated to dryness under reduced pressure. The resulting residue was purified by Biotage silica gel chromatography (gradient 0 to 50% EtOAc in cyclohexane) to give the title compound (30 mg, 61%). 1H NMR (500 MHz, CDCl3): 7.20-7.19 (7H, m), 7.13-7.11 (2H, m), 7.02 (1H, s), 5.00 (1H, br s), 4.56 (2H, s), 3.27 (3H, s), 3.03 (3H, s), 2.52-2.20 (4H, m), 2.00-1.95 (1H, m), 1.79-1.65 (1H, m), 1.40-1.10 (9H, br)
Reaction SMILES: [CH2:1]([C@H:8]1[C@@H:13]([O:14][CH2:15][C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=2)[CH2:12][CH2:11][NH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH2:31]([N:33]([CH2:39][CH3:40])[CH2:34][CH2:35][C:36](O)=[O:37])[CH3:32].CCN(CC)CC.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.O>[CH2:1]([C@H:8]1[C@@H:13]([O:14][CH2:15][C:16]2[CH:17]=[C:18]([C:26]([F:29])([F:27])[F:28])[CH:19]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:21]=2)[CH2:12][CH2:11][N:10]([C:36](=[O:37])[CH2:35][CH2:34][N:33]([CH2:39][CH3:40])[CH2:31][CH3:32])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC)CCC(=O)O
Reactant: FC(F)(F)c1cc(CO[C@H]2CCNC[C@H]2Cc2ccccc2)cc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)CCC(=O)N1CC[C@H](OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 42767.1 %

Procedure:
To a solution of the compound (0.15 g) obtained in Example 404, 3-diethylaminopropionic acid hydrochloride (0.078 mg), Et3N (0.150 ml) and HoBt.H2O (0.083 mg) in DMF (2 ml), WSC.HCl (0.138 mg) was added, and the reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure, and then the residue was dissolved in ethyl acetate. The organic layer was washed with an aqueous saturated sodium bicarbonate solution and brine, dried, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by preparative thin layer chromatography to obtain the title compound as pale yellow oil (0.100 g, 51%).
Reaction SMILES: ClC(OCC(C)C)=O.CN1CCOCC1.[O:16]1[CH2:21][CH2:20][N:19]([CH2:22][C:23]#[C:24][C:25]([OH:27])=O)[CH2:18][CH2:17]1.[NH2:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[N:35]=[CH:34][C:33]([C:39]#[N:40])=[C:32]2[NH:41][C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([Br:48])[CH:43]=1>O1CCCC1.N1C=CC=CC=1>[Br:48][C:44]1[CH:43]=[C:42]([NH:41][C:32]2[C:31]3[C:36](=[CH:37][CH:38]=[C:29]([NH:28][C:25](=[O:27])[C:24]#[C:23][CH2:22][N:19]4[CH2:18][CH2:17][O:16][CH2:21][CH2:20]4)[CH:30]=3)[N:35]=[CH:34][C:33]=2[C:39]#[N:40])[CH:47]=[CH:46][CH:45]=1
Reactant: O=C(O)C#CCN1CCOCC1
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1cccc(Br)c1
Agent: CC(C)COC(=O)Cl
Solvent: c1ccncc1
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: N#Cc1cnc2ccc(NC(=O)C#CCN3CCOCC3)cc2c1Nc1cccc(Br)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 26.5 %

Procedure:
Isobutyl chloroformate (0.161 g, 1.18 mmol) and N-methylmorpholine (0.150 g, 1.48 mmol) were added to an ice cold solution of 0.250 g (1.48 mmol) of 4-morpholino-2-butynoic acid in 10 mL of tetrahydrofuran under N2. After stirring for 30 min, a solution of 0.250 g (0.74 mmol) of 6-amino-4-[(3-bromophenyl)amino]-3-quinolinecarbonitrile in 8 mL of pyridine was added and the mixture was stirred at 0° C. for 2 h. The reaction was quenched with ice water and then poured into saturated sodium bicarbonate and brine. The product was collected, washed with ethyl acetate, and dried in vacuo to give 0.096 g (27%) of yellow solid; ESMS m/z 490.1 (M+H+); mp 112-115° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:18]([OH:20])=O)[C:5]2[CH:10]=[N:9][N:8]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:6]=2[N:7]=1.[NH2:21][CH2:22][C:23]1[C:24](=[O:31])[NH:25][C:26]([CH3:30])=[CH:27][C:28]=1[CH3:29].ON1C2N=CC=CC=2N=N1.C(Cl)CCl.CN1CCOCC1>CS(C)=O>[CH3:29][C:28]1[CH:27]=[C:26]([CH3:30])[NH:25][C:24](=[O:31])[C:23]=1[CH2:22][NH:21][C:18]([C:4]1[C:5]2[CH:10]=[N:9][N:8]([CH2:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:6]=2[N:7]=[C:2]([CH3:1])[CH:3]=1)=[O:20]
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Reactant: Cc1cc(C(=O)O)c2cnn(Cc3ccccc3)c2n1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CS(C)=O
Solvent: CN1CCOCC1
Product: Cc1cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c2cnn(Cc3ccccc3)c2n1

Procedure:
The title compound was prepared in the same manner as described for intermediate 56 using 6-methyl-1-(phenylmethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (200 mg, 0.748 mmol), 3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone (142 mg, 0.935 mmol), 1-hydroxy-7-azabenzotriazole (204 mg, 1.497 mmol), DMSO (10 mL), EDC (287 mg, 1.497 mmol), and N-methylmorpholine (0.329 mL, 2.99 mmol). The final product was collected as 0.25 g (83%). LCMS E-S (M+H)=402.2. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.93-1.12 (m, 4H), 1.42 (d, J=6.82 Hz, 6H), 2.12 (s, 3H), 2.22 (s, 4H), 2.36 (s, 3H), 4.34 (d, J=4.80 Hz, 2H), 4.90-5.11 (m, 1H), 5.87 (s, 1H), 6.99 (s, 1H), 8.58 (s, 1H), 11.51 (s, 1H.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:22])=[CH:4][C:5]2[O:15][CH2:14][C:13](=[O:16])[C:12]3[S:11][C:10]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:9][C:8]=3[C:6]=2[CH:7]=1.[CH:23]([Mg]Br)([CH3:25])[CH3:24].OC1(C)C2SC(C(N)=O)=NC=2C2C=C(C#CC(O)(C)C)C=CC=2OC1>>[Br:1][C:2]1[C:3]([F:22])=[CH:4][C:5]2[O:15][CH2:14][C:13]([OH:16])([CH:23]([CH3:25])[CH3:24])[C:12]3[S:11][C:10]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:9][C:8]=3[C:6]=2[CH:7]=1
Reactant: CC(C)[Mg]Br
Reactant: CCOC(=O)c1nc2c(s1)C(=O)COc1cc(F)c(Br)cc1-2
Agent: CC(C)(O)C#Cc1ccc2c(c1)-c1nc(C(N)=O)sc1C(C)(O)CO2
Product: CCOC(=O)c1nc2c(s1)C(O)(C(C)C)COc1cc(F)c(Br)cc1-2

Procedure:
Ethyl 9-bromo-8-fluoro-4-oxo-[1]benzoxepino[5,4-d]thiazole-2-carboxylate (133 mg) was reacted with isopropylmagnesium bromide similarly to as described in the synthesis of 4-Hydroxy-9-(3-hydroxy-3-methyl-but-1-ynyl)-4-methyl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo {e}azulene-2-carboxylic amide with non-critical modifications to afford ethyl 9-bromo-8-fluoro-4-hydroxy-4-isopropyl-5H-[1]benzoxepino[5,4-d]thiazole-2-carboxylate. Ethyl 9-bromo-8-fluoro-4-hydroxy-4-isopropyl-5H-[1]benzoxepino[5,4-d]thiazole-2-carboxylate (80 mg) was reacted with (3R)-3-ethynyl-3-hydroxy-1-methyl-pyrrolidin-2-one similarly to as described in General Procedure F with non-critical modifications to afford ethyl 8-fluoro-4-hydroxy-9-[2-[(3R)-3-hydroxy-1-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]-4-isopropyl-5H-[1]benzoxepino[5,4-d]thiazole-2-carboxylate which was directed subjected to General Procedure M to afford 12 mg and 13 mg (29% overall yield) after reverse phase purification then chiral separation. The absolute stereochemistry at the 4-hydroxyl substitution position for each isomer was not determined.
Reaction SMILES: [Cl:1][CH:2]([CH3:13])[CH2:3][NH:4][C:5]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:12].[CH3:14][C:15]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:16]=1[NH2:17].[I-].[K+]>C(O)(C)C>[ClH:1].[CH3:12][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([CH3:11])[C:5]=1[NH:4][CH2:3][CH:2]([NH:17][C:16]1[C:18]([CH3:22])=[CH:19][CH:20]=[CH:21][C:15]=1[CH3:14])[CH3:13]
Reactant: Cc1cccc(C)c1NCC(C)Cl
Reactant: Cc1cccc(C)c1N
Agent: [I-]
Agent: [K+]
Solvent: CC(C)O
Product: Cc1cccc(C)c1NCC(C)Nc1c(C)cccc1C
Product: Cl
Temperature: 80 °C
Reaction time: 3 h
Yield: 48.4 %

Procedure:
A mixture of 86 g (0.435 moles) of N-(β-chloropropyl)-2,6-dimethyl-aniline, prepared as described in point (a) above, 110 ml (107.4 g, 0.88 moles) of 2,6-dimethylaniline and 4.2 g (25 mmoles) of potassium iodide is stirred at 140° to 145° C. for 3 hours under nitrogen atmosphere. The mixture is allowed to cool to about 80° C., 300 ml of isopropanol are added, the resulting mixture is allowed to cool to room temperature under stirring, and then allowed to stand overnight. The separated precipitate is filtered off, washed with cold (+5° C.) isopropanol and dried. 67.1 g (42.4%) of crude 1,2-bis(2',6'-dimethylphenyl-amino)-propane hydrochloride (fraction A) are obtained. The filtrate is admixed with 200 ml of 20% aqueous hydrochloric acid, and the mixture is allowed to stand for 24 hours. The separated precipitate is filtered off, washed with water and dried. In this way further 48 g (34.6%) of crude 1,2-bis(2',6'-dimethylphenyl-amino)propane hydrochloride (fraction B) are obtained, thus the total yield is 83.0%. Fractions A and B are combined, dissolved in a mixture of 500 ml of dimethyl formamide and 250 ml of water, and the solution is rendered alkaline (pH=10) with 10 n aqueous sodium hydroxide solution. The solution is admixed with 2 liters of water, the separated precipitate is filtered off, washed with water, and dried. 87.15 g (70.9%) of 1,2-bis(2',6'-dimethylphenyl-amino)-propane (m.p.: 52°-55° C.) are obtained. This product is sufficiently pure to apply it directly in the next step.