Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:20])[CH:14]=2)[NH:9]1.[NH2:21][C:22]([CH3:27])([CH3:26])[C:23]([OH:25])=[O:24].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[Cl:20][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:21][C:22]([CH3:27])([CH3:26])[C:23]([OH:25])=[O:24])[CH2:17][C:16]2([CH3:19])[CH3:18]
Reactant: CC(C)(N)C(=O)O
Reactant: CC1(C)CC(c2ccccc2Br)Nc2ccc(Cl)cc21
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(Nc1ccccc1C1CC(C)(C)c2cc(Cl)ccc2N1)C(=O)O
Temperature: 25 °C
Yield: 59.8 %

Procedure:
A solution of 2-(2-bromo-phenyl)-6-chloro-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline (200 mg, 0.57 mmol), copper(I) iodide (33 mg, 0.17 mmol), 2-amino-2-methyl-propionic acid (235 mg, 2.29 mmol) and potassium carbonate (240 mg, 1.7 mmol) in dimethyl sulfoxide (2.0 mL) was stirred at 120° C. for 16 h. Then the reaction mixture was cooled to room temperature and extracted with ethyl acetate (150 mL×2), washed with water (50 mL×2) and saturated aqueous ammonium chloride solution (50 mL×2), dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2-[2-(6-chloro-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamino]-2-methyl-propionic acid (127 mg, 60.0%) as a white solid: LC/MS m/e obsd. (ESI+) [(M+H)+] 373.1.
Reaction SMILES: CS[CH:3]1[N:6]([CH2:7][C:8](=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5](=[O:16])[CH2:4]1.[Cl:17]Cl>C(Cl)(Cl)(Cl)Cl>[Cl:17][CH:3]1[N:6]([CH2:7][C:8](=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5](=[O:16])[CH2:4]1
Reactant: ClCl
Reactant: CCOC(=O)CC(=O)CN1C(=O)CC1SC
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)CC(=O)CN1C(=O)CC1Cl
Reaction time: 0.05 h
Yield: 105.6 %

Procedure:
Ethyl 4-(4-methylthio-2-oxoazetidin-1-yl)-3-oxobutyrate (400 mg, 1.63 mmole) was dissolved in dry carbon tetrachloride (15 ml) and the solution was stirred and ice-cooled while chlorine (115 mg, 1.6 mmmole) in carbon tetrachloride (1.4 ml) was added in one portion. After addition of the chlorine, the cooling bath was removed and stirring was continued for 3 minutes. The solvent was removed under reduced pressure to yield ethyl 4-(4-chloro-2-oxoazetidin-1-yl)-3-oxobutyrate as a pale yellow gum (400 mg), νmax (CHCl3): 1785 (β-lactam C=O), 1750 and 1730 (keto-ester C=O) cm-1.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.CN(C)C=O.[NH2:25][C:26]1[CH:49]=[CH:48][C:29]([C:30]([N:32]2[C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=3[S:36](=[O:44])(=[O:43])[N:35]3[CH2:45][CH2:46][CH2:47][C@H:34]3[CH2:33]2)=[O:31])=[CH:28][CH:27]=1>O1CCCC1.ClCCl.C(Cl)(Cl)Cl.CO.N1C=CC=CC=1>[C:1]1([C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]([NH:25][C:26]2[CH:27]=[CH:28][C:29]([C:30]([N:32]3[C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=4[S:36](=[O:44])(=[O:43])[N:35]4[CH2:45][CH2:46][CH2:47][C@H:34]4[CH2:33]3)=[O:31])=[CH:48][CH:49]=2)=[O:11])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ccc(C(=O)N2C[C@@H]3CCCN3S(=O)(=O)c3ccccc32)cc1
Reactant: O=C(O)c1ccccc1-c1ccccc1
Solvent: CN(C)C=O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=C(Nc1ccc(C(=O)N2C[C@@H]3CCCN3S(=O)(=O)c3ccccc32)cc1)c1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 22.2 %

Procedure:
To a solution of 2-phenyl benzoic acid (0.1 g) in tetrahydrofuran (2 ml), there was added, with ice-cooling, 0.075 g of thionyl chloride and a catalytic amount of N,N-dimethylformamide and the mixture was heated under reflux for 2 hours. After concentration of the reaction solution, the resulting acid chloride was dissolved in 3 ml of dichloromethane and the resulting solution was dropwise added to a solution of (11aS)-10-(4-aminobenzoyl)-1,2,3,10,11,11a-hexahydro-pyrrolo[1,2-b][1,2,5]benzothiadiazepin-5,5-dioxide (0.15 g) prepared in Reference Example 37 and pyridine (0.05 g) in dichloromethane (3 ml) at room temperature for 15 minutes. After stirring the reaction solution at room temperature for 3 hours, it was poured into ice water and then extracted with ethyl acetate. The resulting organic phase was washed with water and dried over anhydrous magnesium sulfate. After concentration of the organic phase, the resulting residue was subjected to silica gel column chromatography and then eluted with chloroform/methanol (49/1) to thus give 0.05 g (yield 22.6%) of the title compound.
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].[Cl:6][CH2:7][CH2:8][CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)=O>CO.Cl.O>[OH:18][C:15]1[CH:16]=[CH:17][C:12]([C:10](=[N:1][NH:2][C:3](=[S:4])[NH2:5])[CH2:9][CH2:8][CH2:7][Cl:6])=[CH:13][CH:14]=1
Reactant: NNC(N)=S
Reactant: O=C(CCCCl)c1ccc(O)cc1
Agent: Cl
Solvent: CO
Solvent: O
Product: NC(=S)NN=C(CCCCl)c1ccc(O)cc1
Temperature: 25 °C
Yield: 61.3 %

Procedure:
Thiosemicarbazide (6.84 g, 75 mmol) was added under nitrogen to a solution of 4-chloro-4'-hydroxybutyrophenone (10.0 g, 50 mmol) in 175 mL of methanol plus 13.5 mL of 1 N HCl plus 12.5 mL of water and the reaction stirred room temperature for forty hours. The reaction was concentrated under reduced pressure to remove most of the methanol. The residue was partitioned between methylene chloride and water. The organic layer was separated, dried (MgSO4) and the solvent removed under reduced pressure to give 8.33 g of a white solid. Recrystallization of the solid from isopropyl alcohol gave 3.19 g (21%) of the title compound as a light yellow solid, mp 126-129° C.
Reaction SMILES: [C:1]([C:5]1[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=1[O:7][C:8]1[C:13]([NH2:14])=[CH:12][CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].[C:19](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:20]>C(Cl)Cl>[C:1]([C:5]1[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=1[O:7][C:8]1[C:13]([N:14]=[C:19]=[S:20])=[CH:12][CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Reactant: CC(C)(C)c1ccccc1Oc1ncccc1N
Solvent: ClCCl
Product: CC(C)(C)c1ccccc1Oc1ncccc1N=C=S
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 2-(2-tert-Butylphenoxy)-3-aminopyridine (Example 203b) (5.21 g, 21.5 mmol) and 1,1′-thiocarbonyldi-2(1H)-pyridone (5 g, 21.5 mmol) in DCM (100 mL) was stirred at rt for 18 h. The mixture was evaporated and the solid was dissolved in hexanes/DCM (50 mL, 9/1). The residual solid was removed by filtration and the solution was evaporated to provide the title compound as a brown solid. (M+H)+=285.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[C:9]([C:13]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Na+]>O>[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[C:9]([C:13]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1cc(-c2ncccc2F)c(Cl)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cc(-c2ncccc2F)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.4 %

Procedure:
To the organic solution of methyl 2,4-dichloro-5-(3-fluoropyridin-2-yl)benzoate (from Preparation 43A, 1.95 mol) was added a solution of sodium hydroxide (234 g, 5.85 mol) in water (2.8 L) and the reaction stirred at room temperature for 1 hour. The mixture was concentrated in vacuo to remove organic solvents to a volume of approximately 5 L. The remaining aqueous phase was washed with ethyl acetate (3×2 L) and then acidified to pH2 with aqueous HCl (2 M). The resulting precipitate was collected by filtration and washed with water (2 L). The solid was ground to a fine powder and slurried with diethyl ether (2.5 L) and filtered to afford the title compound as an off-white solid (181 g).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][O:5][C:6]2=[O:11].[O:12]=[C:13]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:14](O)=[O:15].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl>ClCCl.O>[O:12]=[C:13]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:14]([NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][O:5][C:6]2=[O:11])=[O:15]
Reactant: O=C(O)C(=O)c1ccccc1
Reactant: Nc1cccc2c1COC2=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O
Product: O=C(Nc1cccc2c1COC2=O)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.3 %

Procedure:
To a solution of 4-aminoisobenzofuran-1(3H)-one (4.0 g, 26.8 mmol), 2-oxo-2-phenylacetic acid (4.1 g, 26.8 mmol), and HBTU (15.2 g, 40.2 mmol) in dichloromethane (240 mL) was added TEA (8 mL). The reaction mixture was stirred at room temperature overnight. The resulting mixture was added water and adjusted to pH=6-7 with 1% aq. HCl, and then was filtered. The filtrate was extracted with ethyl acetate. The ethyl acetate layer was evaporated and the crude product was purified by gradient chromatography (silica gel, petroleum ether/ethyl acetate 6:1 to 3:1) to give the title compound (5.0 g, yield 66%). LC-MS (ESI) m/z: 282 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:24])([C@H:16]([S:18][CH:19]([CH2:22][OH:23])[CH2:20][OH:21])[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.[F:25][C:26]([F:38])([F:37])[C:27]1[CH:36]=[CH:35][C:30](/[CH:31]=[CH:32]/[CH:33]=O)=[CH:29][CH:28]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:24])([C@H:16]([S:18][C@@H:19]1[CH2:20][O:21][C@@H:33](/[CH:32]=[CH:31]/[C:30]2[CH:35]=[CH:36][C:27]([C:26]([F:25])([F:37])[F:38])=[CH:28][CH:29]=2)[O:23][CH2:22]1)[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: C[C@@H](SC(CO)CO)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: O=C/C=C/c1ccc(C(F)(F)F)cc1
Product: C[C@@H](S[C@H]1CO[C@H](/C=C/c2ccc(C(F)(F)F)cc2)OC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
Reaction and treatment were carried out in the same manner as in Example 4 using (2R,3R)-2-(2,4-difluorophenyl)-3-[(1,3-dihydroxy-2-propyl)thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanol and trans-4-(trifluoromethyl)cinnamaldehyde as described in Reference example 22 to obtain the desired compound as a major product (yield: 62%). Physical data and spectral data coincided with those of the compound described in Example 2.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([CH:18]=[CH:19][N:20]=2)[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])[C:7]=1[C:8]#[N:9].B.C1COCC1.Cl.CO>C1COCC1.O1CCOCC1>[NH2:9][CH2:8][C:7]1[C:6]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])=[CH:5][N:4]2[CH:18]=[CH:19][N:20]=[C:3]2[C:2]=1[NH2:1]
Reactant: N#Cc1c(-c2ccc(Cl)cc2Cl)cn2ccnc2c1N
Agent: B
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: NCc1c(-c2ccc(Cl)cc2Cl)cn2ccnc2c1N
Temperature: 0 °C
Yield: 60.9 %

Procedure:
To a solution of 8-amino-6-(2,4-dichloro-phenyl)-imidazo[1,2-a]pyridine-7-carbonitrile (32.5 mg, 0.11 mmol) in THF (1 mL) was added a BH3.THF complex (1.0 M solution in THF, 0.43 mL, 0.43 mmol) followed by 4 M HCl in dioxane (2 drops). The reaction mixture was stirred and refluxed for 4 h, then cooled to 0° C. (ice bath) and poured into MeOH. The mixture was concentrated under vacuum, then the remaining residue was dissolved in TFA, evaporated to dryness and purified by reverse phase prep-HPLC (Waters system) to give the title compound (2TFA salt, 35.7 mg, 0.067 mmol, 62%). MS: 307 [M+1]+; HPLC: AtRet=0.99.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C:11]#[N:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:13]([Mg]Br)[CH3:14].B(F)(F)F.CCOCC.[OH-].[Na+].Cl>C(OCC)C.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH2:1]([O:8][CH2:9][CH2:10][C:11]1([NH2:12])[CH2:14][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CCCOCc1ccccc1
Reactant: CC[Mg]Br
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: Cl
Solvent: CCOCC
Product: NC1(CCOCc2ccccc2)CC1
Reaction time: 0.5 h
Yield: 55 %

Procedure:
To a solution of 3-(benzyloxy)propanenitrile (16.9 g 105 mmol) in diethyl ether (400 mL) were added titanium isopropoxide (35.7 mL, 115 mmol) and ethyl magnesium bromide (210 mL, 1 M in diethyl ether) successively at room temperature. After being stirred for 0.5 hour, boron trifluoride etherate (27 mL, 525 mmol) was added. After stirring for another 0.5 hour, 10% aqueous solution of sodium hydroxide (ca. 5.5 mL) was introduced to the above mixture. The resulting mixture was acidified with 1N hydrochloric acid to pH 3, and then washed with dichloromethane. The aqueous layer was basified with 5% aqueous solution of sodium hydroxide to pH 8˜9 and extracted with dichloromethane (100 mL). The organic layer was washed with brine (100 mL), dried over sodium sulfate and concentrated in vacuo to afford 11 g of 1-[2-(benzyloxy)ethyl]cyclopropanamine (yield was 55%).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][NH:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([CH2:18][C:19]([NH:21][C@H:22]2[CH2:27][C:26]3[CH:28]=[CH:29][CH:30]=[C:31]([C:32]([OH:34])=[O:33])[C:25]=3[O:24][B:23]2[OH:35])=[O:20])[CH2:14][CH2:13]1)(C(C)(C)C)(C)C.Cl>O1CCOCC1>[OH:35][B:23]1[C@@H:22]([NH:21][C:19](=[O:20])[CH2:18][C@H:15]2[CH2:16][CH2:17][C@H:12]([NH:11][CH2:10][CH2:9][OH:8])[CH2:13][CH2:14]2)[CH2:27][C:26]2[CH:28]=[CH:29][CH:30]=[C:31]([C:32]([OH:34])=[O:33])[C:25]=2[O:24]1
Reactant: CC(C)(C)[Si](C)(C)OCCN[C@H]1CC[C@H](CC(=O)N[C@H]2Cc3cccc(C(=O)O)c3OB2O)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(C[C@H]1CC[C@H](NCCO)CC1)N[C@H]1Cc2cccc(C(=O)O)c2OB1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To (R)-3-(2-(trans-4-(2-(tert-butyldimethylsilyloxy)ethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid from step 1 (100 mg) in a flask was added 4 mL 4N HCl in dioxane. The resulting reaction mixture was stirred at RT for 2 hr. The solvent was removed in vacuo and the residue was purified by reverse phase preparative HPLC and dried using lyophilization. ESI-MS m/z 391 (MH)+.
Reaction SMILES: [C:1]1([C:7]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[CH2:12][CH2:11][CH2:10][CH2:9][C:8]2=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C2CCCCC2=O)C=CC=CC=1.ClC1C=CC=CN=1.[H-].[Na+].[CH:42]([C:45]1[CH:50]=[CH:49][CH:48]=[C:47]([CH:51]([CH3:53])[CH3:52])[C:46]=1[N:54]=[C:55]=[O:56])([CH3:44])[CH3:43].C([N-]C(C)C)(C)C.[Li+]>>[CH3:44][CH:42]([C:45]1[CH:50]=[CH:49][CH:48]=[C:47]([CH:51]([CH3:52])[CH3:53])[C:46]=1[NH:54][C:55]([CH:9]1[CH2:10][CH2:11][CH2:12][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[C:8]1=[O:13])=[O:56])[CH3:43]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: O=C1CCCCC1(c1ccccc1)c1ccccn1
Agent: CC(C)[N-]C(C)C
Agent: Clc1ccccn1
Agent: O=C1CCCCC1c1ccccc1
Product: CC(C)c1cccc(C(C)C)c1NC(=O)C1CCCC(c2ccccc2)(c2ccccn2)C1=O

Procedure:
The title compound was prepared from 2-phenyl-2-(2-pyridyl)-cyclohexanone (4.50 g, 0.017 mol, prepared from the alkylation of 2-phenylcyclohexanone with 2-chloropyridine and sodium hydride), 2,6-diisopropyl-phenyl isocyanate (3.60 g, 0.017 mol), and lithium diisopropylamide (0.017 mol) using the procedure described in Example 1.
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]21[CH2:18][C:17]1[C:12](=[CH:13][CH:14]=[C:15]([NH:19][C:20]3[CH:21]=[C:22]([CH:26]=[CH:27][N:28]=3)[C:23]([OH:25])=O)[CH:16]=1)[CH2:11]2.[CH3:29][CH:30]1[CH2:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[NH:31]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH3:29][CH:30]1[CH2:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:31]1[C:23]([C:22]1[CH:26]=[CH:27][N:28]=[C:20]([NH:19][C:15]2[CH:16]=[C:17]3[C:12](=[CH:13][CH:14]=2)[CH2:11][C:3]2([C:4]4[C:5](=[N:6][CH:7]=[CH:8][CH:9]=4)[NH:10][C:2]2=[O:1])[CH2:18]3)[CH:21]=1)=[O:25]
Reactant: CC1Cc2ccccc2N1
Reactant: O=C(O)c1ccnc(Nc2ccc3c(c2)CC2(C3)C(=O)Nc3ncccc32)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1Cc2ccccc2N1C(=O)c1ccnc(Nc2ccc3c(c2)CC2(C3)C(=O)Nc3ncccc32)c1

Procedure:
150 mg (0.40 mmol) 2-(2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-ylamino)isonicotinic acid, 55 μL (0.42 mmol) 2-methylindoline, 0.15 mL (0.87 mmol) DIPEA and 130 mg (0.41 mmol) TBTU in 1.8 mL DMF were stirred overnight at RT. The purification was carried out by preparative HPLC-MS. The product-containing fractions were combined and lyophilised.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][O:5][C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[C:3]1[C:14]([O:16][CH2:17][CH3:18])=[O:15].[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][N:26]=2)[C:21]([CH:28]=O)=[CH:20]1.N1CCCCC1>C(O)C>[NH:19]1[C:27]2=[N:26][CH:25]=[CH:24][CH:23]=[C:22]2[C:21]([CH:28]=[C:6]2[O:5][C:4]([NH:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=3)=[C:3]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:2]2=[O:1])=[CH:20]1
Reactant: CCOC(=O)C1=C(Nc2ccccn2)OCC1=O
Reactant: O=Cc1c[nH]c2ncccc12
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOC(=O)C1=C(Nc2ccccn2)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 2.5 %

Procedure:
To a solution of ethyl 4-oxo-2-(2-pyridinylamino)-4,5-dihydrofuran-3-carboxylate (0.080 g, 0.32 mmol) which similarly prepared according to the procedure described in the Example 4, First step and 7-azaindole-3-carboxaldehyde (0.047 g, 0.32 mmol) in ethanol (2.0 mL), piperidine (0.038 mL, 0.39 mmol) was added at ambient temperature. The mixture was refluxed for 10 h. Cooled to ambient temperature, the precipitate was removed by filtration and the filtrate was purified by preparative HPLC to afford the titled compound as solid (0.0030 g, y. 2.5%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:21]C)[CH:17]=3)[CH:12]=2)=[NH:10])=[CH:4][CH:3]=1.B(Br)(Br)Br.C([O-])(O)=O.[Na+]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([OH:21])[CH:17]=3)[CH:12]=2)=[NH:10])=[CH:4][CH:3]=1
Reactant: COc1ccc2cc(C(=N)Nc3ccc(Cl)cc3)ccc2c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: N=C(Nc1ccc(Cl)cc1)c1ccc2cc(O)ccc2c1
Temperature: 25 °C
Yield: 14.3 %

Procedure:
To a suspension of 0.104 g (0.33 mmol) of N-(4-chloro-phenyl)-6-methoxy -naphthalene-2-carboxamidine in 5 mL of dichloromethane was added 1.5 mL (1 M, 1.5 mmol) of BBr3 in dichloromethane at 0° C. It was warmed to room temperature overnight, poured into 125 mL of saturated NaHCO3 and extracted with three 50 mL portions of ethyl acetate. The combined organic extracts were washed with 125 mL of brine, dried over Na2SO4, filtered and concentrated. The residue was purified by preparative TLC eluting with 50% ethyl acetate in hexanes plus 1% NH4OH to give 0.014 g of N-(4-chloro-phenyl)-6-hydroxy-naphthalene-2-carboxamidine.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:22])[C:4]1[CH:5]=[CH:6][C:7]2[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9][C:8]=2[CH:21]=1.[C:23]([C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[O:34][CH:35]([CH3:37])[CH3:36])[C:28](O)=O)#[N:24].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[C:23]([C:25]1[CH:26]=[C:27]([C:28]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[CH:6][C:7]4[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH2:9][C:8]=4[CH:21]=3)[N:22]=2)[CH:31]=[CH:32][C:33]=1[O:34][CH:35]([CH3:36])[CH3:37])#[N:24]
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc(C(=N)NO)cc2C1
Reactant: CC(C)Oc1ccc(C(=O)O)cc1C#N
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(-c2nc(-c3ccc4c(c3)CN(C(=O)OC(C)(C)C)CCO4)no2)cc1C#N
Temperature: 120 °C
Reaction time: 3 h
Yield: 31.5 %

Procedure:
A solution of 1,1-dimethylethyl 7-[(hydroxyamino)(imino)methyl]-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (Preparation 75) (0.84 g, 2.73 mmol), 3-cyano-4-[(1-methylethyl)oxy]benzoic acid (can be prepared as described in WO2005/58848) (0.617 g, 3.01 mmol), EDC (0.786 g, 4.10 mmol) and HOBT (0.502 g, 3.28 mmol) in DMF (10 ml) was stirred at RT overnight. Additional EDC (0.4 g) was added and the reaction stirred for 3 hours. Then additional 3-cyano-4-[(1-methylethyl)oxy]benzoic acid (0.3 g) was added, the reaction heated at 120° C. for 1 hour and left standing overnight. The reaction mixture was partitioned between EtOAc/water, and the organic layer collected, dried (MgSO4) and evaporated. The resulting crude was purified by flash chromatography eluting with EtOAc/iso-hexane 20-30%. Analysis of the puried fractions by LCMS showed some 3-cyano-4-[(1-methylethyl)oxy]benzoic acid present so sodium bicarbonate and EtOAc was added. The EtOAc layer was separated, dried (MgSO4) and evaporated to give the title compound (410 mg) as a white solid. MS (ES): C26H28N4O5 requires 476; found 421 [M+H−56]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][CH:14]1[CH2:16][CH2:15]1)[C:6]([CH2:17]Cl)=[C:5]2[O:19][CH2:20][CH2:21][CH2:22][CH3:23].[C:24]1(=[O:34])[NH:28][C:27](=[O:29])[C:26]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:25]12.[K].O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][CH:14]1[CH2:16][CH2:15]1)[C:6]([CH2:17][N:28]1[C:24](=[O:34])[C:25]3[C:26](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:27]1=[O:29])=[C:5]2[O:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CCCCOc1c(CCl)n(CC2CC2)c(=O)c2ccc(Br)cc12
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCOc1c(CN2C(=O)c3ccccc3C2=O)n(CC2CC2)c(=O)c2ccc(Br)cc12
Yield: 92.1 %

Procedure:
A solution of 6-bromo-4-butoxy-3-chloromethyl-2-cyclopropylmethyl-1(2H)-isoquinolinone (5.58 g, 14 mmol) and potassium phthalimide (3.89 g, 21 mmol) in N,N-dimethylformamide (50 mL) was stirred at room temperature for 5 h. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the extract with water, the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crystals were recrystallized from tetrahydrofuran-n-hexane to give 2-[(6-bromo-4-butoxy-2-cyclopropylmethyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methyl]-1H-isoindole-1,3(2H)-dione (6.57 g, 94.7%) as crystals.
Reaction SMILES: ClCCl.C([Mg]Cl)(C)C.Br[C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[F:17].CON(C)[C:21](=[O:34])[CH:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:23][C:24]#[CH:25]>C1COCC1>[F:17][C:11]1[CH:12]=[CH:13][C:14]([F:16])=[CH:15][C:10]=1[C:21](=[O:34])[CH:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:30])([CH3:32])[CH3:31])[CH2:23][C:24]#[CH:25]
Reactant: C#CCC(NC(=O)OC(C)(C)C)C(=O)N(C)OC
Reactant: Fc1ccc(F)c(Br)c1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: C#CCC(NC(=O)OC(C)(C)C)C(=O)c1cc(F)ccc1F
Temperature: -15 °C
Reaction time: 2 h

Procedure:
An inerted vessel was charged dichloromethane (866 kg) and cooled to −20 to −10° C. Then iso-propylmagnesium chloride solution in THF (2M, 326.1 kg, 669 mol) was slowly added followed by 1-bromo-2,5-difluorobenzene (120.1 kg, 622 mol). After 2 h at this temperature, an additional charge of iso-propylmagnesium chloride in THF solution was slowly added (2M, 58.65 kg, 121 mol) and the reaction aged 1 h. Then, a drop-wise addition of a dichloromethane solution of tert-butyl (1-[methoxy(methyl)amino]-1-oxopent-4-yn-2-yl)carbamate (70.8 kg, 276 mol in 292 kg dichloromethane) was conducted over 2 h at −20 to −20° C. The mixture was then warmed to room temperature and stirred for 10 h. The reaction was then slowly reverse quenched into aqueous ammonium chloride (175.6 kg in 1550 kg of water) at 5-10° C. The solution pH was then adjusted to ˜7 by adding 68 kg of con. HCl. The layers were then separated and the aqueous extracted with dichloromethane (414 kg). The combined organics were then dried with Na2SO4, filtered, treated with activated carbon (10 kg), filtered, and concentrated to 71-141 L. A constant volume (71-141 L) vacuum distillation solvent switch to n-heptane was then performed to crystallize the product. The slurry was then cooled to 0° C. and stirred 2 h. The slurry was filtered and the cake washed with n-heptane, 2-propanol, and then water. The solids were dried under vacuum at 40-50° C. overnight to give tert-butyl [1-(2,5-difluorophenyl)-1-oxopent-4-yn-2-yl]carbamate.