Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6](B2OC(C)(C)C(C)(C)O2)=[CH:5][CH:4]=1.C(N(C(C)C)C(C)C)C.[C:29]([O:33][C@@H:34]([C:39]1[C:40](I)=[C:41]2[C:48]3[CH2:49][CH2:50][CH2:51][CH2:52][C:47]=3[S:46][C:42]2=[N:43][C:44]=1[CH3:45])[C:35]([O:37][CH3:38])=[O:36])([CH3:32])([CH3:31])[CH3:30]>O1CCOCC1.C(OCC)(=O)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>[C:29]([O:33][C@@H:34]([C:39]1[C:40]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:18])[F:19])=[CH:8][CH:7]=2)=[C:41]2[C:48]3[CH2:49][CH2:50][CH2:51][CH2:52][C:47]=3[S:46][C:42]2=[N:43][C:44]=1[CH3:45])[C:35]([O:37][CH3:38])=[O:36])([CH3:32])([CH3:30])[CH3:31]
Reactant: CC1(C)OB(c2ccc(C(F)(F)F)cc2)OC1(C)C
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2sc3c(c2c1I)CCCC3
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2sc3c(c2c1-c1ccc(C(F)(F)F)cc1)CCCC3
Temperature: 100 °C
Yield: 72.7 %

Procedure:
2-(4-(Trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (115 g, 0.42 mmol), N-ethyl-N-isopropylpropan-2-amine (120 μL, 0.64 mmol) and water (500 μL) were added to a stirred solution of (S)-methyl 2-(tert-butoxy)-2-(4-iodo-2-methyl-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-b]pyridin-3-yl)acetate (100 mg, 0.21 mmol) in dioxane (2 mL) in a reaction tube. The reaction mixture was degassed with argon for 2 minutes, then tetrakis(triphenylphosphine)palladium(0) (25 mg, 21 μmol) was added and the vessel was sealed and heated at 100° C. for 16 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (30 mL) and water (30 mL) and the mixture was passed through a pad of celite. The layers of the filtrate were separated and the organic layer was washed with brine (30 mL), dried (MgSO4) and concentrated in vacuo to yield the crude product as a brown gum. The residue was purified by flash column chromatography eluting with ethyl acetate in heptane (10%) to give the title compound (75 mg, 72%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ=0.96 (s, 9H), 1.85-1.35 (m, 6H), 2.72 (s, 3H), 2.85-2.75 (m, 2H), 3.69 (s, 3H), 4.91 (s, 1H), 7.40 (d, 1H), 7.61 (d, 1H), 7.71 (m, 2H). LCMS (run time=5 minutes, basic): Rt=3.64 minutes; m/z 492.06 [M+H+].
Reaction SMILES: CS([C:5]1[N:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][N:6]=1)(=O)=O.[CH3:19][C:20]1([CH2:24][NH2:25])[CH2:23][O:22][CH2:21]1>>[CH3:19][C:20]1([CH2:24][NH:25][C:5]2[N:10]=[CH:9][C:8]([C:11]#[C:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:7][N:6]=2)[CH2:23][O:22][CH2:21]1
Reactant: CS(=O)(=O)c1ncc(C#Cc2ccccc2)cn1
Reactant: CC1(CN)COC1
Product: CC1(CNc2ncc(C#Cc3ccccc3)cn2)COC1

Procedure:
The title compound, white solid, MS: m/e=280.2 (M+H+), can be prepared in accordance with the general method of example 1, step 3 from 2-methanesulfonyl-5-phenylethynyl-pyrimidine (example 1, step 2) and (3-methyloxetan-3-yl)methanamine.
Reaction SMILES: F[C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH3:22][C:23]1[NH:24][C:25]2[C:30]([CH:31]=1)=[CH:29][C:28]([OH:32])=[CH:27][CH:26]=2.CCOCC>COCCOCCOC>[F:13][C:11]1[CH:10]=[CH:9][C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[C:2]([O:32][C:28]2[CH:29]=[C:30]3[C:25](=[CH:26][CH:27]=2)[NH:24][C:23]([CH3:22])=[CH:31]3)[CH:12]=1
Reactant: Cc1cc2cc(O)ccc2[nH]1
Reactant: CCOC(=O)c1ccc(F)cc1F
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: COCCOCCOC
Product: CCOC(=O)c1ccc(F)cc1Oc1ccc2[nH]c(C)cc2c1

Procedure:
Ethyl 2,4-difluorobenzoate (1.14 g), K3PO4 (1.30 g) and 2-methyl-5-indolol (0.90 g) were stirred at 110° C. in diglyme (12 mL) for 24 hours. The mixture was cooled and poured into ether. The solution was washed three times with 1M NaOH solution, and with brine, and dried. The solution was then concentrated. The concentrate was chromatographed on silica gel with 10% ethyl acetate/hexanes.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:7]2=[N:8][C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:11]=[C:6]2[CH:5]=[C:4]1[C:17]([O:19][CH2:20][CH3:21])=[O:18].[CH3:22][C@@H:23]1OS(=O)(=O)[N:25]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:24]1>CN(C=O)C>[C:33]([O:32][C:30]([NH:25][CH2:24][C@@H:23]([N:3]1[C:7]2=[N:8][C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:11]=[C:6]2[CH:5]=[C:4]1[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH3:22])=[O:31])([CH3:36])([CH3:35])[CH3:34]
Reactant: CCOC(=O)c1ccc2cc(C(=O)OCC)[nH]c2n1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)S(=O)(=O)O1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2cc(C(=O)OCC)n([C@@H](C)CNC(=O)OC(C)(C)C)c2n1
Temperature: 0 °C
Reaction time: 16 h
Yield: 62.7 %

Procedure:
To a suspension of 60% sodium hydride in mineral oil (503 mg, 12.6 mmol) in DMF (10 mL) cooled to 0° C. is added a solution of diethyl 1H-pyrrolo[2,3-b]pyridine-2,6-dicarboxylate (Intermediate D, 3.00 g, 11.4 mmol) in DMF (10 mL), dropwise. The mixture is stirred at 0° C. for 30 min after which a solution of tert-butyl (5S)-5-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (2.71 g, 11.4 mmol) in DMF (10 mL) is added. The mixture is allowed to warm and stir at room temperature for 16 h. The reaction is quenched with H2O and is stirred for 15 min. The mixture is extracted with ethyl acetate and the combined organic phases are washed with brine and are dried (Na2SO4). The solvent is removed in vacuo and the crude material is purified via flash column chromatography using a gradient elution of 0-30% ethyl acetate/heptane to afford the title compound (3.00 g, 63%). LCMS: 442.86 (M+Na+).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([C@@H:8]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9]2)=[O:7])=[CH:4][C:3]=1[F:22].C([BH-](C(CC)C)C(CC)C)(CC)C.[Li+].O>C1COCC1>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH:6]([OH:7])[C@@H:8]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])[CH2:9]2)=[CH:4][C:3]=1[F:22]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](C(=O)c2ccc(Cl)c(F)c2)C1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@@H](C(O)c2ccc(Cl)c(F)c2)C1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
(R)-tert-Butyl 3-(4-chloro-3-fluorobenzoyl)pyrrolidine-1-carboxylate (920 mg, 2.806 mmol) was dissolved in THF (14.0 mL, 0.2M), degassed with N2, and cooled to −78° C. Lithium tri-sec-butylborohydride (1M in THF; 4210 μL, 4.210 mmol) was added slowly drop wise by syringe. The reaction was then stirred at −78° C. for 30 minutes. Water (5 mL) was then added to quench the reaction. The mixture was concentrated by rotovap to remove the bulk of the THF. The remaining mixture was diluted to 50 mL with water and extracted with 4/1 dichloromethane/isopropyl alcohol (2×50 mL). The combined organics were washed with water (100 mL), were isolated, dried over sodium sulfate, filtered and concentrated. The crude product was loaded onto an SP1 samplet and purified by silica gel chromatography using a gradient from 1% to 55% ethyl acetate in hexanes. Product containing fractions were pooled and concentrated to afford (3R)-tert-butyl 3-((4-chloro-3-fluorophenyl)(hydroxy)methyl)pyrrolidine-1-carboxylate as an oil and as a 1:1 mixture of diastereomers (640 mg, 69% yield).
Reaction SMILES: [C:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([OH:11])=[O:10])[CH2:5][CH2:4]1)#[N:2].[H][H]>CO.[Pd].C>[NH2:2][CH2:1][C@H:3]1[CH2:4][CH2:5][C@H:6]([C:9]([OH:11])=[O:10])[CH2:7][CH2:8]1
Reactant: N#C[C@H]1CC[C@H](C(=O)O)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: NC[C@H]1CC[C@H](C(=O)O)CC1

Procedure:
5 g. of trans-4-cyanocyclohexane-1-carboxylic acid was dissolved in 130 ml of methanol. To this solution, 5 g. of 10 % Pd-charcoal was added and the mixture was shaken in an atmosphere of hydrogen under a normal pressure for about 8 hours until 0.066 mole of hydrogen was absorbed. The reaction product was treated as described in Example 1, and 3.5 g. of trans-4-aminomethylcyclohexane-1-carboxylic acid was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:19][CH2:20][CH2:21][C:22]([F:25])([F:24])[F:23])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:18])[NH:16][CH:17]=2)=[O:11])=[CH:4][CH:3]=1.IC.[C:28](=O)([O-])[O-].[K+].[K+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:19][CH2:20][CH2:21][C:22]([F:25])([F:23])[F:24])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:18])[N:16]([CH3:28])[CH:17]=2)=[O:11])=[CH:4][CH:3]=1
Reactant: O=C(CC(CCCC(F)(F)F)c1ccc(Br)cc1)c1ccc(=O)[nH]c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Product: Cn1cc(C(=O)CC(CCCC(F)(F)F)c2ccc(Br)cc2)ccc1=O

Procedure:
In analogy to example 161, step 1, 5-[3-(4-bromo-phenyl)-7,7,7-trifluoro-heptanoyl]-1H-pyridin-2-one was reacted with iodomethane in the presence of potassium carbonate to give the title compound as a light yellow oil, MS (ESI+): m/z=430.2 [M+H]+.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[N:8]([CH:15]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:17][CH2:16]1)[CH2:7]2.Br[CH2:29][CH:30]1[O:34][CH2:33][CH2:32][O:31]1.[K+].[Br-]>CN(C)C=O>[O:31]1[CH2:32][CH2:33][O:34][CH:30]1[CH2:29][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[N:8]([CH:15]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:17][CH2:16]1)[CH2:7]2
Reactant: BrCC1OCCO1
Reactant: O=C1Nc2ccc(O)cc2CN1C1CCN(Cc2ccccc2)CC1
Agent: [Br-]
Agent: [H-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1Nc2ccc(OCC3OCCO3)cc2CN1C1CCN(Cc2ccccc2)CC1
Temperature: 90 °C
Reaction time: 0.25 h

Procedure:
0.36 g (14.25 mmol) of 95% sodium hydride was added batchwise, with stirring, to a solution of 5.0 g (14.82 mmol) of 3,4-dihydro-6-hydroxy-3-(1-phenylmethyl-4-piperidinyl)-2(1H)-quinazolinone in 120 mL of anhydrous dimethylformamide at ambient temperature and the mixture was then kept for 15 minutes at 50° C. A thick, colorless slurry was formed. After the addition of 5.0 g (37.04 mmol) of 2-(bromomethyl)-1,3-dioxolane the mixture was heated to 90° C. for 90 minutes. After cooling, the mixture was stirred into saturated aqueous saline solution and extracted exhaustively with ethyl acetate. The combined extracts were dried over sodium sulfate and evaporated down in vacuo, the residue remaining was purified by column chromatography on silica gel (30-60 μm) using dichloromethane/EE/cyclohexane/methanol/concentrated ammonia 60/16/5/5/0.6 v/v/v/v/v as eluant. Working up the corresponding fractions yielded 2.5 g (41% of theoretical) of a colorless oil, Rf=0.47 (dichloromethane/EE/cyclohexane/methanol/concentrated ammonia 60/16/5/5/0.6 v/v/v/v/v). IR (KBr): 1662 (C═O) cm−1.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:14][C:13]2[CH2:12][CH2:11][N:10](C(OCC)=O)[CH2:9][C:8]=2[CH:7]=1)=[O:5])C.[OH-].[K+]>C(O)C>[S:14]1[C:13]2[CH2:12][CH2:11][NH:10][CH2:9][C:8]=2[CH:7]=[C:6]1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1cc2c(s1)CCN(C(=O)OCC)C2
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cc2c(s1)CCNC2

Procedure:
A solution of 6,7-Dihydro-4H-thieno[3,2-c]pyridine-2,5-dicarboxylic acid diethyl ester (1 eq) obtained in step III and aq. KOH (3 eq.) in ethanol was refluxed for 48 h Reaction mixture was concentrated under reduced pressure and neutralized to pH 7.0 to get 4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylic acid.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3](=[CH2:7])[C:4]([OH:6])=[O:5].[CH:10]([O:12][CH2:13][CH3:14])=[CH2:11]>CCOCC>[F:1][C:2]([F:9])([F:8])[C:3](=[CH2:7])[C:4]([O:6][CH:10]([O:12][CH2:13][CH3:14])[CH3:11])=[O:5]
Reactant: C=COCC
Reactant: C=C(C(=O)O)C(F)(F)F
Solvent: CCOCC
Product: C=C(C(=O)OC(C)OCC)C(F)(F)F
Reaction time: 0.25 h

Procedure:
14.0 g of 2-trifluoromethylacrylic acid (2-TFMAA) and 30 g of ethyl vinyl ether were stirred at room temperature under nitrogen and using a DRY ICE condenser. The initial endotherm gave way to a mild exotherm to approximately 33° C. and some outgassing (reflux). The reaction was complete in 15 minutes. Et2O added. Organics were washed with 10% Na2CO3 (containing a small amount of NaOH), saturated NaHCO3 and finally brine followed by drying with MgSO4. Evaporated on rotary evaporator at 30° C. Yield 29.0 g of colorless liquid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[I-:16].[Na+].[OH-].[Na+].Cl[O-].[Na+].P([O-])(O)(O)=O.[Na+]>CO.S([O-])([O-])(=O)=S.[Na+].[Na+].O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:6][C:7]=1[I:16]
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Reactant: [I-]
Agent: O=P([O-])(O)O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CO
Solvent: O
Product: N#Cc1ccc(-c2ccc(O)c(I)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.5 %

Procedure:
To a solution of 4-hydroxy-4′-cyanobiphenyl (6.00 g, 30.8 mmol), sodium iodide (4.61 g, 30.8 mmol) and sodium hydroxide (1.23 g, 30.8 mmol) in methanol (90 mL) at 0° C. was added an aqueous solution of sodium hypochlorite (47 mL of 5.25% Clorox™, 2.29 g, 30.8 mmol) over 45 minutes. The mixture was stirred cold for 1 hour, warmed to ambient temperature and diluted with sodium thiosulfate solution (10 mL), water (80 mL) and adjusted to a pH of 7 by addition of sodium dihydrogen phosphate. The mixture was extracted with dichloromethane (2×90 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure to give a white powder. The solid was crystallized from dichloroethane/hexane and chromatographed on silica with dichloromethane to give the titled compound (5.19 g, 53%). MS (DCI) m/z 339[M+NH4+]+;
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[C:5]([N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11][N:10]2[CH:18]=[CH:19][CH:20]=[C:9]2[CH2:8]1)=[O:6].[C:24]1([CH3:33])[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:33][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:2]1[CH:23]=[CH:22][CH:21]=[C:4]([C:5]([N:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[CH2:11][N:10]3[CH:18]=[CH:19][CH:20]=[C:9]3[CH2:8]2)=[O:6])[CH:3]=1
Reactant: Cc1ccccc1B(O)O
Reactant: O=C(c1cccc(Br)c1)N1Cc2cccn2Cc2ccccc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: Cc1ccccc1-c1cccc(C(=O)N2Cc3cccn3Cc3ccccc32)c1
Temperature: 75 °C
Reaction time: 16 h
Yield: 83.2 %

Procedure:
A mixture of 10-(3-bromobenzoyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine of Step A (2.0 g, 5.4 mmol), o-tolylboronic acid (0.8 g, 5.9 mmol) and potassium carbonate (2.4 g, 17.7 mmol) in ethylene glycol dimethyl ether: water (20 mL: 5 mL) was purged with nitrogen for 1 hour. [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium [II] (0.22 g, 0.26 mmol) was added and the reaction mixture heated to 75° C. with vigorous stirring for 16 hours. The cooled reaction mixture was then filtered through Celite and the cake washed with dichloromethane (100 mL). The organic phase was separated, washed with 1 M sodium hydroxide (100 mL) and brine (100 mL), dried over anhydrous potassium carbonate and concentrated in vacuo to give the crude product (2.3 g) as a dark brown solid. Purification by flash chromatography using a solvent gradient of 40% to 100% dichloromethane in hexane afforded the title compound (1.7 g, 85%) as a white solid.
Reaction SMILES: O[C@H:2]([CH2:7][CH2:8][I:9])[C:3]([O:5][CH3:6])=[O:4].N1C(C)=CC=CC=1C.[NH:18]([C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])[NH2:19]>C(Cl)Cl>[I:9][CH2:8][CH2:7][C@H:2]([NH:19][NH:18][C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)[C@H](O)CCI
Reactant: NNC(=O)OCc1ccccc1
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: COC(=O)[C@H](CCI)NNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.9 %

Procedure:
To a solution of methyl (2R)-2-hydroxy-4-iodobutanoate (3.35 g, 13.7 mmol) in DCM (100 mL) under N2 at −70° C. was added 2,6-lutidine (5.67 g, 55 mmol), followed by triflate anhydride (4.07 g, 144.4 mmol) dropwise. Stirring continued at the same temperature for 1 hour. Phenylmethyl hydrazinecarboxylate (2.74 g, 16.5 mmol) was added in one portion, and the reaction mixture was allowed to warm up to room temperature and stirred for 24 hours. The reaction mixture was concentrated, and the crude oil was purified by column chromatography (PE:EA=20:1 to 1:1) to provide phenylmethyl 2-{(1S)-3-iodo-1-[(methyloxy)carbonyl]propyl}hydrazinecarboxylate as yellow oil (3.7 g, 83%). 1H NMR (300 MHz, CDCl3) δ 7.35-7.34 (m, 5H), 6.51 (s, 1H), 5.13 (s, 2H), 4.27 (s, 1H), 3.76-3.70 (m, 4H), 3.42-3.30 (m, 2H), 2.25-2.06 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=2)[CH:7]=[C:6](Br)[CH:5]=1.COCCOC.[CH:25]1([CH2:28][N:29]2[C:33](B(O)O)=[CH:32][CH:31]=[N:30]2)[CH2:27][CH2:26]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=2)[CH:7]=[C:6]([C:33]2[N:29]([CH2:28][CH:25]3[CH2:27][CH2:26]3)[N:30]=[CH:31][CH:32]=2)[CH:5]=1
Reactant: COC(=O)c1cc(Br)cc(-c2ccc(C)cn2)c1
Reactant: OB(O)c1ccnn1CC1CC1
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1cc(-c2ccc(C)cn2)cc(-c2ccnn2CC2CC2)c1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 100.3 %

Procedure:
3-Bromo-5-(5-methyl-pyridin-2-yl)-benzoic acid methyl ester (1.0 g, 3.27 mmol) and palladium tetrakis(triphenylphosphine) (0.189 g, 0.164 mmol) were added to 25 mL DME, and the mixture was stirred at 60° C. for 10 minutes. 1-Cyclopropylmethyl-1H-pyrazole-5-boronic acid (0.65 g, 3.92 mmol) was added, followed by a solution of K3PO4 (1.39 g, 6.54 mmol) in 5 mL water. The mixture was refluxed for six hours, then cooled to room temperature and partitioned between water and EtOAc. The combined organic layers were washed with water, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified via flash chromatography (3:1 EtOAc/hexanes) to give 1.14 g of 3-(2-cyclopropylmethyl-2H-pyrazol-3-yl)-5-(5-methyl-pyridin-2-yl)-benzoic acid methyl ester, MS (M+H)=348.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([OH:9])=O)=[C:5]([CH3:10])[O:4][N:3]=1.[NH2:11][C:12]1[C:21]2[N:22]=[C:23]([CH2:28][CH2:29][CH2:30][CH3:31])[N:24]([CH2:25][CH2:26][NH2:27])[C:20]=2[C:19]2[N:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N:13]=1>>[NH2:11][C:12]1[C:21]2[N:22]=[C:23]([CH2:28][CH2:29][CH2:30][CH3:31])[N:24]([CH2:25][CH2:26][NH:27][C:7]([C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[CH3:10])=[O:9])[C:20]=2[C:19]2[N:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N:13]=1
Reactant: Cc1noc(C)c1C(=O)O
Reactant: CCCCc1nc2c(N)nc3cccnc3c2n1CCN
Product: CCCCc1nc2c(N)nc3cccnc3c2n1CCNC(=O)c1c(C)noc1C
Yield: 33.2 %

Procedure:
Using the general method of Example 97 3,5-dimethylisoxazole-4-carboxylic acid (0.25 g, 1.7 mmole) was reacted with 2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethaneamine (0.5 g, 1.7 mmol) to provide 0.23 g of N-[2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]-3,5-dimethyl-4-isoxazolecarboxamide as a white powder, m.p. 188–189° C. Analysis: Calculated for C21H25N7O2: % C, 61.90; % H, 6.18; % N, 24.06; Found: % C, 61.92; % H, 6.15; % N, 24.28. HRMS (EI) calcd for C21H25N7O2 (M+) 407.2069 found 407.2068.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH2:14][CH:15]([OH:32])[CH2:16][N:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=3[O:30][CH3:31])[CH2:19][CH2:18]2)[N:8]=1)=[O:6].Cl[C:34]1[N:39]=[C:38]([C:40]([NH2:42])=[O:41])[CH:37]=[CH:36][N:35]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[NH2:42][C:40]([C:38]1[CH:37]=[CH:36][N:35]=[C:34]([NH:1][CH2:2][CH2:3][NH:4][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH2:14][CH:15]([OH:32])[CH2:16][N:17]3[CH2:22][CH2:21][N:20]([C:23]4[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=4[O:30][CH3:31])[CH2:19][CH2:18]3)[N:8]=2)=[O:6])[N:39]=1)=[O:41]
Reactant: NC(=O)c1ccnc(Cl)n1
Reactant: COc1ccc(Cl)cc1N1CCN(CC(O)CNc2nccc(C(=O)NCCN)n2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(Cl)cc1N1CCN(CC(O)CNc2nccc(C(=O)NCCNc3nccc(C(N)=O)n3)n2)CC1

Procedure:
2.32 g (4.96 mmol) of (±)-N-(2-aminoethyl)-2-[[3-[4-(5-chloro-2-methoxyphenyl) piperazin-1-yl]-2-hydroxypropyl]amino]pyrimidine-4-carboxamide, 0.8 g (5.1mmol) of 2-chloropyrimidine-4-carboxamide and 1 g (7.2 mmol) of potassium carbonate are introduced, under an argon atmosphere, into 150 ml of acetonitrile in a 0.5 l round-bottomed flask and the mixture is heated at reflux for 17 h.
Reaction SMILES: [CH3:1][C:2]1([CH3:34])[O:6]/[C:5](=[C:7]2/[C:8](=[O:20])[NH:9][C:10]3[C:15]/2=[CH:14][C:13]([C:16]([O:18]C)=[O:17])=[CH:12][CH:11]=3)/[CH:4]=[C:3]1[C:21]1[CH:26]=[CH:25][C:24]([CH2:27][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[CH:23][CH:22]=1.[OH-].[Na+].Cl>CO>[CH3:1][C:2]1([CH3:34])[O:6]/[C:5](=[C:7]2/[C:8](=[O:20])[NH:9][C:10]3[C:15]/2=[CH:14][C:13]([C:16]([OH:18])=[O:17])=[CH:12][CH:11]=3)/[CH:4]=[C:3]1[C:21]1[CH:26]=[CH:25][C:24]([CH2:27][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[CH:23][CH:22]=1
Reactant: COC(=O)c1ccc2c(c1)/C(=C1/C=C(c3ccc(CN4CCOCC4)cc3)C(C)(C)O1)C(=O)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)O/C(=C2/C(=O)Nc3ccc(C(=O)O)cc32)C=C1c1ccc(CN2CCOCC2)cc1
Temperature: 50 °C

Procedure:
To a stirred solution of methyl (3E)-3-{5,5-dimethyl-4-[4-(morpholin-4-ylmethyl)phenyl]furan-2(5H)-ylidene}-2-oxoindoline-5-carboxylate (18 mg, 0.039 mmol) in MeOH (1 mL) was added 1M NaOH solution (1 mL, 1 mmol). The mixture was heated in 50° C. bath under nitrogen for 4 hours, cooled to room temp, and neutralized with 1M HCl to about pH 7. The mixture was extracted with 10% MeOH/CHCl3 solution (3×30 mL). The organic layers were combined, dried over Na2SO4, and evaporated to dryness to give (3E)-3-{5,5-dimethyl-4-[4-(morpholin-4-ylmethyl)phenyl]furan-2(5H)-ylidene}-2-oxoindoline-5-carboxylic acid as yellow solid. Yield: 15 mg, 88%.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Br:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[Cl:16])[C:3]=1[CH2:17][CH2:18][C:19]([NH:21][C:22]1[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=1[Cl:29])=[O:20].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.[Cu]I>[Br:8][C:6]1[CH:7]=[C:2]2[C:3]([CH2:17][CH2:18][C:19](=[O:20])[N:21]2[C:22]2[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:29])=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[Cl:16])[N:5]=1
Reactant: O=C(CCc1c(Br)cc(Br)nc1-c1ccc(F)cc1Cl)Nc1c(Cl)cccc1Cl
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1CCc2c(cc(Br)nc2-c2ccc(F)cc2Cl)N1c1c(Cl)cccc1Cl
Temperature: 155 °C

Procedure:
To 3-[4,6-dibromo-2-(2-chloro-4-fluorophenyl)pyridin-3-yl]-N-(2,6-dichlorophenyl)propanamide (3.14 g, 5.40 mmol) in DMF (50 mL) was added K2CO3 (1.49 g, 10.8 mmol) and CuI (1.54 g, 10.8 mmol). The resulting reaction mixture was evacuated and purged with argon 3 times, and then heated at 155° C. (oil bath) for 35 min. The reaction mixture was cooled to rt and diluted with 240 mL of half-saturated aqueous NaHCO3 and 120 mL of ethyl acetate. The layers were separated and the aqueous layer was extracted with 2×180 mL of ethyl acetate. The combined organic layers were washed with 120 mL of brine, dried over Na2SO4, and concentrated under reduced pressure. The product was purified by flash chromatography on 2 Biotage 40M columns, eluting with 50:50 hexanes-CH2Cl2 to yield 7-bromo-5-(2-chloro-4-fluorophenyl)-1-(2,6-dichlorophenyl)-3,4-dihydro-1,6-naphthyridin-2(1H)-one. Mass spectrum (ESI) 499.2 (M+1).