Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]2[CH:17]=[C:18]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:28][CH:27]=3)[CH:19]=[CH:20][C:21]=2[CH2:22][CH2:23]CO)[CH:8]=[CH:9][C:10]=1[N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])([CH3:4])([CH3:3])[CH3:2].C(P(CCCCCCCC)CCCCCCCC)CCCCCCC.[C:62]([Br:66])(Br)(Br)Br.O>C(OCC)C>[Br:66][CH2:62][CH2:23][CH2:22][C:21]1[CH:20]=[CH:19][C:18]([C:26]2[CH:27]=[CH:28][C:29]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:30][CH:31]=2)=[CH:17][C:16]=1[C:7]1[CH:8]=[CH:9][C:10]([N:11]([CH2:12][CH3:13])[CH2:14][CH3:15])=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=1
Reactant: BrC(Br)(Br)Br
Reactant: CCOC(=O)c1ccc(-c2ccc(CCCO)c(-c3ccc(N(CC)CC)c(C(C)(C)C)c3)c2)cc1
Agent: CCCCCCCCP(CCCCCCCC)CCCCCCCC
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)c1ccc(-c2ccc(CCCBr)c(-c3ccc(N(CC)CC)c(C(C)(C)C)c3)c2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 83.8 %

Procedure:
6.4 g of ethyl 3″-tert-butyl-4″-diethylamino-4′-(3-hydroxypropyl)-[1,1′;3′,1″]terphenyl-4-carboxylate obtained in Example 32c (13 mmol) are dissolved in 128 mL of diethyl ether. The dissolution is performed under cold conditions (0° C.), and 11.4 mL of trioctylphosphine are then added (26 mmol) followed by addition of a solution of 8.5 g of carbon tetrabromide (26 mmol) dissolved in 10 volumes of Et2O added dropwise. The reaction medium is stirred at 0° C. for 30 minutes and then for 1 hour 30 minutes at room temperature. The reaction is stopped by adding 100 mL of water and then extracted with 100 mL of ethyl acetate. The organic phases are washed with 400 mL of water and then dried over magnesium sulfate. The solvents are evaporated off and the residue is then purified by chromatography on silica gel (eluent: 9/1 heptane/ethyl acetate). 6 g of ethyl 4′-(3-bromopropyl)-3″-tert-butyl-4″-diethylamino[1,1′;3′,1″]terphenyl-4-carboxylate are obtained (yield=83%) in the form of a thick brown oil.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]2[N:23]=[C:24]([NH:37][C:38](=[O:40])[CH3:39])[S:25][C:26]=2[C:27]2[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=2)=[CH:16][CH:15]=1.CNN>CN(C)C=O>[NH2:3][O:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][C:22]2[N:23]=[C:24]([NH:37][C:38](=[O:40])[CH3:39])[S:25][C:26]=2[C:27]2[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=2)=[CH:18][CH:19]=1
Reactant: CC(=O)Nc1nc(CCc2ccc(CON3C(=O)c4ccccc4C3=O)cc2)c(-c2ccc(S(C)(=O)=O)cc2)s1
Agent: CNN
Solvent: CN(C)C=O
Product: CC(=O)Nc1nc(CCc2ccc(CON)cc2)c(-c2ccc(S(C)(=O)=O)cc2)s1
Temperature: 20 °C
Reaction time: 4 h
Yield: 9.3 %

Procedure:
To a solution of N-{4-[2-(4-{[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)oxy]methyl}phenyl)ethyl]-5-[4-(methylsulfonyl)phenyl]-1,3-thiazol-2-yl}acetamide (116.8 mg) in N,N-dimethylformamide (1.1 ml) was added methylhydrazine (11.9 μl) under N2 atmosphere, and the mixture was stirred at 20° C. for 4 hrs. The reaction mixture was concentrated in vacuo. Ethyl acetate was added to the residue, and the precipitate was filtered off. The filtrate was concentrated in vacuo to give a crude yellow solid (105.1 mg). The crude material was purified by preparative thin-layer chromatography over silica gel with chloroform/methanol (30:1) as an eluent to give a pale yellow powder. The obtained powder was washed with acetonitrile, and the precipitate was collected by filtration to give N-{4-(2-{4-[(aminooxy)methyl]phenyl}ethyl)-5-[4-(methylsulfonyl)phenyl]-1,3-thiazol-2-yl}acetamide (8.4 mg) as a white solid.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=1.[CH3:10][Mg]I>C1COCC1>[Br:1][C:2]1[N:7]=[C:6]([CH:8]([OH:9])[CH3:10])[CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cccc(Br)n1
Reactant: C[Mg]I
Solvent: C1CCOC1
Product: CC(O)c1cccc(Br)n1
Reaction time: 1 h

Procedure:
6-Bromo-2-pyridine carboxaldehyde (1.0 g, 5.37 mmol) in dry THF (20 mL) was cooled to −78° C. followed by adding MeMgI (2.0 mL, 5.91 mmol) dropwise via the addition funnel. The cooling bath was removed. The resulting mixture was stirred for 1 h then quenched with sat. NH4Cl. Solvent was removed. The residue was partitioned between water and CHCl3. The organic layer was washed with H2O, brine, dried over MgSO4. Solvent was removed and crude compound was purified by chromatography on silica gel. Elution with hexane:acetone mixture (70:30) gave a white solid. MS m/z: 201.9(M+H). Calc'd. for C7H8BrNO-200.98.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([CH2:26][NH2:27])=[CH:22][CH:21]=2)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C:35]([C:37]1[CH:45]=[CH:44][C:40]([C:41](Cl)=[O:42])=[CH:39][CH:38]=1)#[N:36]>C1COCC1.CCOC(C)=O>[C:1]([O:5][C:6](=[O:28])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([CH2:26][NH:27][C:41](=[O:42])[C:40]3[CH:44]=[CH:45][C:37]([C:35]#[N:36])=[CH:38][CH:39]=3)=[CH:22][CH:21]=2)=[CH:11][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1ccc(OCCCOc2ccc(CN)cc2)cc1
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCc1ccc(OCCCOc2ccc(CNC(=O)c3ccc(C#N)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 60.2 %

Procedure:
To a suspension of {4-[3-(4-aminomethyl-phenoxy)-propoxy]-benzyl}-carbamic acid tert-butyl ester prepared in Example 78 (3.00 g,7.76 mmol) in THF (30 mL) was added a 10% aqueous solution of potassium carbonate (53.90 mL, 38.81 mmol). 4-Cyanobenzoyl chloride (1.29 g, 7.76 mmol) was then added in one portion and the reaction mixture was stirred at room temperature for 16 hours. The mixture was then diluted with EtOAc (150 mL), washed with 1N aqueous HCl (2×150 mL), dried over MgSO4, and concentrated to provide the desired compound as a yellow solid (2.41 g, 60% yield) which did not require any further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([NH:12][C:13]2[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=2[C:15]([O:17][CH3:18])=[O:16])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:23]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]([C:13]2[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=2[C:15]([O:17][CH3:18])=[O:16])[CH3:23])(=[O:10])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1ccccc1NS(=O)(=O)c1ccc(Cl)c(Cl)c1
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COC(=O)c1ccccc1N(C)S(=O)(=O)c1ccc(Cl)c(Cl)c1
Temperature: 40 °C

Procedure:
Methyl 2-(3,4-dichlorophenylsulfonamido)benzoate (21.3 g, 59.1 mmol) was dissolved in acetone (300 ml), and K2CO3 (16.3 g, 118.3 mmol, 2 eq.) was added thereto. Methyl iodide (7.4 ml, 118.3 mmol, 2 eq.) was then added, and the suspension was heated overnight at 40° C. The solid materials were filtered off and the filtrate was concentrated using a rotary evaporator. Purification was carried out by filtration over silica gel (DCM).
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH2:8])=[C:6]([N+:9]([O-])=O)[CH:5]=[C:4]([N+:12]([O-])=O)[CH:3]=1.C(O)(=O)CCCCC(O)=O.[H][H]>[Ni].O>[Cl:1][C:2]1[C:7]([NH2:8])=[C:6]([NH2:9])[CH:5]=[C:4]([NH2:12])[CH:3]=1
Reactant: [H][H]
Reactant: Nc1c(Cl)cc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [Ni]
Agent: O=C(O)CCCCC(=O)O
Solvent: O
Product: Nc1cc(N)c(N)c(Cl)c1
Reaction time: 2 h

Procedure:
109 Parts of finely ground 6-chloro-2,4-dinitro-aniline together with 73 parts of adipic acid, 10 parts of a commercial-type nickel catalyst (about 50% Ni on kieselguhr) and 500 parts by volume of water charged into a hydrogenation autoclave equipped with a double-acting, magnetically operated agitator. After the autoclave had been sealed, air was expelled from the free volume by passing nitrogen over it (for 15 minutes). Heating and agitator were then put to work, 120 atmsg. of hydrogen were forced in under pressure, and hydrogenation was effected. Hydrogen absorption started at about 60° C., and was complete within about 2 hours at a maximum temperature of 95° C. Evidence for 6-chloro-1,2,4-triamino-benzene obtained was provided by releasing the residual hydrogen, freeing the mixture from the catalyst by filtration through a pressure filter under a nitrogen pressure of 20 atmsg. and passing the filtrate into another stirrer-equipped vessel which contained 150 parts of urea. The mixture was then refluxed for 5 hours while maintaining the pH at 4 - 5 by adding a total of about 112 parts of sulfuric acid monohydrate. The ph was then adjusted to 6 by means of 54 parts of a 33% sodium hydroxide solution, and the mixture was cooled to room temperature. About 90 parts of a compound were obtained, which has a melting point of 341° C. and whose analytical data for C, H, Cl and N corresponded to the calculated values for the urea compound of the formula
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][CH:8]([CH2:11][OH:12])[CH2:7][C:6]=2[CH:5]=[C:4]([C:13]([F:16])([F:15])[F:14])[CH:3]=1.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>>[CH3:27][C:17]1[CH:22]=[CH:21][C:20]([S:23]([O:12][CH2:11][CH:8]2[CH2:7][C:6]3[CH:5]=[C:4]([C:13]([F:16])([F:14])[F:15])[CH:3]=[C:2]([Br:1])[C:10]=3[O:9]2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC1Cc2cc(C(F)(F)F)cc(Br)c2O1
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cc(C(F)(F)F)cc(Br)c3O2)cc1
Yield: 70 %

Procedure:
Treatment of (±)-[7-bromo-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methanol (3.59 g, 12.1 mmol) with p-toluenesulfonyl chloride (3.6 g, 18.2 mmol) generally according to described for Intermediate 10 provided 3.82 g (70%) (±)-[7-bromo-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate. mp 95-97° C.
Reaction SMILES: [N+:1]1([O-])[C:2]([CH3:8])=[CH:3][C:4]([CH3:7])=[CH:5][CH:6]=1.C1(C)C=CC(S([Cl:19])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[Cl:19][CH2:8][C:2]1[CH:3]=[C:4]([CH3:7])[CH:5]=[CH:6][N:1]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1cc[n+]([O-])c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ccnc(CCl)c1
Yield: 364.4 %

Procedure:
2,4-Lutidine-1-oxide (10 g, 8.10 mmol) was dissolved in anhydrous dioxane (125 ml) under nitrogen atomsphere, and herein p-toluenesulfonyl chloride (31.5 g, 162 mmol) was added and refluxed for 5 hours. The solution was neutralized with the saturated aqueous solution of potassium carbonate and extracted twice with methylene chloride. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to get crude product. The residue was separated and purified by column-chromatography over silica gel to obtain 2-chloromethyl-4-methylpyridine (4.18 g, yield=36%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:29])=[C:6]([C:8]2[C:9]3[CH:19]=[CH:18][C:17](=[O:20])[N:16]([C:21]4[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=4[F:28])[C:10]=3[N:11]=[C:12]([S:14][CH3:15])[N:13]=2)[CH:7]=1.CCN(CC)CC.[S:37]1[CH:41]=[CH:40][CH:39]=[C:38]1[C:42](Cl)=[O:43]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:27][C:26]1[CH:25]=[CH:24][CH:23]=[C:22]([F:28])[C:21]=1[N:16]1[C:10]2[N:11]=[C:12]([S:14][CH3:15])[N:13]=[C:8]([C:6]3[CH:7]=[C:2]([NH:1][C:42]([C:38]4[S:37][CH:41]=[CH:40][CH:39]=4)=[O:43])[CH:3]=[CH:4][C:5]=3[CH3:29])[C:9]=2[CH:19]=[CH:18][C:17]1=[O:20]
Reactant: O=C(Cl)c1cccs1
Reactant: CSc1nc(-c2cc(N)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CSc1nc(-c2cc(NC(=O)c3cccs3)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of 4-(5-amino-2-methylphenyl)-8-(2,6-difluorophenyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (411.0 mg, 1.0 mmol) in CH2Cl2 (10 mL) at 0° C. was added Et3N (200.0 mg, 2.0 mmol, 2.0 eq), DMAP (5.0 mg, 0.2 mmol, 0.2 eq) and 2-thiophenecarbonyl chloride (292.0 mg, 2.0 mmol, 2.0 eq). After addition the reaction mixture was stirred for about 14 h at ambient temperature. The mixture was concentrated and mixed with H2O (5.0 mL) and EtOAc (20.0 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (3×15 mL). The combined organic phases were washed with saturated aq. NaCl solution, dried over Na2SO4, filtered, and concentrated. Purification via a CombiFlash system (hexane:EtOAc; 4:1) then afforded the title compound: LC-MS m/z 521 (M+H)+, 2.57 min (ret time).
Reaction SMILES: [CH3:1][C:2]1[C:3](Cl)=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.O.[NH2:14][NH2:15]>>[NH:14]([C:3]1[C:2]([CH3:1])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[NH2:15]
Reactant: NN
Reactant: Cc1cc2ccccc2nc1Cl
Solvent: O
Product: Cc1cc2ccccc2nc1NN

Procedure:
73.5 g of 3-methyl-2-chloroquinoline in 102 ml of hydrazine hydrate are heated under reflux for 3 hours. The reaction mixture is cooled and the solid is filtered off, washed and dried. The crystalline mass obtained is recrystallized from isopropanol to give 50.5 g of 2-hydrazino-3-methylquinoline melting at 128° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2OS(C(F)(F)F)(=O)=O)=[CH:4][CH:3]=1.[Cl:22][C:23]1[CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:26]=[CH:25][N:24]=1.C(=O)([O-])[O-].[Na+].[Na+].CN(C=O)C>C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[Cl:22][C:23]1[CH:28]=[C:27]([C:9]2[CH2:10][CH2:11][CH2:12][CH2:13][C:8]=2[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH:26]=[CH:25][N:24]=1
Reactant: O=S(=O)(OC1=C(c2ccc(F)cc2)CCCC1)C(F)(F)F
Reactant: CC1(C)OB(c2ccnc(Cl)c2)OC1(C)C
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccc(C2=C(c3ccnc(Cl)c3)CCCC2)cc1
Temperature: 100 °C
Yield: 58.3 %

Procedure:
Trifluoro-methanesulfonic acid 2-(4-fluoro-phenyl)-cyclohex-1-enyl ester (200 mg, 0.62 mmol), 2-Chloro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (162 mg, 0.68 mmol), Bis(triphenylphosphine)Palladium (II) dichloride (43 mg, 0.062 mmol), Sodium Carbonate solution (2.0 M, 1.54 mL, 3.1 mmol) and DMF (3 mL) are mixed in a 5 mL microwave tube with a stir bar and the mixture is heated to 100° C. in microwave reactor for 30 min. The mixture is poured to water (10 mL) and extracted with EtOAc (10 mL×3). The organic extracts are washed with water (20 mL×1), brine (20 mL×1) and dried over anhydrous sodium sulfate. After concentration, the crude is purified by silica flash column chromatography using EtOAc in Heptane (gradient from 0% to 20%) to give 104 mg of the desired product.
Reaction SMILES: BrC1C=C[C:5](NCC(OC)=O)=[N:6]C=1.[F:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17]([CH:25]=O)=[CH:18][N:19]2[CH3:24].CN1C2C(=CC=CC=2)C(C)=C1C=O>>[F:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17]([CH2:25][NH:6][CH3:5])=[CH:18][N:19]2[CH3:24]
Reactant: Cn1cc(C=O)c2c(F)cccc21
Reactant: COC(=O)CNc1ccc(Br)cn1
Agent: Cc1c(C=O)n(C)c2ccccc12
Product: CNCc1cn(C)c2cccc(F)c12
Yield: 77 %

Procedure:
According to the procedure of Preparation 11 (c), except substituting 4-fluoro-1-methyl-1H-indole-3-carboxaldehyde (0.3 g, 1.69 mmole) for the 1,3-dimethyl-1H-indole-2-carboxaldehyde, the title compound (0.2 g, 77%)was prepared as a viscous oil: MS (ES) m/e 193 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][CH:13]3[CH2:17][CH2:16][O:15][CH2:14]3)[C:7](=[O:18])[C:6]3([CH3:23])[CH2:19][O:20][CH2:21][CH2:22][N:5]3[C:4]=2[N:3]=1.[CH:24]1([NH:27][C:28]([NH:30][C:31]2[CH:36]=[CH:35][C:34](B3OC(C)(C)C(C)(C)O3)=[CH:33][CH:32]=2)=[O:29])[CH2:26][CH2:25]1.CC([O-])(C)C.[Na+]>O1CCOCC1.CO>[CH:24]1([NH:27][C:28]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([C:2]3[N:11]=[CH:10][C:9]4[N:8]([CH2:12][CH:13]5[CH2:17][CH2:16][O:15][CH2:14]5)[C:7](=[O:18])[C:6]5([CH3:23])[CH2:19][O:20][CH2:21][CH2:22][N:5]5[C:4]=4[N:3]=3)=[CH:33][CH:32]=2)=[O:29])[CH2:26][CH2:25]1
Reactant: CC1(C)OB(c2ccc(NC(=O)NC3CC3)cc2)OC1(C)C
Reactant: CC12COCCN1c1nc(Cl)ncc1N(CC1CCOC1)C2=O
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: CC12COCCN1c1nc(-c3ccc(NC(=O)NC4CC4)cc3)ncc1N(CC1CCOC1)C2=O
Temperature: 100 °C
Yield: 15.4 %

Procedure:
2-Chloro-6a-methyl-5-((tetrahydrofuran-3-yl)methyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (390 mg, 1.151 mmol) PdCl2(dppf)-CH2Cl2 (188 mg, 0.230 mmol), 1-cyclopropyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (417 mg, 1.381 mmol) and sodium 2-methylpropan-2-olate (1.5 ml, 1.151 mmol) were combined in 1,4-dioxane (3 ml). The suspension was heated by microwave irradiation at 100° C. for 30 minutes, the reaction was filtered, cooled, and purified by mass-triggered preparative HPLC using 22-25% ACN (containing 0.035% TFA) in water (containing 0.05% TFA) on a Phenomenex Gemini 5 μm C18, 75×30 mm column). Product containing fractions were evaporated in vacuo to give a residue. The residue was dissolved in methanol for transfer. The solvent was removed under a stream of nitrogen gas to give 85 mg of the title compound as a pale yellow solid. 1H NMR (400 MHz, MeOD) δ ppm 0.48-0.57 (m, 2H) 0.71-0.79 (m, 2H) 1.73 (s, 3H) 1.73 (m, 1H) 2.02-2.14 (m, 1H) 2.61 (m, 1H) 2.68-2.80 (m, 1H) 3.55-3.65 (m, 2H) 3.68 (dd, J=12, 4 Hz, 1H) 3.71-3.81 (m, 3H) 3.84 (d, J=12 Hz, 2H) 3.91-4.05 (m, 2H) 4.08-4.21 (m, 2H) 4.75 (d, J=16 Hz, 1H) 7.67 (d, J=8 Hz, 2H) 8.03 (s, 1H) 8.11 (dd, J=8, 4 Hz, 2 H) [M+H] found 479.
Reaction SMILES: O[C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=O)=CC=1.[OH:11][C:12]1[CH:24]=[CH:23][C:15]([C:16]([N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=1>>[C@@H:10]12[CH2:9][C@@H:5]1[CH2:6][N:8]([CH2:6][CH2:5][CH2:9][CH2:10][O:11][C:12]1[CH:24]=[CH:23][C:15]([C:16]([N:18]([CH2:19][CH3:20])[CH2:21][CH3:22])=[O:17])=[CH:14][CH:13]=1)[CH2:2]2
Reactant: NC(=O)c1ccc(O)cc1
Reactant: CCN(CC)C(=O)c1ccc(O)cc1
Product: CCN(CC)C(=O)c1ccc(OCCCCN2C[C@H]3C[C@H]3C2)cc1

Procedure:
The experimental procedure is the same as Steps 1 and 2 of Example 3, but replacing the 4-hydroxybenzamide in Step 1 by 4-hydroxy-N,N-diethylbenzamide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]#[CH:9])[CH:7]=1.[F:10][C:11]1[CH:20]=[CH:19][C:18](I)=[CH:17][C:12]=1[C:13]([NH:15][CH3:16])=[O:14].C(N(CC)CC)C>C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:18]2[CH:19]=[CH:20][C:11]([F:10])=[C:12]([CH:17]=2)[C:13]([NH:15][CH3:16])=[O:14])[CH:5]=[N:4][CH:3]=1
Reactant: CNC(=O)c1cc(I)ccc1F
Reactant: C#Cc1cncc(Cl)c1
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CNC(=O)c1cc(C#Cc2cncc(Cl)c2)ccc1F
Temperature: 70 °C
Reaction time: 0.17 h
Yield: 74.8 %

Procedure:
Add bis(triphenylphosphine)palladium (II) dichloride (45 mg, 0.06 mmol), copper (I) iodide (26 mg, 0.14 mmol), and 3-chloro-5-ethynylpyridine, (prepared as described in PREPARATION 27), (200 mg, 1.45 mmol) to a solution of 2-fluoro-5-iodo-N-methylbenzamide, (prepared as described in PREPARATION 39), (0.39 g, 1.39 mmol) in triethylamine (6 mL, 43 mmol) and heat at 70° C. After 10 min, add toluene (10 mL) to the solidified reaction mixture and heat at 70° C. for 1 h. Concentrate and purify using silica gel chromatography, eluting with 40:60 ethyl acetate:hexanes, to give the title compound as a white solid (300 mg, 72%).
Reaction SMILES: [CH2:1]([N:4]1[C:11]([NH2:12])=[C:10]([NH2:13])[C:8](=[O:9])[N:7]([CH2:14][CH2:15][CH3:16])[C:5]1=[O:6])[CH2:2][CH3:3].[CH:17]12[CH2:23][CH:20]([CH2:21][CH2:22]1)[CH2:19][CH:18]2[C:24](O)=[O:25]>>[NH2:12][C:11]1[N:4]([CH2:1][CH2:2][CH3:3])[C:5](=[O:6])[N:7]([CH2:14][CH2:15][CH3:16])[C:8](=[O:9])[C:10]=1[NH:13][C:24]([CH:18]1[CH2:19][CH:20]2[CH2:23][CH:17]1[CH2:22][CH2:21]2)=[O:25]
Reactant: O=C(O)C1CC2CCC1C2
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Product: CCCn1c(N)c(NC(=O)C2CC3CCC2C3)c(=O)n(CCC)c1=O
Yield: 93 %

Procedure:
The substantially same operations as in Example 1 were repeated using 3.0 g (13.3 mmol) of 1,3-dipropyl-5,6-diaminouracil and 2.61 g (18.6 mmol) of bicyclo[2.2.1]heptane-2-carboxylic acid to afford 4.31 g (yield: 93%) of amorphous 6-amino-5-(bicyclo[2.2.1]heptan-2-yl)carbonylamino-1,3-dipropyluracil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:28](=[CH:29][CH:30]=1)[C:9]1=[N:10][O:11][C:12]([C:13]3[C:17]([C:18]([F:21])([F:20])[F:19])=[C:16]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[O:15][N:14]=3)=[C:8]1[CH2:7][CH2:6]2.CN(C)C=[O:34].C(OO)(C)(C)C>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:28](=[CH:29][CH:30]=1)[C:9]1=[N:10][O:11][C:12]([C:13]3[C:17]([C:18]([F:21])([F:19])[F:20])=[C:16]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[O:15][N:14]=3)=[C:8]1[CH2:7][C:6]2=[O:34]
Reactant: COc1ccc2c(c1)CCc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F
Reactant: CN(C)C=O
Agent: CC(C)(C)OO
Solvent: CC#N
Product: COc1ccc2c(c1)C(=O)Cc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F
Temperature: 50 °C
Yield: 36 %

Procedure:
To a stirred solution of 7-methoxy-3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazole (Preparation 66A, 0.103 g, 0.250 mmol) and cuprous iodide (0.476 mg, 0.0025 mmol) in acetonitrile (2.0 mL) at room temperature [note: the reactant was sparingly soluble in acetonitrile, so dimethyl formamide (0.5 ml) was added to solubilize the reactant] was added t-butyl hydroperoxide (0.250 mL, 1.50 mmoL). The reaction mixture was heated at 50° C. overnight. An additional aliquot of t-butyl hydroperoxide (0.250 mL, 1.50 mmol) was added, and the reaction was heated at 50° C. overnight. A small change in the amount of product was noted, so an additional aliquot of t-butyl hydroperoxide (0.250 mL, 1.50 mmol) was added. The reaction mixture was heated at 50° C. overnight. The reaction mixture was concentrated in vacuo, and the crude mixture was chromatographed using reverse-phase preparative HPLC to give the product [39 mg, 0.094 mmol, 36% yield] as a tan solid. The product had an HPLC ret. time=3.90 min. (condition B). LC/MS M+1=427.10.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:13]([OH:15])=O)[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][CH:23]([C:26]2[CH:27]=[CH:28][C:29]([F:38])=[C:30]([NH:32][C:33](=[O:37])[CH2:34][CH2:35][CH3:36])[CH:31]=2)[CH2:22][CH2:21]1>>[C:33]([NH:32][C:30]1[CH:31]=[C:26]([CH:23]2[CH2:24][CH2:25][N:20]([CH2:19][CH2:18][CH2:17][NH:16][C:13]([C:8]3([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[CH2:9][CH2:10][CH2:11][CH2:12]3)=[O:15])[CH2:21][CH2:22]2)[CH:27]=[CH:28][C:29]=1[F:38])(=[O:37])[CH2:34][CH2:35][CH3:36]
Reactant: CCCC(=O)Nc1cc(C2CCN(CCCN)CC2)ccc1F
Reactant: O=C(O)C1(c2ccc(F)cc2)CCCC1
Product: CCCC(=O)Nc1cc(C2CCN(CCCNC(=O)C3(c4ccc(F)cc4)CCCC3)CC2)ccc1F

Procedure:
Example 107 was prepared from 1-(4-fluorophenyl)cyclopentanecarboxylic acid and N-{5-[1-(3-aminopropyl)-4-piperidinyl]-2-fluorophenyl}butanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 8.30–8.13 (m, 1H), 8.09–7.95 (br, 1H), 7.47–7.26 (m, 3H), 7.08–6.87 (m, 3H), 6.75–6.54 (br, 1H), 3.30–3.07 (m, 4H), 2.59–2.44 (m, 3H), 2.44–2.33 (m, 2H), 2.33–2.19 (m, 2H), 1.99–1.69 (m, 16H), 1.02 (t, 3H, J=7.2 Hz); ESMS m/e: 512.3 (M+H)+.