Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:42])[CH2:15][NH:16][C:17]([C:19]2[CH:23]=[C:22]([O:24][CH2:25][C:26]([O:28]CC3C=CC=CC=3)=[O:27])[N:21]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[N:20]=2)=[O:18])[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4]>C1COCC1.[Pd]>[CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:42])[CH2:15][NH:16][C:17]([C:19]2[CH:23]=[C:22]([O:24][CH2:25][C:26]([OH:28])=[O:27])[N:21]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[N:20]=2)=[O:18])[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)N1CCN(C(=O)CNC(=O)c2cc(OCC(=O)OCc3ccccc3)n(-c3ccccc3)n2)CC1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCOC(=O)N1CCN(C(=O)CNC(=O)c2cc(OCC(=O)O)n(-c3ccccc3)n2)CC1
Reaction time: 12 h

Procedure:
To a solution of 3.6 g 4-{2-[(5-Benzyloxycarbonylmethoxy-1-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetyl}-piperazine-1-carboxylic acid butyl ester in 80 ml THF were added 0.6 g Pd/C (10%) and the suspension stirred under an atmosphere of hydrogen (3 bar) for 12 h. The reaction mixture was filtrated over a plug of Celite, washed with THF and concentrated to give the crude product which was used in the subsequent reaction.
Reaction SMILES: [C:1]([OH:24])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]#[CH:22].CN(C1C=CC=CN=1)C.[C:34](O)([CH3:37])([CH3:36])[CH3:35].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)(Cl)Cl.C(O)C>[C:1]([O:24][C:34]([CH3:37])([CH3:36])[CH3:35])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]#[CH:22]
Reactant: CC(C)(C)O
Reactant: C#CCCCCCCCCCCCCCCCCCCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: C#CCCCCCCCCCCCCCCCCCCCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.5 %

Procedure:
The acid (32) (6.4 g, 0.019 mol) was dissolved in dry, ethanol free, chloroform (120 ml) at room temperature under nitrogen and sequentially treated with dimethylaminopyridine (2.55 g, 0.0209 mol), tert butanol (14.09 g, 0.19 mol), dimethylaminopyridine-trifluoroacetic acid complex (4.94 g, 0.0209 mol) and dicyclohexylcarbodiimide (4.31 g, 0.0209 mol). The resulting solution was stirred at room temperature overnight then filtered, the organic layer washed with 5% acetic acid in water, then dried (MgSO4), filtered and evaporated. The residue was purified by chromatography on silica gel (50 g). Elution with 10% ether in petrol gave the title compound (33) as white crystals (6.45 g, 86%) mp 44°-45° C.
Reaction SMILES: C([O:3][C:4]([C:6]12[CH2:23][CH:22]1[CH:21]=[CH:20][CH2:19][CH2:18][CH2:17][CH2:16][N:15]([CH3:24])[C:14](=[O:25])[CH:13]1[CH:9]([CH2:10][CH:11]([O:26][C:27]3[C:36]4[C:31](=[C:32]([CH3:39])[C:33]([O:37][CH3:38])=[CH:34][CH:35]=4)[N:30]=[C:29]([C:40]4[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=4)[N:28]=3)[CH2:12]1)[C:8](=[O:48])[NH:7]2)=[O:5])C.BrCC(=O)C(C)C.[OH-].[Li+]>C1COCC1>[CH3:38][O:37][C:33]1[C:32]([CH3:39])=[C:31]2[C:36]([C:27]([O:26][CH:11]3[CH2:10][CH:9]4[CH:13]([C:14](=[O:25])[N:15]([CH3:24])[CH2:16][CH2:17][CH2:18][CH2:19][CH:20]=[CH:21][CH:22]5[C:6]([C:4]([OH:5])=[O:3])([NH:7][C:8]4=[O:48])[CH2:23]5)[CH2:12]3)=[N:28][C:29]([C:40]3[CH:41]=[CH:42][C:43]([O:46][CH3:47])=[CH:44][CH:45]=3)=[N:30]2)=[CH:35][CH:34]=1
Reactant: CCOC(=O)C12CC1C=CCCCCN(C)C(=O)C1CC(Oc3nc(-c4ccc(OC)cc4)nc4c(C)c(OC)ccc34)CC1C(=O)N2
Agent: CC(C)C(=O)CBr
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(-c2nc(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)C4C3)c3ccc(OC)c(C)c3n2)cc1
Temperature: 50 °C
Yield: 57.2 %

Procedure:
Compound 136 (420 mg, 0.639 mmol) was dissolved in a 96 mL solvent mixture (THF 2:methanol 1:water 1). Aqueous lithium hydroxide (6.4 mL, 1M) was added and the reaction mixture was heated at 50° C. over-night. Purification by column chromatography (silica gel, 5% methanol in dichloromethane) gave the title compound (230 mg, 57%). MS (M+H)+ 629.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([N+:24]([O-])=O)[C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]([OH:14])=[O:13])[C:2]1C=CC=[CH:4][CH:3]=1.C(OC1C=C(C=C([N+]([O-])=O)C=1C1C=CC=CC=1)C(O)=O)CCC>>[NH2:24][C:16]1[C:17]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[C:9]([O:8][CH2:1][CH2:2][CH2:3][CH3:4])[CH:10]=[C:11]([CH:15]=1)[C:12]([OH:14])=[O:13]
Reactant: O=C(O)c1cc(OCc2ccccc2)c(-c2ccccc2)c([N+](=O)[O-])c1
Agent: CCCCOc1cc(C(=O)O)cc([N+](=O)[O-])c1-c1ccccc1
Product: CCCCOc1cc(C(=O)O)cc(N)c1-c1ccccc1

Procedure:
By replacing in Example 2, step D, 3-benzyloxy-5-nitro-4-phenylbenzoic acid with 3-n-butoxy-5-nitro-4-phenylbenzoic acid, and following the procedure described, 5-amino-3-n-butoxy-4-phenylbenzoic acid is obtained with a melting point of 122°-124° C.
Reaction SMILES: C(O)(=O)C.Br.C(OP([N:14]1[CH2:27][CH2:26][N:25]([S:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[N+:37]([O-:39])=[O:38])(=[O:30])=[O:29])[CH2:24][CH2:23][CH2:22][C:21]([F:41])([F:40])[CH2:20][CH2:19][CH2:18][N:17]([S:42]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=2[N+:51]([O-:53])=[O:52])(=[O:44])=[O:43])[CH2:16][CH2:15]1)(=O)OCC)C>C(OCC)C>[F:41][C:21]1([F:40])[CH2:22][CH2:23][CH2:24][N:25]([S:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[N+:37]([O-:39])=[O:38])(=[O:30])=[O:29])[CH2:26][CH2:27][NH:14][CH2:15][CH2:16][N:17]([S:42]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=2[N+:51]([O-:53])=[O:52])(=[O:43])=[O:44])[CH2:18][CH2:19][CH2:20]1
Reactant: CCOP(=O)(OCC)N1CCN(S(=O)(=O)c2ccccc2[N+](=O)[O-])CCCC(F)(F)CCCN(S(=O)(=O)c2ccccc2[N+](=O)[O-])CC1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)N1CCCC(F)(F)CCCN(S(=O)(=O)c2ccccc2[N+](=O)[O-])CCNCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.3 %

Procedure:
Acetic acid (10 ml), saturated with anhydrous hydrogen bromide (gas) was added to [11,11-difluoro-1,7-bis(2-nitro-benzenesulfonyl)-1,4,7-triaza-cyclotetradec-4-yl]-phosphonic acid diethyl ester (311 mg, 0.41 mmol) contained in round-bottomed flask closed by glass stopper. The resulting mixture was allowed to stir for 18 hours at room temperature and then diethyl ether (50 ml) was added. The white precipitate which formed was allowed to settle to the bottom of the flask and the diethyl ether solution was decanted off. This white solid was re-dissolved in methanol, stirred with K2CO3 (solid) for 30 mins and the mixture was diluted with 100-ml ethyl acetate. The solids were removed by filtration and the filtrates were evaporated to give the title compound (239 mg, 94%) as white form. 1H NMR (CDCl3) δ 1.82–1.91 (m, 4H), 1.99–2.15 (m, 4H), 2.91 (t, 4H, J=5.1 Hz), 3.30–3.38 (m, 8H), 7.60–7.63 (m, 2H), 7.69–7.75 (m, 4H), 7.90–7.94 (m, 2H); 13C NMR (CDCl3) δ 23.25, 32.22, 32.57, 32.90, 50.22, 50.86, 50.96, 123.50, 124.60, 126.71, 129.89, 130.73, 132.02, 132.22, 134.27, 148.94; 19F NMR (CDCl3) δ −14.12 (t); ES-MS m/z 606.3 (M+H).
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=1.[CH:9]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH2:10].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CCN(CC)CC>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH:11]1(/[CH:9]=[CH:10]/[C:2]2[O:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=Cc1ccc(Br)o1
Reactant: C=CC1CCCCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=Cc1ccc(/C=C/C2CCCCC2)o1
Temperature: 25 °C

Procedure:
A mixture of 5-bromofuran-2-carbaldehyde (1.03 g, 5.89 mmol), vinylcyclohexane (0.86 g, 7.80 mmol), P(o-Tol)3 (0.089 g, 0.29 mmol), Pd(OAc)2 (0.070 g, 0.31 mmol) and Et3N (2.0 mL) in anhydrous DMF (3.0 mL) was degassed by bubbling Ar then alternating vacuum/Ar three times. The reaction mixture was heated under inert atmosphere at +90° C. for 20 hrs and cooled to room temperature. Aqueous NH4Cl was added to the reaction mixture and the mixture was extracted twice with hexanes and EtOAc. Combined organic layers were washed with brine, concentrated under reduced pressure. Purification by flash chromatography (3%-8% EtOAc—hexanes gradient) gave (E)-5-(2-cyclohexylvinyl)furan-2-carbaldehyde as a yellow oil. Yield (0.40 g, 33%); 1H NMR (400 MHz, CDCl3) δ 9.53 (s, 1H), 7.19 (d, J=3.8 Hz, 1H), 6.55 (dd, J=7.0, 16.1 Hz, 1H), 6.34 (d, J=3.5 Hz, 1H), 6.19-6.26 (m, 1H), 2.10-2.19 (m, 1H), 1.52-1.92 (m, 6H), 1.10-1.42 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.N1C=CC=CC=1.CN(C1C=CC=CN=1)C.[CH3:27][N:28]([CH3:32])[C:29](Cl)=[O:30]>C(Cl)Cl>[CH3:27][N:28]([CH3:32])[C:29]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1)=[O:30]
Reactant: COC(=O)c1ccc(N)cc1
Reactant: CN(C)C(=O)Cl
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc(NC(=O)N(C)C)cc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 12.1 %

Procedure:
Methyl 4-aminobenzoate (Aldrich, 5.0 g, 33 mmol) was dissolved in 120 mL of anhydrous methylene chloride containing pyridine (3.2 mL, 39.6 mmol), and dimethylaminopyridine (DMAP, 500 mg) was added. To the ice-cooled mixture was added dimethylcarbamyl chloride (3.34 mL, 36.3 mmol) while stirring. The stirring was continued for 16 h at room temperature. The reaction was quenched with water (50 mL) and the organic layer separated. The aqueous layer was extracted with chloroform (50 mL). The combined organic extract was dried over sodium sulfate. The volatiles were evaporated on a rotoevaporator to give a residue, which was applied to a column of silica gel (2 cm dia, 16.5 cm high, 42 g). Chloroform (1.2 L) eluted the starting material (3 g) while the desired material was washed with 1% methanol in chloroform (700 mL) and crystallized from chloroform-methanol-hexane. The white solid was separated, dried in air followed by drying in a pistol at acetone reflux in vacuo to give 885 mg (30% based on starting material consumed) of methyl 4-(N,N-dimethylcarbamyl)aminobenzoate, mp 169°-170° C.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8](/[CH:13]=[CH:14]/[C:15]([O:17][CH3:18])=[O:16])[CH:9]=[CH:10][C:11]=1I)[CH2:2][CH2:3][CH3:4].[CH3:19][NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23](B2OC(C)(C)C(C)(C)O2)[CH:22]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C)C=O>[CH2:1]([O:5][C:6]1[CH:7]=[C:8](/[CH:13]=[CH:14]/[C:15]([O:17][CH3:18])=[O:16])[CH:9]=[CH:10][C:11]=1[C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([NH:20][CH3:19])[CH:22]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1cc(/C=C/C(=O)OC)ccc1I
Reactant: CNc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: CCCCOc1cc(/C=C/C(=O)OC)ccc1-c1cccc(NC)c1
Yield: 86.5 %

Procedure:
In a manner similar to that of Example (18d), by reaction of 28 mg (1 mol %) of palladium acetate, 88 mg (2 mol %) of dicyclohexylbiphenylphosphine, 4.5 g (12.5 mmol, 1.0 eq) of methyl (E)-3-(3-butoxy-4-iodophenyl)acrylate and 3.79 g (16.2 mmol, 1.3 eq) of methyl[3-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)phenyl]amine (prepared in Example 7a) in 72 mL of a mixture of dimethylformamide/2M potassium phosphate solution (5/1) at 90° C. for 2 hours, 3.67 g of methyl (E)-3-(2-butoxy-3′-methylaminobiphenyl-4-yl)acrylate are obtained in the form of crystals. Yield=86%
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][N:5]2[CH:14]=[CH:15][N:16]=[C:4]2[N:3]=1.[CH:17]([C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1)=[O:18].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.ClCCl.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]>[C:8]1([C:7]2[C:2]([C:22]3[CH:23]=[CH:24][C:19]([CH:17]=[O:18])=[CH:20][CH:21]=3)=[N:3][C:4]3[N:5]([CH:14]=[CH:15][N:16]=3)[CH:6]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Clc1nc2nccn2cc1-c1ccccc1
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: COCCOC
Product: O=Cc1ccc(-c2nc3nccn3cc2-c2ccccc2)cc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a mixture of 6 g of the crude product obtained in step 3 and 5.1 g 4-formylphenylboronic acid in 210 ml 1,2-dimethoxyethane are added 0.96 g dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct and 42 ml of a 10% w/w sodium carbonate solution. The resulting mixture is heated to 80° C. under an inert gas atmosphere for 15 h. The work up is performed by diluting the reaction mixture with water and dichloromethane, separating the phases and extraction of the aqueous phase with dichloromethane. The combined organic layers are dried over sodium sulphate and evaporated. The residue is suspended in ethyl acetate and the resulting mixture stirred for 2 h at room temperature. The product is collected by filtration and used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14](=[O:16])[CH3:15])[CH:9]=2)=[CH:4][CH:3]=1.[I-:17].[K+].II>N.O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14](=[O:16])[CH3:15])[CH:9]=2)=[CH:6][C:7]=1[I:17]
Reactant: [I-]
Reactant: CC(=O)c1cccc(-c2ccc(O)cc2)c1
Agent: II
Agent: N
Agent: [K+]
Solvent: O
Product: CC(=O)c1cccc(-c2ccc(O)c(I)c2)c1
Yield: 21 %

Procedure:
The product from Example 136A (5.76 g, 27 mmol) was suspended in concentrated aqueous ammonia (400 mL) and treated with a solution of potassium iodide (23.3 g, 140 mmol) and iodine (7.24 g, 28.5 mmol) in water (100 mL). As the reaction did not go to completion, the mixture was treated with a second solution of potassium iodide (15.8 g, 95 mmol) and iodine (4.83 g, 19 mmol) in water (50 mL). After an hour the ammonia was removed under reduced pressure on a rotary evaporator. The mixture was extracted with EtOAc, and the combined organic phases were washed consecutively with pH 6 potassium phosphate buffer and brine, then dried (Na2SO4), concentrated, and chromatographed through silica with 1% acetic acid in a gradient of 0 to 5% EtOAc/CH2Cl2 to provide the title compound as a beige powder (21% yield). MS (ESI APCI negative ion detection) m/z 337 (M−H)−; 1HNMR (300 MHz, CDCl3) δ 2.65 (s, 3H), 5.37 (bs, 1H), 7.08 (d, 1H), 7.48-7.55 (m, 2H), 7.71 (ddd, 1H), 7.88-7.93 (m, 2H), 8.09 (dd, 1H).
Reaction SMILES: C([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:19][N:20]2[CH2:24][CH2:23][O:22][C:21]2=[O:25])[CH:7]=1)C.[OH-].[Li+]>CO.O>[O:25]=[C:21]1[N:20]([CH2:19][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[O:12][C:8]2[CH:7]=[C:6]([CH2:5][C:4]([OH:26])=[O:3])[CH:11]=[CH:10][CH:9]=2)[CH2:24][CH2:23][O:22]1
Reactant: CCOC(=O)Cc1cccc(Oc2ccccc2CN2CCOC2=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)Cc1cccc(Oc2ccccc2CN2CCOC2=O)c1

Procedure:
Hydrolysis of {3-[2-(2-oxo-oxazolidin-3-ylmethyl)-phenoxy]-phenyl}-acetic acid ethyl ester with lithium hydroxide in MeOH and H2O provided the desired product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.Cl[C:10]1[C:15]2[N:16]=[CH:17][O:18][C:14]=2[CH:13]=[CH:12][CH:11]=1>C1COCC1.[Cl-].[Zn+2].[Cl-].[Pd].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:5]1([CH3:8])[CH:6]=[CH:7][C:2]([C:10]2[C:15]3[N:16]=[CH:17][O:18][C:14]=3[CH:13]=[CH:12][CH:11]=2)=[CH:3][CH:4]=1
Reactant: Cc1ccc(Br)cc1
Reactant: Clc1cccc2ocnc12
Agent: [Pd]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1CCOC1
Product: Cc1ccc(-c2cccc3ocnc23)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
a 500 mL 2-neck round-bottomed flask was equipped with a reflux condenser and replaced by nitrogen. 70 mL of THF that was dried with 0.11 mol of Mg metal was added to the above flask and then, 0.10 mol of 1-bromo-4-methylbenzene was added in a dropwise fashion. The reaction was significantly exodermic and thus a cooling bath was equipped to reduce the temperature inside the reactor less than 50° C. It was agitated for 2 hours at room temperature, 0.11 mol of zinc chloride was added with 100 mL of THF, and further agitated for 2 hours to obtain a slurry-phase reaction mixture. Another flask was replaced by nitrogen and then 0.10 mol of 4-chlorobenzo[d]oxazole derivative, 0.10 mol of Pd, and 3 mol % of Pd(PPh3)4 were dissolved in 100 mL of THF. The prepared solution was added to the reaction mixture and then agitated 60° C. for 24 hours. After the reaction is complete, the resulting product was placed on a silica gel column to remove an inorganic slurry, and then a THF solution was concentrated under vacuum to obtain 4-para-tolylbenzo[d]oxazole using column chromatography at a yield of 91%.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=C(N)[S:8][C:4]=2[CH:3]=1.[OH-].[K+].Cl>O>[NH2:6][C:5]1[CH:10]=[CH:11][C:2]([Cl:1])=[CH:3][C:4]=1[SH:8]
Reactant: Nc1nc2ccc(Cl)cc2s1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Nc1ccc(Cl)cc1S
Temperature: 25 °C
Yield: 68 %

Procedure:
A solution of 6-chloro-benzothiazol-2-ylamine (Example 200, 17.8 g, 96.7 mmol) and KOH (EM, 87 g, 1.55 mol) in 150 mL of water was refluxed for 2 d. The mixture was cooled to room temperature and was diluted with ice. The solution was brought to pH 5 with concentrated HCl. The mixture was extracted 3× with EtOAc (300 mL). The organic layers were combined and washed twice with a brine solution (300 mL), dried over Na2SO4. Removal of the solvent under reduced pressure gave 10.5 g product.
Reaction SMILES: [C:1]([C@@:3]1([F:25])[C@H:7]([OH:8])[CH2:6][O:5][C@H:4]1[N:9]1[CH:17]=[N:16][C:15]2[C:14](=[O:18])[NH:13][C:12]([NH:19]C(=O)C(C)C)=[N:11][C:10]1=2)#[CH:2]>N.C(OCC)(=O)C>[C:1]([C@@:3]1([F:25])[C@H:7]([OH:8])[CH2:6][O:5][C@H:4]1[N:9]1[CH:17]=[N:16][C:15]2[C:14](=[O:18])[NH:13][C:12]([NH2:19])=[N:11][C:10]1=2)#[CH:2]
Reactant: C#C[C@@]1(F)[C@H](O)CO[C@H]1n1cnc2c(=O)[nH]c(NC(=O)C(C)C)nc21
Agent: N
Solvent: CCOC(C)=O
Product: C#C[C@@]1(F)[C@H](O)CO[C@H]1n1cnc2c(=O)[nH]c(N)nc21
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Compound B4 (0.78 g, 1.33 mmol) was dissolved in saturated methanolic ammonia (62 mL) and stirred at room temperature for 20 h. The reaction mixture was then evaporated to dryness under reduced pressure. The residue was dissolved in water and washed twice with ethyl acetate. The aqueous layer was evaporated and purified on reverse phase column chromatography (C 18) eluting with a gradient 2-15% of acetonitrile in water. The residue obtained was then dissolved in hot ethyl acetate, filtered and dried to give D961 (Compound B5) (134 mg, 33%) as a yellow solid. NMR 1H (400 MHz, DMSO-d6): δ 10.70 (ls, 1H, NH), 7.98 (s, 1H, H-8), 6.60 (ls, 2H, NH2), 6.21 (d, 1H, OH-3′, JOH-3′=7.6 Hz), 5.83 (d, 1H, H-1′, J1′-F=16.9 Hz), 5.29 (t, 1H, OH-5′, JOH-5′=5.2 Hz), 4.50 (td, 1H, H-3′, J3′-F=22.8 Hz, J3′-4=9.2 Hz), 3.93-3.81 (m, 3H, H-4′, H-5′ and ethynyl), 3.70 (m, 1H, H-5″). NMR 13C (100 MHz DMSO-d6): δ 157.2 (C-6), 154.3 (C-2), 151.05 (C-4), 135.1 (C-8), 116.7 (C-5), 96.4 (d, C-2′, 1JC-F=182.1 Hz), 87.4 (d, C-1′, 2JC-F=39.2 Hz), 83.1 (d, CCH, JC-F=9.1 Hz), 82.4 (C-4′), 76.2 (d, CCH, 2JC-F=31.2 Hz), 73.2 (d, C-3′, 2JC-F=20.1 Hz), 59.5 (C-5′). NMR 19F (235 MHz, DMSO-d6): δ −158.5 (m). LC/MS (A): (M+H+) 310.1 (5.55 min). LRFAB-MS (GT): 619 (2M+H)+, 310 (M+H)+, 152 (B+H)+, 617 (2M−H)+, 308 (M−H)−. UV: λmax=254 nm.
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[N:13]=[C:12]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=2[Cl:24])[N:11]2[CH2:25][CH2:26][N:27]([CH:30]([CH3:32])[CH3:31])[C:28](=[O:29])[C:10]=12)C1C=CC=CC=1.Cl>CO>[Cl:24][C:18]1[C:19]([Cl:23])=[CH:20][CH:21]=[CH:22][C:17]=1[CH2:16][C:12]1[N:11]2[CH2:25][CH2:26][N:27]([CH:30]([CH3:32])[CH3:31])[C:28](=[O:29])[C:10]2=[C:9]([OH:8])[C:14](=[O:15])[N:13]=1
Reactant: CC(C)N1CCn2c(Cc3cccc(Cl)c3Cl)nc(=O)c(OCc3ccccc3)c2C1=O
Agent: Cl
Solvent: CO
Product: CC(C)N1CCn2c(Cc3cccc(Cl)c3Cl)nc(=O)c(O)c2C1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 96.4 %

Procedure:
To a stirred solution of 9-benzyloxy-6-(2,3-dichlorobenzyl)-2-isopropyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (134) (70 mg, 0.095 mmol) in methanol (3 mL) was added concentrated HCl (3 mL) and the reaction mixture was stirred for 5 h at room temperature. After completion of the reaction, the mixture was evaporation and the residue was basified with saturated aqueous NaHCO3 solution. The mixture was extracted with 10% methanol in dichloromethane, the organic part was separated. The drying over sodium sulfate was conducted and concentration to get a crude product, which was washed with ether followed by pentene to get 6-(2,3-dichlorobenzyl)-9-hydroxy-2-isopropyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (135) (35 mg, 61.7%) as a brown colored solid.
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].FC(F)(F)C(O)=O.[F:13][C:14]1[CH:15]=[C:16]([NH:31]C(=O)OC(C)(C)C)[CH:17]=[CH:18][C:19]=1[O:20][C:21]1[CH:22]=[N:23][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][CH:26]=1>>[F:13][C:14]1[C:19]([O:20][C:21]2[CH:22]=[N:23][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][CH:26]=2)=[CH:18][C:17]([N+:1]([O-:4])=[O:2])=[C:16]([NH2:31])[CH:15]=1
Reactant: O=[N+]([O-])[O-]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Oc2ccc(S(C)(=O)=O)nc2)c(F)c1
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)c1ccc(Oc2cc([N+](=O)[O-])c(N)cc2F)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.98 g of potassium nitrate was added to a trifluoroacetic acid (35 ml) solution of 3.38 g of tert-butyl (3-fluoro-4-(6-methanesulfonyl-pyridin-3-yloxy)-phenyl)-carbamate obtained in (step 2), the reaction liquid was stirred at room temperature for 1 hour, and then the solvent was evaporated away under reduced pressure. The residue was diluted with ethyl acetate, washed with aqueous saturated sodium bicarbonate and saturated saline in order, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (developing solvent: hexane/ethyl acetate=1/2) to obtain the entitled compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]2)[CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][N:9]([C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[CH3:22])[C:16](O)=[O:17])[C:8]2=[O:23])#[N:2].[NH2:31][C:32]1[CH:36]=[CH:35][O:34][N:33]=1>>[C:1]([C:3]1[CH:4]=[C:5]([N:24]2[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]2)[CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][N:9]([C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[CH3:22])[C:16]([NH:31][C:32]1[CH:36]=[CH:35][O:34][N:33]=1)=[O:17])[C:8]2=[O:23])#[N:2]
Reactant: Nc1ccon1
Reactant: Cc1ccc(C(=O)O)cc1-n1cnc2c(C#N)cc(N3CCN(C)CC3)cc2c1=O
Product: Cc1ccc(C(=O)Nc2ccon2)cc1-n1cnc2c(C#N)cc(N3CCN(C)CC3)cc2c1=O

Procedure:
Using an analogous procedure to that described paragraph (A) in the portion of Example 4, 3-[8-cyano-6-(4-methylpiperazin-1-yl)-4-oxoquinazolin-3(4H)-yl]-4-methylbenzoic acid was reacted with 3-aminoisoxazole to give 3-[8-cyano-6-(4-methylpiperazin-1-yl)-4-oxoquinazolin-3(4H)-yl]-N-isoxazol-3-yl-4-methylbenzamide; NMR Spectrum: (DMSOd6) 2.19 (s, 3H), 2.24 (s, 3H), 2.49 (m, 4H), 3.35 (m, 4H), 7.04 (d, 1H), 7.61 (d, 1H), 7.70 (d, 1H), 8.11 (m, 3H), 8.30 (s, 1H), 8.84 (d, 1H), 11.46 (s, 1H); Mass Spectrum: M+H+ 470.