Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[OH:11].Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C=O)C>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH3:14])=[CH:6][C:5]=1[OH:11]
Reactant: CCCCCCCCCCCCCCCCCCBr
Reactant: COC(=O)c1ccc(O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCOc1ccc(C(=O)OC)c(O)c1

Procedure:
A mixture of 1 g (5.95 mmol) of 2,4-dihydroxybenzoic acid methyl ester, 1.98 g (5.95 mmol) of 1-bromooctadecane and 0.825 g (5.95 mmol) of potassium carbonate was stirred at reflux for 40 hours in 20 ml of acetone and 2 ml of DMF. The usual workup followed by purification by HPLC using 1% ethyl acetate-hexane gave 2-hydroxy -4-(octadecyloxy)benzoic acid methyl ester, mp 61°-64°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C:11]([OH:13])=O)[CH:5]=[CH:6][C:7]=1[F:8].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH2:42][CH2:43][C:44]1[CH:59]=[CH:58][C:47]([C:48]([NH:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=2[NH2:57])=[O:49])=[CH:46][CH:45]=1>CN(C=O)C>[NH2:57][C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][C:51]=1[NH:50][C:48](=[O:49])[C:47]1[CH:46]=[CH:45][C:44]([CH2:43][NH:42][C:11](=[O:13])[C:10]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:9][C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=2)=[CH:59][CH:58]=1
Reactant: O=C(O)C(=Cc1ccc(F)c(F)c1)c1ccc(F)cc1
Reactant: NCc1ccc(C(=O)Nc2ccccc2N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Nc1ccccc1NC(=O)c1ccc(CNC(=O)C(=Cc2ccc(F)c(F)c2)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 35.2 %

Procedure:
To a solution of 3-(3,4-difluorophenyl)-2-(4-fluorophenyl)acrylic acid (0.5 g, 1.7 mmol) in DMF (5 mL) was added TEA (0.75 mL, 5.4 mmol), EDCI (0.68 g, 3.5 mmol), HOBt (0.25 g, 1.8 mmol) followed by the 4-(aminomethyl)-N-(2-aminophenyl)benzamide (0.52 g, 1.9 mmol). The reaction mixture was stirred at room temperature for 12 hours. Subsequently it was concentrated under reduced pressure to half the volume and the resulted solution was poured into water. Upon standing a white precipitate formed, was filtered, washed with water followed by ether gave the pure product (0.3 g, 30% yield). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 4.41 (2H, d, CH2), 4.88 (2H, s, NH2), 6.59 (1H, t, Ar—H), 6.77 (1H, d, Ar—H), 6.88 (1H, s, Ar—H), 6.96 (2H, m, Ar—H), 7.16 (1H, d, Ar—H), 7.24-7.38 (7H, m, Ar—H), 7.47 (1H, s, ═CH), 7.92 (2H, d, Ar—H), 8.14 (1H, t, NH), 9.61 (1H, s, NH). MS m/z: 502.1 (M++1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[N:12]=[C:11]([NH2:13])[S:10][CH:9]=2)[CH:5]=[CH:4][C:3]=1[F:14].[Cl:15][C:16]1[C:17]([CH3:26])=[C:18]([S:22](Cl)(=[O:24])=[O:23])[CH:19]=[CH:20][CH:21]=1>>[Cl:15][C:16]1[C:17]([CH3:26])=[C:18]([S:22]([NH:13][C:11]2[S:10][CH:9]=[C:8]([C:6]3[CH:5]=[CH:4][C:3]([F:14])=[C:2]([CH3:1])[CH:7]=3)[N:12]=2)(=[O:24])=[O:23])[CH:19]=[CH:20][CH:21]=1
Reactant: Cc1cc(-c2csc(N)n2)ccc1F
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Product: Cc1cc(-c2csc(NS(=O)(=O)c3cccc(Cl)c3C)n2)ccc1F

Procedure:
The title compound was prepared from 2-amino-4-(4′-fluoro-3′-methyl)phenylthiazole and 3-chloro-2-methylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (39.7 mg) with purity >90%. MS (pos) m/z 397.1.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[NH2:7][S:8]([C:11]1[C:12]([Cl:38])=[CH:13][C:14]([NH:31][CH2:32][C:33]2[O:34][CH:35]=[CH:36][CH:37]=2)=[C:15]([CH:30]=1)[C:16]([O:18][CH2:19][CH2:20][CH2:21][O:22][C:23](=[O:29])[CH2:24]CC(O)=O)=[O:17])(=[O:10])=[O:9]>ClCCl>[NH2:7][S:8]([C:11]1[C:12]([Cl:38])=[CH:13][C:14]([NH:31][CH2:32][C:33]2[O:34][CH:35]=[CH:36][CH:37]=2)=[C:15]([CH:30]=1)[C:16]([O:18][CH2:19][CH2:20][CH2:21][O:22][C:23](=[O:29])[CH2:24][CH2:1][C:2]([Cl:4])=[O:3])=[O:17])(=[O:9])=[O:10]
Reactant: O=C(Cl)C(=O)Cl
Reactant: NS(=O)(=O)c1cc(C(=O)OCCCOC(=O)CCC(=O)O)c(NCc2ccco2)cc1Cl
Solvent: ClCCl
Product: NS(=O)(=O)c1cc(C(=O)OCCCOC(=O)CCC(=O)Cl)c(NCc2ccco2)cc1Cl
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of oxalyl chloride (0.040 mole) in dichloromethane (20 mL) is added dropwise to an ice bath cooled solution of 4-(3-(5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoyloxy)propoxy)(4-oxo)butanoic acid (810) (0.040 mole) in dichloromethane (50 mL). The reaction is stirred at ambient temperature for 5 hours. The reaction solution is washed with 5% aqueous sodium bicarbonate, with water, and then with a saturated sodium chloride solution. The organic layer is dried over sodium sulfate, filtered and concentrated in vacuo to provide 4-(3-(5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoyloxy)propoxy)(4-oxo)butanoyl chloride (813). See eg., D. L. Musso, et. al., J. Med. Chem., (2003) 46: 409.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]([CH3:13])[CH3:12])[N:6]=[C:5]2[C:14]([O:16]CC)=[O:15].[OH-].[Na+].Cl>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]([CH3:12])[CH3:13])[N:6]=[C:5]2[C:14]([OH:16])=[O:15]
Reactant: CCOC(=O)c1nn(C(C)C)c2ccc(F)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)n1nc(C(=O)O)c2cc(F)ccc21
Temperature: 60 °C
Reaction time: 20 h
Yield: 95.4 %

Procedure:
To a stirred solution of ethyl 5-fluoro-1-isopropyl-1H-indazole-3-carboxylate (125 mg, 0.5 mmol, step 1 of Example 11) in tetrahydrofuran (8 mL) was added 1N aqueous sodium hydroxide solution (1.0 mL, 1.0 mmol) at room temperature. The resulting mixture was stirred at 60° C. for 20 h. The mixture was acidified with 2 N hydrochloric acid (1 mL) and extracted with ethyl acetate (50 mL×3). The combined organic layer was dried over sodium sulfate, and concentrated under reduced pressure to give 106 mg (95%) of the title compound as a white amorphous solid.
Reaction SMILES: [NH2:1][C@H:2]([C:13]([OH:15])=[O:14])[CH2:3][CH2:4][CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[OH-].[Na+].[CH2:18]([S:25](Cl)(=[O:27])=[O:26])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O1CCOCC1>[CH2:18]([S:25]([NH:1][C@H:2]([C:13]([OH:15])=[O:14])[CH2:3][CH2:4][CH2:5][C:6]([O:8][C:9]([CH3:10])([CH3:11])[CH3:12])=[O:7])(=[O:27])=[O:26])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)CCC[C@H](N)C(=O)O
Reactant: O=S(=O)(Cl)Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)CCC[C@H](NS(=O)(=O)Cc1ccccc1)C(=O)O
Reaction time: 16 h
Yield: 28.7 %

Procedure:
To a stirred solution of 0.5 g of H-Aad(OtBu)-OH in 4.4 mL of aqueous 1 N sodium hydroxide was added 0.42 g of benzylsulfonylchloride in 2 mL of dioxane. After 16 hours at room temperature, additional 1.4 mL of aqueous 2 N sodium hydroxide, 0.5 mL of dioxane and 0.09 g of benzylsulfonylchloride were added and the reaction mixture stirred for an additional day. The dioxane was removed, water was added, the mixture made acid (pH 3) using hydrochloric acid and extracted twice with diethyl ether. The combined ether layers were dried over sodium sulfate and concentrated to give 235 mg of BzlSO2-Aad(OtBu)-OH.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])=[CH:6][N:7]=1.Cl.O.[NH:17]1[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[Cl:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:5]1[N:4]=[N:3][C:2]([N:17]2[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]2)=[N:7][CH:6]=1
Reactant: O=C1CCNCC1
Reactant: Clc1ncc(-c2ccccc2Cl)nn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C1CCN(c2ncc(-c3ccccc3Cl)nn2)CC1

Procedure:
1.5 g of 3-chloro-6-(2-chlorophenyl)-1,2,4-triazine, 3.05 g of piperidin-4-one monohydrate hydrochloride and 3.1 g of sodium carbonate are heated under reflux in 100 ml of ethanol for 4 hours.
Reaction SMILES: [OH:1][P:2]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([CH2:4][CH2:5][C:6]([N:8]1[CH2:19][CH2:18][CH2:17][C@H:9]1[C:10]([O:12]C(C)(C)C)=[O:11])=[O:7])=[O:3].FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>>[OH:3][P:2]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([CH2:4][CH2:5][C:6]([N:8]1[CH2:19][CH2:18][CH2:17][C@H:9]1[C:10]([OH:12])=[O:11])=[O:7])=[O:1]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)CCP(=O)(O)c1ccccc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)[C@@H]1CCCN1C(=O)CCP(=O)(O)c1ccccc1

Procedure:
1-[3-(Hydroxyphenylphosphinyl)-1-oxopropyl]-L-proline, 1,1-dimethylethyl ester (1.40 gm., 0.0038 mol.) is dissolved in 20 ml. trifluoroacetic acid and 5ml. anisole and stirred 1 hour. The acid is removed in vacuo and the residue triturated several times with ether/hexane. The residue is taken up in water and the solution washed with ether, millipore filtered and lyophilized. The resulting foam is crystallized from ethyl acetate to give 1-[3-(hydroxyphenylphosphinyl)-1-oxopropyl]-L-proline m.p., 125°-128°, total 300 mg. (25%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([S:12]([OH:15])(=[O:14])=[O:13])=[CH:7]2.N1C=CC=CC=1.[C:22](OC(=O)C)(=[O:24])[CH3:23].[Na]>CO.C(OCC)C>[C:22]([NH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([S:12]([OH:15])(=[O:13])=[O:14])=[CH:7]2)(=[O:24])[CH3:23]
Reactant: Nc1cccc2cc(S(=O)(=O)O)ccc12
Reactant: CC(=O)OC(C)=O
Agent: [Na]
Solvent: CO
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(=O)Nc1cccc2cc(S(=O)(=O)O)ccc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To 29.3 g (0.13 mol) of 5-amino-2-naphthalenesulfonic Acid (Compound 72) was added 40 mL of pyridine and 26 mL of acetic anhydride. The resulting suspension was allowed to stir at ambient temperature. After 24 hr, the resulting solution was diluted with 60 mL of methanol. Then, a solution of 3.6 g (0.156 mol) of sodium in 100 mL of methanol was added. After a solid precipitate began to form, 200 mL of diethyl ether was added and the suspension allowed to stir. The solid was collected by vacuum filtration and was washed with diethyl ether. This provided 38.9 g (0.11 mol) of the desired product. The product was identified by 1H NMR and mass spectroscopy and purity was assessed by RP-HPLC.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:18][CH3:19])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[Cl:20][C:21]1[N:22]=[CH:23][N:24]([C:26]2[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][C:27]=2[O:33][CH3:34])[CH:25]=1>C1COCC1.C(O)(=O)C>[Cl:20][C:21]1[N:22]=[CH:23][N:24]([C:26]2[CH:32]=[CH:31][C:29]([NH:30][C:2]3[N:3]=[C:4]([NH:18][CH3:19])[C:5]4[CH2:10][CH2:9][CH:8]([C:11]5[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=5)[C:6]=4[N:7]=3)=[CH:28][C:27]=2[O:33][CH3:34])[CH:25]=1
Reactant: CNc1nc(Cl)nc2c1CCC2c1ccc(F)cc1
Reactant: COc1cc(N)ccc1-n1cnc(Cl)c1
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CNc1nc(Nc2ccc(-n3cnc(Cl)c3)c(OC)c2)nc2c1CCC2c1ccc(F)cc1
Yield: 40.4 %

Procedure:
A solution of 2-chloro-7-(4-fluorophenyl)-N-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (307.5 mg, 1.107 mmol) and 4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (248 mg, 1.107 mmol) in THF (3 mL) and acetic acid (3.00 mL) was heated at 80° C. overnight. The solvent was removed in vacuum and the residue was triturated with methanol, cooled in the freezer and filtered. The precipitate was thoroughly washed with methanol and dried to give N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-N4-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine (207.9 mg, 0.447 mmol, 40.4% yield) as off-white solid. LC-MS (M+H)+=465.0. 1H NMR (500 MHz, CDCl3) δ ppm 9.18 (1H, s), 8.15 (1H, d, J=1.8 Hz), 7.73 (1H, d, J=1.5 Hz), 7.41 (1H, d, J=1.5 Hz), 7.18-7.26 (2H, m), 7.07-7.18 (2H, m), 6.88-7.00 (1H, m), 4.12-4.20 (1H, m), 4.04-4.12 (1H, br s), 3.60 (3H, s), 3.17 (1H, s), 2.96 (3H, d, J=4.6 Hz), 2.71-2.81 (1H, m), 2.52-2.66 (2H, m), 1.83-1.96 (1H, m).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:10]=[C:11]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][NH:25][C:26]([C:28]4[C:29](=[O:43])[N:30]([CH2:34][C:35]5[CH:40]=[CH:39][C:38]([F:41])=[C:37]([F:42])[CH:36]=5)[CH:31]=[CH:32][CH:33]=4)=[O:27])[CH:19]=3)=[CH:16][N:15]([S:44]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)(=[O:46])=[O:45])[C:12]2=[N:13][CH:14]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:7][CH2:8][C:9]1[CH:10]=[C:11]2[C:17]([C:18]3[CH:19]=[C:20]([CH:21]=[CH:22][CH:23]=3)[CH2:24][NH:25][C:26]([C:28]3[C:29](=[O:43])[N:30]([CH2:34][C:35]4[CH:40]=[CH:39][C:38]([F:41])=[C:37]([F:42])[CH:36]=4)[CH:31]=[CH:32][CH:33]=3)=[O:27])=[CH:16][N:15]([S:44]([C:47]3[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=3)(=[O:45])=[O:46])[C:12]2=[N:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)NCc1cnc2c(c1)c(-c1cccc(CNC(=O)c3cccn(Cc4ccc(F)c(F)c4)c3=O)c1)cn2S(=O)(=O)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCc1cnc2c(c1)c(-c1cccc(CNC(=O)c3cccn(Cc4ccc(F)c(F)c4)c3=O)c1)cn2S(=O)(=O)c1ccccc1
Reaction time: 0.5 h

Procedure:
Into a vial was dissolved (1-benzenesulfonyl-3-[3-({[1-(3,4-difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carbonyl]-amino}-methyl)-phenyl]-1H-pyrrolo[2,3-b]pyridin-5-ylmethyl}-carbamic acid tert-butyl ester (0.259 mmol) in methylene chloride (2.00 mL, Acros) and trifluoroacetic acid (2.00 mL, 0.0260 mol; Acros). The reaction was stirred for 30 min, then the reaction was evaporated to dryness to give the crude amine.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][C:19]2([OH:32])[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]2)[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].[H-].[Na+].[CH:35]([S:37]([CH3:40])(=[O:39])=[O:38])=[CH2:36]>O1CCCC1>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][C:19]2([O:32][CH2:36][CH2:35][S:37]([CH3:40])(=[O:39])=[O:38])[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]2)[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2]
Reactant: CCOCc1nc2cnc3ccccc3c2n1CC1(O)CCN(C(=O)OC(C)(C)C)CC1
Reactant: C=CS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOCc1nc2cnc3ccccc3c2n1CC1(OCCS(C)(=O)=O)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.17 h
Yield: 17 %

Procedure:
To a solution of tert-butyl 4-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}-4-hydroxypiperidine-1-carboxylate (prepared as described in Part E of Example 4, 1.9 g, 4.3 mmol) in tetrahydrofuran (17 mL) at rt was added solid NaH (60%, 17 mg, 0.43 mmol). After 10 min, methyl vinyl sulfone (0.92 g, 8.6 mmol) was added dropwise. After 1 h, the reaction was quenched with water (50 mL) and extracted with ethyl acetate (50 mL). The organic layer was concentrated under reduced pressure to afford a yellow oil. Purification by flash chromatography (silica gel, eluted with 5% methanol/dichloromethane) yielded tert-butyl 4-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}-4-[2-(methylsulfonyl)ethoxy]piperidine-1-carboxylate (0.40 g, 19%).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:11]=[CH:12][C:13]3[N:14]=[CH:15][N:16]=[C:17]([NH2:20])[C:18]=3[N:19]=2)[CH:7]=[CH:8][CH:9]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:47]1[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=1[C:53](O)=[O:54].CCN(C(C)C)C(C)C>CN(C=O)C.O>[F:22][C:2]([F:1])([F:21])[O:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:11]=[CH:12][C:13]3[N:14]=[CH:15][N:16]=[C:17]([NH:20][C:53](=[O:54])[C:48]4[CH:49]=[CH:50][CH:51]=[CH:52][N:47]=4)[C:18]=3[N:19]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(O)c1ccccn1
Reactant: Nc1ncnc2ccc(-c3cccc(OC(F)(F)F)c3)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(Nc1ncnc2ccc(-c3cccc(OC(F)(F)F)c3)nc12)c1ccccn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 0.1 %

Procedure:
To a solution of 6-(3-(trifluoromethoxy)phenyl)pyrido[3,2-d]pyrimidin-4-amine (50 mg, 163 mmol) in DMF (1 mL) was added HATU (124 mg, 330 mmol), pyridine-2-carboxylic acid (20 mg, 163 mmol) and DIPEA (0.07 mL, 330 mmol). The mixture was stirred at room temperature for 18 hours. The reaction mixture was treated with water and extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4), concentrated to dryness and the crude product was purified by prep-TLC (10% Methanol in CH2Cl2) to afford N-(6-(3-(trifluoromethoxy)phenyl)pyrido[3,2-d]pyrimidin-4-yl)picolinamide as a yellow solid (57 mg, 85% yield). MS (ESI) calcd for C20H12F3N5O2 (m/z): 411.09. found: 412 [M+1].
Reaction SMILES: I[C:2]1[C:7]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=[C:4]([CH3:23])[N:3]=1.[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:26]=1B(O)O.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:26]=1[C:2]1[C:7]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=[C:4]([CH3:23])[N:3]=1
Reactant: OB(O)c1c(Cl)cccc1Cl
Reactant: COc1cc2nccc(Oc3ccc(C)nc3I)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(C)nc3-c3c(Cl)cccc3Cl)c2cc1OC
Temperature: 80 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
4-[(2-Iodo-6-methyl-3-pyridyl)oxy]-6,7-dimethoxyquinoline (compound 116) (84 mg), 2,6-dichlorophenylboronic acid (191 mg), and tetrakistriphenylphosphine palladium (12 mg) were dissolved in toluene (1 ml) to prepare a solution. A saturated aqueous sodium hydrogencarbonate solution (1 ml) was added to the solution, and the mixture was stirred at 80° C. for 3 hr. The reaction solution was filtered, the solvent was then removed by distillation under the reduced pressure, and the residue was purified by column chromatography using methanol-chloroform to give the title compound (79 mg, yield 90%).
Reaction SMILES: Br[C:2]1[C:3]([CH3:20])=[C:4]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:5]([CH3:11])=[C:6]([CH3:10])[C:7]=1[O:8][CH3:9].C([Li])CCC.[CH3:26][CH:27]([CH3:37])[C:28]([C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=1)=[O:29].O>O1CCCC1>[OH:29][C:28]([C:2]1[C:3]([CH3:20])=[C:4]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:5]([CH3:11])=[C:6]([CH3:10])[C:7]=1[O:8][CH3:9])([C:30]1[CH:31]=[CH:32][C:33]([CH3:36])=[CH:34][CH:35]=1)[CH:27]([CH3:37])[CH3:26]
Reactant: Cc1ccc(C(=O)C(C)C)cc1
Reactant: COc1c(C)c(C)c(NC(=O)OC(C)(C)C)c(C)c1Br
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1c(C)c(C)c(NC(=O)OC(C)(C)C)c(C)c1C(O)(c1ccc(C)cc1)C(C)C
Reaction time: 0.33 h
Yield: 75.4 %

Procedure:
To a solution of tert-butyl 3-bromo-4-methoxy-2,5,6-trimethylphenylcarbamate (27.8 g, 80.8 mmol) in tetrahydrofuran (150 ml) was added at -78° C. n-butyllithium (1.6 M, 110 ml, 176 mmol) and the reaction mixture was stirred at the same temperature for 20 minutes. To the reaction solution was added 2-methyl-1-(4-methylphenyl)propan-1-one (13.1 g, 80.7 mmol) and the resulting mixture was stirred at room temperature for 1 hour. Water (150 ml) was added into the reaction mixture and the product was extracted three times with ethyl acetate. The combined organic layers were washed with water, dried on magnesium sulfate, filtered, and then concentrated under reduced pressure to obtain 26.0 g of tert-butyl 3-[1-hydroxy-2-methyl-1-(4-methylphenyl)propyl]-4-methoxy-2,5,6-trimethylphenylcarbamate as a crude product. A mixture of this compound and 47% hydrobromic acid (100 ml) was refluxed with heating for 4 hours under an argon atmosphere. The reaction mixture was cooled down to room temperature and neutralized with an 8 N aqueous solution of sodium hydroxide. The product was extracted twice with ethyl acetate. The combined extracts were washed with an aqueous saturated solution of sodium hydrogen carbonate, dried on magnesium sulfate, filtered, and then concentrated under reduced pressure. The residue was crystallized from isopropyl ether-hexane to obtain 14.8 g (62% yield) of the title compound. Melting point: 114-115° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=1[C:16]1[CH2:20][CH2:19][CH2:18][C:17]=1B(O)O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:24]([O:26][C:27]([C:29]1[CH:34]=[N:33][CH:32]=[C:31](Cl)[N:30]=1)=[O:28])[CH3:25]>>[CH2:24]([O:26][C:27]([C:29]1[CH:34]=[N:33][CH:32]=[C:31]([C:17]2[CH2:18][CH2:19][CH2:20][C:16]=2[C:10]2[CH:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:9]=2[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:30]=1)=[O:28])[CH3:25]
Reactant: Cc1ccc(OCc2ccccc2)c(C2=C(B(O)O)CCC2)c1
Reactant: CCOC(=O)c1cncc(Cl)n1
Product: CCOC(=O)c1cncc(C2=C(c3cc(C)ccc3OCc3ccccc3)CCC2)n1

Procedure:
Prepared by general procedure C(iii) but using 2-[2-(benzyloxy)-5-methylphenyl]cyclopentene-1-boronic acid instead of 2-(2-benzyloxy-5-chlorophenyl)cyclopentene-1-boronic acid and 6-chloropyrazine-2-carboxylic acid ethyl ester instead of 2-chloropyrimidine-4-carboxylic acid methyl ester.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=2)[C:3]=1[C:14]([OH:16])=O.Cl.C(N=C=NCCCN(C)C)C.[F:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)=[CH:32][CH:31]=1>ClCCl>[NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=2)[C:3]=1[C:14]([N:39]1[CH2:38][CH2:37][N:36]([C:33]2[CH:32]=[CH:31][C:30]([F:29])=[CH:35][CH:34]=2)[CH2:41][CH2:40]1)=[O:16]
Reactant: Nc1onc(-c2cccc(F)c2)c1C(=O)O
Reactant: Fc1ccc(N2CCNCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: Nc1onc(-c2cccc(F)c2)c1C(=O)N1CCN(c2ccc(F)cc2)CC1
Yield: 81.5 %

Procedure:
In a similar manner as described in Example 1, by using dichloromethane (30 mL), 5-amino-3-(3-fluorophenyl)isoxazol-4-carboxylic acid (409 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol) and 1-(4-fluorophenyl)piperazine (332 mg, 1.84 mmol), a white solid required compound (576 mg, 1.50 mmol, 81%) was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].[CH:10](=O)[CH3:11]>O1CCCC1>[CH:10](=[N:4][C:3]1[C:5]([CH3:9])=[CH:6][CH:7]=[CH:8][C:2]=1[CH3:1])[CH3:11]
Reactant: Cc1cccc(C)c1N
Reactant: CC=O
Solvent: C1CCOC1
Product: CC=Nc1c(C)cccc1C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2,6-Dimethylaniline (61.8 g, 0.51 mol) was added to a stirred solution of acetaldehyde (35.5 g, 0.81 mol) in tetrahydrofuran (500 mL). After stirring the reaction mixture for 1 day at room temperature, the volatiles were removed in vacuo, the residue was dissolved in THF (500 mL), acetaldehyde (35.5 g) was added to the resulting solution and the reaction mixture was allowed to react for another day at room temperature. This procedure was repeated several times until the conversion of 2,6-dimethylaniline was >98% as determined by gas chromatographic analysis. Yield: 76.7 g (102%).