Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10]([O:14][C:15](=[O:26])[CH2:16][CH:17]([CH:19]1[CH2:24][CH:23]2[CH2:25][CH:20]1[CH:21]=[CH:22]2)[OH:18])([CH3:13])([CH3:12])[CH3:11].[CH3:27][O:28][CH2:29]Cl>C(Cl)Cl>[C:10]([O:14][C:15](=[O:26])[CH2:16][CH:17]([CH:19]1[CH2:24][CH:23]2[CH2:25][CH:20]1[CH:21]=[CH:22]2)[O:18][CH2:27][O:28][CH3:29])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)CC(O)C1CC2C=CC1C2
Reactant: COCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOC(CC(=O)OC(C)(C)C)C1CC2C=CC1C2
Temperature: 25 °C
Yield: 81 %

Procedure:
66 g of diisopropyl ethyl amine was dropped to a solution prepared by dissolving 100 g of 3-bicyclo[2.2.1]hept-5-en-2-yl-3-hydroxy-propionic acid tert-butyl ester (BHP) i and 44 g of chloromethyl methyl ether ii in 1 L of methylene chloride while stirring at room temperature. The mixture was stirred at room temperature for 4 hours, and reaction was evaluated by thin-layer chromatography (TLC) and terminated. This was followed by workup twice with 400 ml of each of a 1 N HCl solution and a 10% Na2CO3 solution, the resultant was washed with 400 ml of distilled water, and an organic layer was collected. Methylene chloride was removed from the organic layer at reduced pressure to obtain 96 g of 3-bicyclo[2,2,1]hept-5-en-2-yl-3-methoxymethoxy-propionic acid t-butyl ester iii (Yield: 81%). The structure was identified using 1H NMR.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([N:11]2[CH2:15][C:14]3[CH2:16][C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=4[O:23][C:13]=3[C:12]2=[O:24])[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[NH2:47][C:48]1[CH:52]=[CH:51][N:50]([CH2:53][C:54]([CH3:57])([OH:56])[CH3:55])[N:49]=1>C(Cl)Cl>[CH:1]1([CH2:6][C@H:7]([N:11]2[CH2:15][C:14]3[CH2:16][C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=4[O:23][C:13]=3[C:12]2=[O:24])[C:8]([NH:47][C:48]2[CH:52]=[CH:51][N:50]([CH2:53][C:54]([OH:56])([CH3:55])[CH3:57])[N:49]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)[C@H](CC1CCCC1)N1CC2=C(Oc3ccccc3C2)C1=O
Reactant: CC(C)(O)Cn1ccc(N)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(O)Cn1ccc(NC(=O)[C@H](CC2CCCC2)N2CC3=C(Oc4ccccc4C3)C2=O)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 72 %

Procedure:
A solution of (S)-3-Cyclopentyl-2-(3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-propionic acid (200 mg, 0.61 mmol) in methylene chloride (10 mL) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI-HCl) (130 mg, 0.67 mmol), 1-hydroxybenzotriazole (HOBT) (90 mg, 0.67 mmol) and commercially available 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (114 mg, 0.73 mmol). The reaction mixture was stirred for 18 hours at 25° C., under N2. The reaction mixture was diluted with methylene chloride, washed with 2N HCl, saturated sodium bicarbonate solution, and a saturated sodium chloride solution and dried over magnesium sulfate. The crude product obtained after concentration was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 12 g; (0% to 100% ethyl acetate/hexane) to afford (S)-3-Cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-(3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-propionamide as a white powder, 205 mg (72% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 1.04 (br. s., 3 H), 1.06 (br. s., 3 H), 1.09-1.83 (m, 10 H), 1.83-1.97 (m, 1 H), 3.75 (s, 2 H), 3.89 (s, 2 H), 4.03 (d, J=19.2 Hz, 1 H), 4.40 (d, J=19.2 Hz, 1 H), 4.67 (s, 1 H), 4.87 (dd, J=10.3, 4.8 Hz, 1 H), 6.44 (d, J=1.8 Hz, 1 H), 7.03-7.15 (m, 2 H), 7.20-7.28 (m, 2 H), 7.53 (d, J=1.8 Hz, 1 H), 10.86 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][N:8]=[C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:6]=2[CH:5]=[CH:4][C:3]=1[SH:18].C([O-])([O-])=O.[K+].[K+].Br[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].CN(C=O)C>O>[CH2:30]([O:29][C:27](=[O:28])[CH2:26][S:18][C:3]1[CH:4]=[CH:5][C:6]2[C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])=[N:8][O:9][C:10]=2[C:2]=1[Cl:1])[CH3:31]
Reactant: CCOC(=O)CBr
Reactant: Fc1ccccc1-c1noc2c(Cl)c(S)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CSc1ccc2c(-c3ccccc3F)noc2c1Cl
Temperature: 50 °C

Procedure:
3.2 g of 7-chloro-3-(2-fluorophenyl)-6-mercapto-1,2-benzisoxazole, 3.1 g K2CO3 and 3.67 g of ethyl bromoacetate are added to 60 ml DMF and warmed for two hours at 50° C. with stirring. The solution is poured into 700 ml H2O and extracted with ethyl acetate. The combined organic extracts are dried over K2CO3, and the solvent is removed in vacuo to afford ethyl{[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazole-6-yl]thio}-acetate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]3[N:11]([C:15](C(O)=O)=[C:16]([S:18][CH3:19])[N:17]=3)[N:12]=[CH:13][CH:14]=2)=[C:5]([CH3:23])[CH:4]=1.C(O)(C)(C)C.C([N:31](CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>C1(C)C=CC=CC=1.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]3[N:11]([C:15]([NH2:31])=[C:16]([S:18][CH3:19])[N:17]=3)[N:12]=[CH:13][CH:14]=2)=[C:5]([CH3:23])[CH:4]=1
Reactant: CCN(CC)CC
Reactant: COc1ccc(-c2ccnn3c(C(=O)O)c(SC)nc23)c(C)c1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CC(C)(C)O
Solvent: Cc1ccccc1
Product: COc1ccc(-c2ccnn3c(N)c(SC)nc23)c(C)c1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
The resulting 8-(4-methoxy-2-methylphenyl)-2-(methylsulfanyl)imidazo[1,2-b]pyridazine-3-carboxylic acid was dissolved in toluene (10 mL), then tert-butyl alcohol (10 mL), triethylamine (0.49 mL) and diphenylphosphorylazide (0.38 mL) were added thereto, and the mixture was heated at 100° C. for 4 hours. After completion of the reaction, water was added thereto, which was extracted with ethyl acetate, washed with water, dried over anhydrous magnesium sulfate, and evaporated. The resulting Boc compound was dissolved in ethyl acetate (10 mL) without purification, then a 4N hydrochloric acid-ethyl acetate solution (15 mL) was added thereto, and the mixture was stirred at room temperature for 3 hours. Under ice-cooling, a 5N aqueous sodium hydroxide solution was added thereto, which was neutralized and extracted with ethyl acetate. The material was washed with water, dried over anhydrous magnesium sulfate, and evaporated. The resulting residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:2) to give the title compound (73 mg) as a brown oil.
Reaction SMILES: [CH2:1]([N:5]1[C:10](=[O:11])[C:9]([CH2:12]OS(C)(=O)=O)=[CH:8][C:7]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)=[N:6]1)[CH:2]([CH3:4])[CH3:3].[NH2:25][CH2:26][CH2:27][OH:28]>>[OH:28][CH2:27][CH2:26][NH:25][CH2:12][C:9]1[C:10](=[O:11])[N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[N:6]=[C:7]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)[CH:8]=1
Reactant: Cc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CC(C)C)n2)cc1
Reactant: NCCO
Product: Cc1ccc(-c2cc(CNCCO)c(=O)n(CC(C)C)n2)cc1

Procedure:
Following the procedure of Example 9(4), 2-isobutyl-4-methanesulfonyloxymethyl-6-(4-methylphenyl)-2H-pyridazin-3-one and 2-aminoethanol were reacted to yield the title compound as a slightly yellow oil (yield: 80.3%). 1H NMR(400 MHz, CDCl3)δ: 0.98(6H, d, J=6.8 Hz), 2.20–2.38(3H, m), 2.39(3H, s), 2.84(2H, t, J=5.1 Hz), 3.72(2H, t, J=5.1 Hz), 3.82(2H, d, J=1.2 Hz), 4.07(2H, d, J=7.3 Hz), 7.26(2H, d, J=8.1 Hz), 7.68(1H, s), 7.70(2H, d, J=8.1 Hz). IR(Neat) cm−1: 3429, 1652, 1601, 1519. Mass m/z: 315(M+).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[NH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][OH:17])[CH2:11][CH2:10]1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C(=O)C>O>[CH3:8][C:5]1[N:4]=[N:3][C:2]([N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][OH:17])[CH2:11][CH2:10]2)=[CH:7][CH:6]=1
Reactant: OCCC1CCNCC1
Reactant: Cc1ccc(Cl)nn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1ccc(N2CCC(CCO)CC2)nn1
Temperature: 150 °C
Reaction time: 5 h
Yield: 71.1 %

Procedure:
A mixture of 19.3 parts of 3-chloro-6-methylpyridazine, 19.4 parts of 4-piperidinethanol, 16 parts of sodium carbonate and 0.85 parts of N,N-dimethylacetamide was stirred for 5 hours at 150° C. After cooling, the reaction mixture was diluted with water and extracted with dichloromethane (2×). The combined extracts were washed with water, dried, filtered and evaporated. The residue was purified by column chromatography (silica gel;CHCl3 /CH3OH 98:2). The eluent of the desired fraction was evaporated, yielding 23.6 parts (71.1%) of 1-(6-methyl-3-pyridazinyl)-4-piperidineethanol; p. 99°-100° C. at 8 Pa (interm. 24).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:15]2[C:16]([C:22](=[O:32])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[N+:29]([O-])=O)=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)[CH2:12][O:13][CH3:14])(=[O:10])=[O:9])=[CH:4][C:3]=1[C:33]([F:36])([F:35])[F:34]>CC(O)=O.[Fe]>[NH2:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:22]([C:16]1[C:15]([N:11]([CH2:12][O:13][CH3:14])[S:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:33]([F:36])([F:35])[F:34])[CH:4]=2)(=[O:10])=[O:9])=[CH:20][C:19]([Cl:21])=[CH:18][N:17]=1)=[O:32]
Reactant: COCN(c1cc(Cl)cnc1C(=O)c1ccccc1[N+](=O)[O-])S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: [Fe]
Solvent: CC(=O)O
Product: COCN(c1cc(Cl)cnc1C(=O)c1ccccc1N)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred suspension of Fe (376 mg, 6.73 mmol) in glacial AcOH (10 mL) at 80° C. was added a solution 4-chloro-N-[5-chloro-2-(2-nitro-benzoyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (700 mg, 1.34 mmol) in AcOH (5 mL) over 15 min. After complete addition, the mixture was stirred for 2 h and the progress of the reaction was followed by LCMS. Upon consumption of reactants, the reaction mixture was cooled to room temperature, diluted with EtOAc, and filtered through a pad of Celite. The filtrate was concentrated under reduced pressure and residue was partitioned with aqueous NaHCO3 and EtOAc. The organic portion was separated and the aqueous portion was extracted with EtOAc. The combined extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to provide N-[2-(2-amino-benzoyl)-5-chloro-pyridin-3-yl]-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide. MS m/z: 556.0 (M+Na).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([O:12][CH2:13][CH3:14])=[CH:5][C:4]=1F)[CH3:2].[CH3:16][S:17]([CH2:20][CH2:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)(=[O:19])=[O:18].C([O-])([O-])=O.[K+].[K+].CS(C)=O>O>[CH2:1]([C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([O:12][CH2:13][CH3:14])=[CH:5][C:4]=1[N:25]1[CH2:26][CH2:27][CH:22]([CH2:21][CH2:20][S:17]([CH3:16])(=[O:19])=[O:18])[CH2:23][CH2:24]1)[CH3:2]
Reactant: CCOc1cc(F)c(CC)cc1[N+](=O)[O-]
Reactant: CS(=O)(=O)CCC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCOc1cc(N2CCC(CCS(C)(=O)=O)CC2)c(CC)cc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 64 %

Procedure:
To 1-ethyl-4-(ethyloxy)-2-fluoro-5-nitrobenzene (0.19 g, 0.89 mmol), 4-[2-(methylsulfonyl)ethyl]piperidine (Example 101, Step D) (0.20 g, 1.1 mmol), and K2CO3 (0.43 g, 3.1 mmol) was added DMSO (12 mL). The reaction was heated to 100° C. for two days. Reaction was determined to be complete by TLC. The reaction mixture was diluted with H2O and extracted with DCM and EtOAc sequentially for two iterations. The organic was dried (MgSO4), filtered, and rotovapped down. Purification by flash chromatography provided the title compound of Step B (0.22 g, 0.57 mmol, 65% yield). 1H NMR (400 MHz, CDCl3) δ 7.80 (s, 1H), 6.57 (s, 1H), 4.13 (q, J=6.9 Hz, 2H), 3.20 (d, J=11.6 Hz, 2H), 3.00-3.13 (m, 2H), 2.92 (s, 3H), 2.67 (t, J=11.7 Hz, 2H), 2.57 (q, J=7.4 Hz, 2H), 1.77-1.97 (m, 4H), 1.36-1.68 (m, 6H), 1.24 (t, 3H).
Reaction SMILES: Br.[NH2:2][C@H:3]([C:14]([OH:16])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.N1([C:29](=O)[C:28]2N(C)C=N[C:23]=2N(C)C1=O)C>O>[CH:28]([O:15][C:14](=[O:16])[C@H:3]([CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)[NH2:2])([CH3:29])[CH3:23]
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: Cn1c(=O)c2c(ncn2C)n(C)c1=O
Agent: Br
Solvent: O
Product: CC(C)OC(=O)[C@@H](N)Cc1c[nH]c2ccccc12

Procedure:
HBr (120 g) and tryptophan (5 g) were dissolved in water (1 L). Caffeine (100 g) was added into the mixture and the mixture was stirred for a few minutes. The mixture was filled into either spray bottles or roll-on bottles.
Reaction SMILES: C1(O[C:8](=[O:29])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[CH:22]=[C:21]([F:23])[C:20]([CH3:24])=[CH:19][C:18]=3[F:25])[C:11]=2[C:26](=[O:28])[NH2:27])C=CC=CC=1.[NH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][N:37]1[CH2:42][CH2:41][N:40]([CH2:43][CH2:44][OH:45])[CH2:39][CH2:38]1>>[F:25][C:18]1[CH:19]=[C:20]([CH3:24])[C:21]([F:23])=[CH:22][C:17]=1[CH2:16][O:15][C:12]1[C:11]([C:26]([NH2:27])=[O:28])=[C:10]([NH:9][C:8]([NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][N:37]2[CH2:42][CH2:41][N:40]([CH2:43][CH2:44][OH:45])[CH2:39][CH2:38]2)=[O:29])[S:14][N:13]=1
Reactant: NCCCCCCN1CCN(CCO)CC1
Reactant: Cc1cc(F)c(COc2nsc(NC(=O)Oc3ccccc3)c2C(N)=O)cc1F
Product: Cc1cc(F)c(COc2nsc(NC(=O)NCCCCCCN3CCN(CCO)CC3)c2C(N)=O)cc1F

Procedure:
The title compound was prepared from [4-carbamoyl-3-(2,5-difluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester and 2-[4-(6-amino-hexyl)-piperazin-1-yl]-ethanol by the procedure analogous to Example 6. HPLC ret. time: 3.0 minutes. 1H NMR (400 MHz, CD3OD) δ 7.17 (d, 1H, J=6.4, 9.6 Hz), 7.01 (m, 1H), 5.44 (s, 2H), 3.64 (t, 2H, J=5.6 Hz), 3.18 (t, 2H, J=6.8 Hz), 2.7-2.4 (bm, 8H), 2.50 (t, 2H, J=6.0 Hz), 2.23 (m, 2H), 2.23 (s, 3H), 1.50 (m, 4H), 1.35 (m, 4H) ppm; MS (APCl, m/z): 555 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[CH3:14])[CH3:2].[CH3:19][C:20]1[S:24][C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:22][C:21]=1[CH2:31][CH2:32]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:32][CH2:31][C:21]2[N:22]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[S:24][C:20]=2[CH3:19])=[CH:9][C:8]=1[CH3:14])[CH3:2]
Reactant: Cc1sc(-c2ccccc2)nc1CCO
Reactant: CCOC(=O)C(Cc1ccc(O)cc1C)OCC
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)C(Cc1ccc(OCCc2nc(-c3ccccc3)sc2C)cc1C)OCC

Procedure:
In analogy to the procedure described in example 10 c], [rac]-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-propionic acid ethyl ester (example 10 b]) was reacted with 2-(5-methyl-2-phenyl-thiazol-4-yl)-ethanol [PCT Int. Appl. (2002), WO 02/18355 A1] in the presence of triphenylphosphine and diethyl azodicarboxylate to yield [rac]-2-ethoxy-3-{2-methyl-4-[2-(5-methyl-2-phenyl-thiazol-4-yl)-ethoxy]-phenyl}-propionic acid ethyl ester as colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([O:13][CH3:14])=[O:12])[C:5]([OH:7])=[O:6].O=S(Cl)Cl.[CH3:19]O>>[Br:1][C:2]1[CH:3]=[C:4]([C:5]([O:7][CH3:19])=[O:6])[CH:8]=[CH:9][C:10]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1ccc(C(=O)O)cc1Br
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(C(=O)OC)c(Br)c1
Yield: 98 %

Procedure:
To a solution of 3-bromo-4-(methoxycarbonyl)benzoic acid (3.0 g, 11.6 mmol) in MeOH (50 mL) was slowly added SOCl2 (2.76 g, 23.2 mmol) dropwise. After the addition completion, the reaction mixture was refluxed for 5 h. Then MeOH was removed and water was added. It was extracted with EA and the organic layer was washed with aqueous sodium bicarbonate solution, brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give dimethyl 2-bromoterephthalate (3.1 g, yield 98%) as a white solid. It was used without further purification in the next step.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][OH:16].CCN(CC)CC.[O:24](S(C1C=CC(C)=CC=1)(=O)=O)[S:25]([C:28]1[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=1)(=O)=[O:26]>C(Cl)Cl.[NH4+].[Cl-]>[CH3:32][C:31]1[CH:33]=[CH:34][C:28]([S:25]([O:16][CH2:15][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)(=[O:26])=[O:24])=[CH:29][CH:30]=1
Reactant: OCc1ccccc1COC1CCCCO1
Reactant: Cc1ccc(S(=O)(=O)OS(=O)(=O)c2ccc(C)cc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCc2ccccc2COC2CCCCO2)cc1
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 78.7 %

Procedure:
A solution of {2-[(tetrahydro-2H-pyran-2-yloxy)methyl]phenyl}methanol (5.52 g, 24.84 mmol) in CH2Cl2 (100 ml) was cooled to 0° C. and treated with Et3N (6.92 ml, 49.68 mmol) followed by the addition of Ts2O (8.9 g, 27.33 mmol). The reaction stirred at 0° C. for 3.5 hours. The mixture was diluted with sat. NH4Cl and extracted with CH2Cl12 (2×). The combined organic solutions were washed with water, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by normal phase chromatography (10% EtOAc/hexanes—20%) to give a light brown oil (7.36 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH2:6][N:5]=[C:4]2[O:15][CH:16]=[CH:17][C:3]=12.[Cl:18][C:19]1[CH:20]=[C:21]([C:26]2([C:29](Cl)=[O:30])[CH2:28][CH2:27]2)[CH:22]=[CH:23][C:24]=1[Cl:25]>N1C=CC=CC=1>[NH2:1][C:2]1[N:7]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][C:29]([C:26]3([C:21]4[CH:22]=[CH:23][C:24]([Cl:25])=[C:19]([Cl:18])[CH:20]=4)[CH2:28][CH2:27]3)=[O:30])=[CH:12][CH:13]=2)[CH2:6][N:5]=[C:4]2[O:15][CH:16]=[CH:17][C:3]=12
Reactant: NC1=c2ccoc2=NCN1c1ccc(N)cc1
Reactant: O=C(Cl)C1(c2ccc(Cl)c(Cl)c2)CC1
Solvent: c1ccncc1
Product: NC1=c2ccoc2=NCN1c1ccc(NC(=O)C2(c3ccc(Cl)c(Cl)c3)CC2)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To compound 4-Amino-3-(4-aminophenyl)furo[2,3-d]pyrimidine (9) (0.3 mL of a 0.324 M solution in pyridine 0.1 mmol) 1-(3,4-Dichloro-phenyl)-cyclopropanecarbonyl chloride (0.2 mL of a 1 M solution in pyridine, 0.2 mmol) was added in one portion. After the mixture was stirred at room temperature for 3 d, the reaction was purified by hplc to afford the title compound. MS(ES) m/e 439 [M+H].
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][C:6]=1[C:14]([F:17])([F:16])[F:15])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[OH:39][C:40]1(O)[C:48]2[CH:47]=[CH:46][CH:45]=[C:44]([C:49](=[NH:51])[NH2:50])[C:43]=2[CH2:42][CH2:41]1.[Na+].[Cl-]>CN(C=O)C>[CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]2[O:11][N:51]=[C:49]([C:44]3[CH:45]=[CH:46][CH:47]=[C:48]4[C:43]=3[CH2:42][CH2:41][CH:40]4[OH:39])[N:50]=2)=[CH:7][C:6]=1[C:14]([F:17])([F:16])[F:15])([CH3:2])[CH3:3]
Reactant: CC(C)Oc1ccc(C(=O)O)cc1C(F)(F)F
Reactant: N=C(N)c1cccc2c1CCC2(O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CCC4O)no2)cc1C(F)(F)F
Temperature: 130 °C
Reaction time: 0.33 h
Yield: 68 %

Procedure:
In a microwave vial, a stirring solution of 4-isopropoxy-3-(trifluoromethyl)benzoic acid (700 mg, 2.82 mmol) in DMF was treated with HOBt (495 mg, 3.67 mmol) and EDCI (702 mg, 3.67 mmol) at room temperature. The reaction was stirred for 20 min followed by addition, in a single portion, of NJ-dihydroxy-2,3-dihydro-1H-indene-4-carboximidamide (650 mg, 3.38 mmol). The reaction was stirred for additional 30 min at room temperature and then heated to 130° C. for 35 min in the initiator. The reaction was diluted using a saturated solution of NaCl and extracted with EtOAc (100 ml×3). The organic phase was dried over Na2SO4 anhydrous and concentrated under reduced pressure. The product was purified by column chromatography using CH2Cl2:MeOH (9:1) to offer the product as white solid in 68% yield (780 mg). 1H NMR (300 MHz, CDCl3-CH3OD): δ 8.38 (d, J=1.8 Hz, 1H), 8.28 (dd, J1=2.4 Hz, J2=8.7 Hz, 1H), 8.06 (d, J=7.8 Hz, 1H), 7.55 (d, J=7.5 1H), 7.7.37 (t, J=7.5 Hz, 1H), 7.11 (dd, J1=2.4 Hz, J2=9.0 Hz, 1H), 5.24 (t, J=6.3 Hz, 1H), 4.20 (q, J=6.9 Hz, 1H), 3.48-3.40 (m, 1H), 3.19-3.09 (m, 1H), 2.57-2.46 (m, 1H), 2.04-1.92 (m, 1H), 1.46 (t, J=6.9 Hz, 3H), 1.39 (d, J=6.0 Hz, 3H); 13C NMR (75 MHz, CDCl3-CH3OD): δ 169.05, 158.85, 146.82, 143.33, 133.55, 128.79, 127.41, 127.22, 116.23, 113.38, 104.88, 65.27, 35.55, 31.44, 21.87, 14.55. MS (EI) m/z 405 (M+), HRMS (EI) for C21H19N2O3 (M+): calcd 405.1420. found 405.1424.
Reaction SMILES: [NH:1]([C:3]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[C:7](=[O:16])[N:6]([CH2:17][CH2:18][CH3:19])[C:5](=[O:20])[CH:4]=1)[NH2:2].[CH3:21][N:22]=[C:23]=S.CO>CN(C=O)C>[CH3:21][NH:22][C:23]1[C:4]2[C:5](=[O:20])[N:6]([CH2:17][CH2:18][CH3:19])[C:7](=[O:16])[N:8]([CH2:9][C:10]3[CH:11]=[CH:12][N:13]=[CH:14][CH:15]=3)[C:3]=2[NH:1][N:2]=1
Reactant: CN=C=S
Reactant: CCCn1c(=O)cc(NN)n(Cc2ccncc2)c1=O
Solvent: CN(C)C=O
Solvent: CO
Product: CCCn1c(=O)c2c(NC)n[nH]c2n(Cc2ccncc2)c1=O
Reaction time: 14 h

Procedure:
A solution of 6-hydrazino-1-(4-pyridylmethyl)-3-propyluracil (1.5 g, 5.7 mM) and methyl isothiocyanate (1.55 ml, 23 mM) in DMF (15 ml) was heated at 90° C. for 14 hours and then at 110° C. for 14 hours. To the reaction solution was added 50% methanol (10 ml) and the mixture was cooled to give crystals. Recrystallization from DMF/ethanol/water afforded colorless needles (1.02 g, 57%), m.p. >300° C.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:8]([C:11]1[CH:29]=[CH:28][C:14]2[O:15][CH2:16][C:17](=[O:27])[N:18](CCCC(OCC)=O)[C:13]=2[CH:12]=1)(=[O:10])[CH3:9]>>[C:8]([C:11]1[CH:29]=[CH:28][C:14]2[O:15][CH2:16][C:17](=[O:27])[N:18]([CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:13]=2[CH:12]=1)(=[O:10])[CH3:9]
Reactant: CCOC(=O)CBr
Reactant: CCOC(=O)CCCN1C(=O)COc2ccc(C(C)=O)cc21
Product: CCOC(=O)CN1C(=O)COc2ccc(C(C)=O)cc21

Procedure:
The compound 23b was synthesized by reacting 22 and 6d following the same protocol described for the synthesis of compound 23a. White solid (0.47 g, 32%). 1H NMR (400 MHz, CDCl3): δ 1.30 (t, J=7.2 Hz, 3H); 2.55 (s, 3H); 4.25 (q, J=7.2 Hz, 2H); 4.70 (s, 2H); 4.74 (s, 2H); 7.05 (dd, J=1.6, 8.4 Hz, 1H); 7.41-7.42 (m, 1H); 7.60-7.63 (m, 1H).
Reaction SMILES: O[CH:2]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]([CH3:14])[CH3:13])=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].[CH3:15][C:16]1[CH:17]=[C:18](O)[CH:19]=[C:20]([CH3:22])[CH:21]=1>C(OCC)(=O)C.CCCCCC>[CH:12]([C:9]1[CH:10]=[CH:11][C:6]([CH:2]2[C:17]3[C:16]([CH3:15])=[CH:21][C:20]([CH3:22])=[CH:19][C:18]=3[O:5][C:3]2=[O:4])=[CH:7][CH:8]=1)([CH3:14])[CH3:13]
Reactant: Cc1cc(C)cc(O)c1
Reactant: CC(C)c1ccc(C(O)C(=O)O)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1cc(C)c2c(c1)OC(=O)C2c1ccc(C(C)C)cc1
Yield: 45 %

Procedure:
Using hydroxy(4-isopropylphenyl)acetic acid synthesized in Reference Example 1 and 3,5-dimethylphenol, the title compound was synthesized in the same manner as in Reference Example 2. Yield 45%. Melting point: 76-77° C. (ethyl acetate-hexane).