Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:13])=[C:4]([C:9]([CH3:12])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].S(OC)(O[CH3:18])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>C1(S(CC2C(C(OC)=O)=C3C(C4C=COC=4CO3)=CC=2)(=O)=O)C=CC=CC=1>[Br:1][C:2]1[C:3]([O:13][CH3:18])=[C:4]([C:9]([CH3:12])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COS(=O)(=O)OC
Reactant: COC(=O)c1c(C)ccc(Br)c1O
Agent: COC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc2c1OCc1occc1-2
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1c(C)ccc(Br)c1OC

Procedure:
A mixture of methyl 3-bromo-2-hydroxy-6-methylbenzoate (Intermediate 44, 114.5 g), dimethyl sulfate (61 mL) and potassium carbonate (166 g) in acetone (11) was heated at reflux for 2.5 hours. After cooling, the mixture was filtered and the filtrate was evaporated to dryness. The residue was dissolved in DCM and washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of tert-butyl methyl ether and pentane with a gradient of 0-40%. The product was purified again by chromatography on silica, eluting with a mixture of tert-butyl methyl ether and pentane with a gradient of 0-10%. The product was again purified by chromatography on silica, eluting with a mixture of tert-butyl methyl ether and pentane with a gradient of 0-10% to give methyl 3-bromo-2-methoxy-6-methylbenzoate (66 g).
Reaction SMILES: [OH:1][C:2]1([C:5]([OH:7])=O)[CH2:4][CH2:3]1.S(Cl)(Cl)=O.[C:12]1([S:18]([C:21]2[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C>CC(N(C)C)=O>[C:12]1([S:18]([C:21]2[CH:22]=[CH:23][C:24]([NH:25][C:5]([C:2]3([OH:1])[CH2:4][CH2:3]3)=[O:7])=[CH:26][CH:27]=2)(=[O:19])=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1ccc(S(=O)(=O)c2ccccc2)cc1
Reactant: O=C(O)C1(O)CC1
Agent: C
Solvent: CC(=O)N(C)C
Solvent: O=S(Cl)Cl
Product: O=C(Nc1ccc(S(=O)(=O)c2ccccc2)cc1)C1(O)CC1
Temperature: -15 °C
Reaction time: 1 h

Procedure:
A solution of 1-hydroxycyclopropanecaboxylic acid (0.66 g, 6.44 mmol) in dry dimethylacetamide (10 ml) was stirred under a nitrogen atmosphere at -15° C. Thionyl chloride (0.77 g, 6.44 mmol) was added and the resulting mixture was allowed to stir at -15° C. for 1 hour. 4-Phenylsulfonylaniline (1.0 g, 4.29 mmol) was then added and the reaction mixture was stirred at -15° C. for a further 15 mins. The solution was then allowed to warm to room temperature where it was stirred overnight. The reaction mixture was poured onto ice, extracted with ethyl acetate, and the combined ethyl acetate portions were washed with 1M HCl. After drying (MgSO4) the ethyl acetate was removed by evaporation to give a buff-colored solid. Crystallization of this material from ethyl acetate/hexane yielded the title tertiary carbinol, (0.82 g, 60%) as a white solid; mp=214.5°-216° C. 1H-NMR (250 MHz, d6 -DMSO): 0.98 (m, 2H, 2 CH2), 1.15 (m, 2H, CH2), 6.63 (s, 1H, OH), 7.65 (m, 3H, ARM), 7.95 (m, 6H, ArH), 10.29 (s, 1H, NH). MS (CI, CH4): 318(M+1, 100).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].Br[C:13]1[S:14][CH:15]=[CH:16][N:17]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:13]2[S:14][CH:15]=[CH:16][N:17]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccc(O)cc1
Reactant: Brc1nccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)Oc1ccc(Oc2nccs2)cc1
Yield: 91.4 %

Procedure:
A mixture of Example 1A (15.5 g, 0.1 mol), 2-bromothiazole (18.2 g, 0.11 mol) and potassium carbonate (15.2 g, 0.11 mol) in dimethylsulfoxide was heated at 160° C. under nitrogen for 6 hours. It was then cooled and treated with water, and the aqueous phase was extracted with methylene chloride. The organic layer washed with brine, dried (MgSO4) and concentrated to give 27.5 g of the crude material which was purified on silica gel (5˜35% ethyl acetate in hexane) to afford 21.5 g of the title compound (91% yield) 1H NMR (500 MHz, CDCl3) δ ppm 1.32-1.36 (m, 6 H) 1.34 (none, 6 H) 1.34 (none, 5 H) 4.45-4.57 (m, 1 H) 6.76 (d, J=3.91 Hz, 1 H) 6.87-6.93 (m, 2 H) 7.15-7.20 (m, 2 H) 7.21 (d, J=3.91 Hz, 1 H). MS (ESI): m/z 236 (M−H).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C@H:5]([CH2:7][C:8]([OH:10])=[O:9])[C:4](=[O:11])[O:3]1.C(Cl)(=O)C(Cl)=O.CN(C)C=O.[Cl:24][C:25]1[CH:26]=[CH:27][C:28](O)=[C:29]([CH:43]=1)[C:30]([NH:32][C:33]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][C:34]=1[Cl:42])=[O:31]>C(Cl)(Cl)Cl.N1C=CC=CC=1>[CH3:1][C:2]1([CH3:12])[O:6][C@H:5]([CH2:7][C:8]([O:10][C:28]2[CH:27]=[CH:26][C:25]([Cl:24])=[CH:43][C:29]=2[C:30](=[O:31])[NH:32][C:33]2[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][C:34]=2[Cl:42])=[O:9])[C:4](=[O:11])[O:3]1
Reactant: O=C(Nc1ccc([N+](=O)[O-])cc1Cl)c1cc(Cl)ccc1O
Reactant: CC1(C)OC(=O)[C@@H](CC(=O)O)O1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC1(C)OC(=O)[C@@H](CC(=O)Oc2ccc(Cl)cc2C(=O)Nc2ccc([N+](=O)[O-])cc2Cl)O1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A suspension of (R)-(−)-2,2-Dimethyl-5-oxo-1,3-dioxolane-4-acetic acid (Sigma-Aldrich, St. Louis, Mo.) (2.17 g, 12.46 mmol) in chloroform (24 mL) was treated with oxalyl chloride (2.11 mL, 25 mmol) and a drop of N,N-dimethylformamide was added. The progression of reaction was monitored by the observation of gas evolution by means of a bubbler. After 2 hours at room temperature, the reaction mixture was warmed to 50° C. for 2 hours, cooled to room temperature, and concentrated to remove volatiles. This residue was diluted with chloroform (10 mL) and added to a suspension of 5-Chloro-N-(2-chloro-4-nitrophenyl)-2-hydroxybenzamide (2.04 g, 6.23 mmol) in pyridine (30 mL) in which 4-dimethylaminopyride (20 mg) had been previously dissolved. The reaction mixture was stirred at room temperature for 16 h and then was partitioned between 1N aqueous HCl and ethyl acetate. The ethyl acetate solution was dried over magnesium sulfate and concentrated to a dark oil. The residue was dissolved in chloroform and placed upon a short column of silica gel (60 mm i.d.×15 mm). The product was eluted with chloroform and concentrated to an oil. The product was crystallized with a mixture of hexanes and ethyl acetate. 1HNMR (300 MHz, DMSO-d6): δ1.456 (s, 3H), 1.495 (s, 3H), 4.939 (m, 1H), 7.352 (d, J=9 Hz, 1H, H3), 7.730 (dd, J=3.9 Hz, 1H, H4), 7.851 (d, J=3 Hz, 1H, H6), 8.110 (d, J=9 Hz, 1H, H6′), 8.255 (dd, J=3, 9 Hz, 1H, H5′), 8.411 (d, J=3 Hz, 1H, H3′), 10.481 (s, 1H, NH).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Br:20])=[CH:4][N:3]=1.[F:21][C:22]1[CH:23]=[C:24]([CH:28]=O)[CH:25]=[CH:26][CH:27]=1.C([O-])(=O)C.[NH4+]>>[Br:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:28]([C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([F:21])[CH:23]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: O=Cc1cccc(F)c1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Br)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: NC(=O)[C@@H]1[C@H](Nc2c(Br)cnc3[nH]c(-c4cccc(F)c4)nc23)[C@H]2C=C[C@@H]1C2
Yield: 64.8 %

Procedure:
In a similar fashion to compound CXXV, (1S,2S,3R,4R)-3-(2,3-Diamino-5-bromo-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (100.00 mg, 0.29568 mmol), 3-FC6H4CHO (40.4 mg, 0.325 mmol) and Ammonium acetate (45.6 mg, 0.591 mmol) were reacted to yield 84.7 mg (65%) of the title compound. (300 MHz, DMSO-d6) 13.33 (s, 1H), 8.18 (m, 2H), 8.04 (s, 1H), 7.75 (s, 1H), 7.41 (t, J=16.5 Hz, 8 Hz, 2H), 7.22 (s, 1H), 6.39 (d, J=15 Hz, 2H), 5.22 (t, J=17 Hz, 8.5 Hz, 1H), 2.89 (s, 1H), 2.78 (s, 1H), 2.62 (d, J=8 Hz, 1H), 2.24 (d, J=8 Hz, 1H), 1.39 (d, J=8 Hz, 1H). MS=444 (M+H), HPLC: 2.56 min. (G Method)
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[CH:11]=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:19][C:20](=O)[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:23]=1[CH3:29].C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[CH3:17][O:16][C:14]([C:12]1[CH:11]=[CH:10][N:9]2[C:8]([CH:13]=1)=[C:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:20]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:23]=1[CH3:29])=[CH:19]2)=[O:15]
Reactant: Cc1c(F)cccc1CC(=O)CBr
Reactant: COC(=O)c1ccnc(Cc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COC(=O)c1ccn2cc(Cc3cccc(F)c3C)c(-c3ccccc3)c2c1
Temperature: 105 °C
Reaction time: 2 h
Yield: 19.5 %

Procedure:
The compound of step 1 (1.555 g, 6.84 mmol) and the compound of example 1, step 2 (1.677 g, 6.84 mmol) were dissolved in 28.5 ml of acetone and the solution was heated to reflux overnight. The mixture was then evaporated to dryness under reduced pressure and the residue dissolved in 28.5 ml of isopropanol. Sodium carbonate (2.176 g, 20.53 mmol) was added and the mixture was heated at 105° C. with stirring for 2 h. The solids were filtered off and the filtrate was evaporated to dryness under reduced pressure. The residue was purified by chromatography on silica gel (cyclohexane/EA, 100:0, then 95:5) to give 0.497 g of the title compound as a yellow solid melting at 55° C.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:14](=[O:15])[C:13]2[N:11]([CH3:12])[CH:10]=[N:9][C:8]=2[N:6]([CH3:7])[C:4]1=[O:5].Br[CH2:17][CH2:18][CH2:19][CH:20]=[CH2:21].O>CS(C)=O>[CH2:21]([N:3]1[C:14](=[O:15])[C:13]2[N:11]([CH3:12])[CH:10]=[N:9][C:8]=2[N:6]([CH3:7])[C:4]1=[O:5])[CH2:20][CH2:19][CH:18]=[CH2:17]
Reactant: Cn1cnc2c1c(=O)[nH]c(=O)n2C
Reactant: C=CCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: C=CCCCn1c(=O)c2c(ncn2C)n(C)c1=O
Reaction time: 0.33 h
Yield: 77.9 %

Procedure:
This example illustrates a synthesis of 1-(4,5-Oxipentyl)-3,7- dimethylxanthine. Sodium hydride (95%) (1.38 g, 55 mmol) was added to a solution of theobromine (9.0 g, 50 mmol) in dimethylsulfoxide (300 mL). After 20 minutes of stirring, 1-bromo-4-pentene (7.45 g, 50 mmol) was added. After 16 hours of stirring at room temperature, the reaction was poured into a separatory funnel containing 1 L of water and extracted with dichloromethane (5×200 mL). The organic extracts were combined, washed with water (100 mL) and brine (100 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crude product obtained was further purified by flash chromatography over silica gel using 20% petroleum ether/ethyl acetate eluant to yield 9.67 g (92% yield) 1-(4-pentenyl)-3,7-dimethylxanthine (inventive compound no. 1575).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[O:41]1[CH2:46][CH2:45][O:44][CH2:43][CH:42]1[C:47]1[C:55]2[S:54][C:53]([NH2:56])=[N:52][C:51]=2[C:50]([O:57][CH3:58])=[CH:49][CH:48]=1>C1COCC1.C(Cl)(Cl)Cl>[O:41]1[CH2:46][CH2:45][O:44][CH2:43][CH:42]1[C:47]1[C:55]2[S:54][C:53]([NH:56][C:5](=[O:7])[CH2:4][CH2:3][O:2][CH3:1])=[N:52][C:51]=2[C:50]([O:57][CH3:58])=[CH:49][CH:48]=1
Reactant: COc1ccc(C2COCCO2)c2sc(N)nc12
Reactant: COCCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COCCC(=O)Nc1nc2c(OC)ccc(C3COCCO3)c2s1

Procedure:
From 3-methoxypropionic acid, HATU and N-ethyldiisopropylamine in THF, then treatment with (+)-7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-ylamine. [α]D20=+24.4° (c=1.02, CHCl3), ES-MS m/e (%): 353 (M+H+, 100).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([F:20])[C:10]([F:19])=[C:11]([NH:15][CH2:16][CH2:17][OH:18])[C:12]=3[F:14])[C:7](=[O:21])[C:6]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:5]2)[CH2:3][CH2:2]1.[C:27]1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCOCC)C.C(#N)C>C(Cl)(Cl)Cl>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([F:20])[C:10]([F:19])=[C:11]([N:15]4[CH2:16][CH2:17][O:18][CH2:27]4)[C:12]=3[F:14])[C:7](=[O:21])[C:6]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(NCCO)c(F)c(F)c2c1=O
Solvent: CC#N
Solvent: CCOCOCC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cn(C2CC2)c2c(F)c(N3CCOC3)c(F)c(F)c2c1=O
Reaction time: 3 h

Procedure:
A mixture of 0.74 g of ethyl 1-cyclopropyl-5,6,8-trifluoro-7-(2-hydroxyethylamino)-1,4-dihydro-4-oxoquinoline-3-carboxylate, 0.08 g of p-toluenesulfonic acid, 2.08 g of diethoxymethane and 20 ml of acetonitrile was stirred for 3 hours under reflux. The reaction mixture was allowed to cool down, followed by the addition of 100 ml of chloroform. The resultant mixture was washed successively with 5% aq. sodium carbonate solution and saturated saline, dried over anhydrous magnesium sulfate, and then concentrated.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[N:8]=[CH:7][N:6]=[C:5](O)[CH:4]=1.P(Cl)(Cl)(Cl)=O.[OH-].[NH4+:18]>>[F:1][C:2]([F:11])([F:10])[C:3]1[N:8]=[CH:7][N:6]=[C:5]([NH2:18])[CH:4]=1
Reactant: [NH4+]
Reactant: Oc1cc(C(F)(F)F)ncn1
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: Nc1cc(C(F)(F)F)ncn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 14 %

Procedure:
The procedure was derived from methods described in U.S. Pat. No. 5,756,275 and WO 02/38569. In a 250 mL round bottom flask, 6-trifluoromethyl-4-pyrimidinol (10 g, 60.9 mmol) was dissolved in 70 mL phosphorus oxychloride (0.73 mol). The solution was heated at reflux for 7 h. The cooled reaction solution was then added gradually to 200 mL 30% ammonium hydroxide, and the resulting mixture was stirred overnight at room temperature. The reaction mixture was extracted with ethyl acetate (2×100 mL), and the combined extracts were dried (MgSO4) and evaporated in vacuo to give 6-trifluoromethyl-pyrimidin-4-ylamine (1.4 g, yield 14%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.50 (s, 1 H), 7.60 (broad s, 2 H), 6.90 (s, 1 H); LC-MS m/z 164.1 [M+H]+.
Reaction SMILES: [C:1]([C:3]1([OH:10])[CH2:8][CH2:7][CH2:6][CH:5]([CH3:9])[CH2:4]1)#[CH:2].[CH3:11][CH2:12][NH:13][C:14]([C@H:16]1[O:20][C@@H:19]([N:21]2[C:25]3[N:26]=[C:27](I)[N:28]=[C:29]([NH2:30])[C:24]=3[N:23]=[CH:22]2)[CH:18]([OH:32])[C@H:17]1[OH:33])=[O:15]>>[CH2:12]([NH:13][C:14]([CH:16]1[CH:17]([OH:33])[CH:18]([OH:32])[CH:19]([N:21]2[CH:22]=[N:23][C:24]3[C:25]2=[N:26][C:27]([C:2]#[C:1][C:3]2([OH:10])[CH2:8][CH2:7][CH2:6][CH:5]([CH3:9])[CH2:4]2)=[N:28][C:29]=3[NH2:30])[O:20]1)=[O:15])[CH3:11]
Reactant: C#CC1(O)CCCC(C)C1
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(N)nc(I)nc32)C(O)[C@H]1O
Product: CCNC(=O)C1OC(n2cnc3c(N)nc(C#CC4(O)CCCC(C)C4)nc32)C(O)C1O

Procedure:
The reaction of 1-Ethynyl-3-methyl-cyclohexanol (JR3149B) (100 mg, 0.72 mmol) with 2-iodo-NECA (25 mg, 0.06 mmol) under the general coupling conditions gave JR3179 (15.0 mg, 59%) as a white solid after purification by a silica plug and RP-HPLC. 1H NMR (CD3OD-d4) δ 8.49 (s, 1 H), 6.06 (d, J=6.9 Hz, 1 H), 4.75 (dd, J=6.4 Hz, J=4.9 Hz, 1 H), 4.46 (d, J=1.9 Hz, 1 H), 4.34 (dd, J=4.9 Hz, J=2.1 Hz, 1 H), 3.42 (m, 2 H), 2.09 (d, J=12.3 Hz, 2 H), 1.73 (m, 4 H), 1.46 (m, 1 H), 1.23 (m, 1 H), 1.16 9 (t, J=7.1 Hz, 3 H), 0.95 (d, J=6.2 Hz, 3 H), 0.89 (m, 1 H). 13C NMR (CD3OD-d4) δ. APCI m/z (rel intensity) 445.3 (MH+, 100), 427.4 (40), 254.4 (4).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[NH:28][C:27](=[O:29])[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)[CH2:14][CH2:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH:30]1(I)[CH2:34][CH2:33][CH2:32][CH2:31]1.C(=O)([O-])[O-].[K+].[K+].CC#N>CN(C=O)C>[CH:30]1([O:29][C:27]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=[C:19]([CH2:18][N:15]3[CH2:14][CH2:13][N:12]([S:9]([C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=4)(=[O:10])=[O:11])[CH2:17][CH2:16]3)[N:28]=2)[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: IC1CCCC1
Reactant: COc1ccc(S(=O)(=O)N2CCN(Cc3nc4ccccc4c(=O)[nH]3)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: COc1ccc(S(=O)(=O)N2CCN(Cc3nc(OC4CCCC4)c4ccccc4n3)CC2)cc1
Temperature: 90 °C

Procedure:
A mixture of 2-[4-(4-Methoxy-benzenesulfonyl)-piperazin-1-ylmethyl]-3H-quinazolin-4-one (83 mg, 0.2 mmol), cyclopentyl iodide (46 μL, 0.4 mmol), and potassium carbonate (138 mg, 1 mmol) in DMF (1 mL) was heated to 90° C. for 1 day. The reaction mixture was partitioned between dichloromethane and water. The organic layer was concentrated in vacuo and the residue was purified by HPLC (in the absence of TFA) to yield the product. 1H NMR (400 MHz, CDCl3) δ 8.11 (d, J=8.1 Hz, 1H), 7.88 (d, J=8.4 Hz, 1H), 7.78 (t, J=7.6 Hz, 1H), 7.71 (d, J=8.8 Hz, 2H), 7.51 (t, J=7.5 Hz, 1H), 7.00 (d, J=8.8 Hz, 2H), 5.73 (quintet, J=3.0 Hz, 1H), 3.88 (m, 5H), 3.12 (m, 4H), 2.84 (m, 4H), 1.90 (m, 8H); HPLC ret. time 2.85 min, 10-99% CH3CN, 5 min run; ESI-MS m/z 483.5 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:8]([O:13][CH3:14])=[C:7]([F:15])[C:3]=1C(O)=O.C([N:18](CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(O)(C(F)(F)F)=O>C(O)(C)(C)C.ClCCl>[Cl:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:8]([O:13][CH3:14])=[C:7]([F:15])[C:3]=1[NH2:18]
Reactant: COc1cc(OC)c(Cl)c(C(=O)O)c1F
Reactant: CCN(CC)CC
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CC(C)(C)O
Product: COc1cc(OC)c(Cl)c(N)c1F
Temperature: 82 °C
Reaction time: 0.08 h
Yield: 60 %

Procedure:
A suspension of 2-chloro-6-fluoro-3,5-dimethoxybenzoic acid (10.8 g, 0.0077 mol) and triethyl amine (0.934 g, 0.0092 mol) in tert-BuOH (50 mL) was stirred for 5 min. To the resulting reaction mixture, Diphenyl phosphoryl azide (2.53 g, 0.0092 mol) was added and heated up to 82° C. and kept at this temperature for overnight. The reaction mixture was then concentrated in vacuo to obtain a crude residue. The crude residue was dissolved in dichloromethane (20 mL) and cooled to 0° C. TFA (4 mL) was added to the reaction mixture and the resultant reaction mixture was then stirred at room temperature for 2 h. The solvents were removed under vacuum and the crude residue was diluted with ethyl acetate and saturated sodium carbonate solution. The aqueous layer was separated and extracted with ethyl acetate (3×30 mL). The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography using the eluent (gradient hexane to hexane-ether (65:35)) to afford the title compound (0.95 g, yield: 60%) as solid. MS (ESI): 205.7 [M+H]+.
Reaction SMILES: II.Br[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH:5]=1.[Mg].[Cl-].[NH4+:17]>C1COCC1.CCC(=O)CC>[CH:12]1([CH2:11][O:10][C:6]2[CH:5]=[C:4]([C:4]([NH2:17])([CH2:9][CH3:8])[CH2:5][CH3:6])[CH:9]=[CH:8][CH:7]=2)[CH2:14][CH2:13]1
Reactant: Brc1cccc(OCC2CC2)c1
Reactant: [NH4+]
Agent: II
Agent: [Cl-]
Agent: [Mg]
Solvent: CCC(=O)CC
Solvent: C1CCOC1
Product: CCC(N)(CC)c1cccc(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of magnesium (280 mg) in THF (2.5 mL), iodine (10 mg) was added at room temperature. Then, a small amount of a solution of 1-bromo-3-(cyclopropylmethoxy)benzene (2.27 g) obtained according to a method described in the document (Izvestiya akademi Nauk SSSR, Seriya Khimicheskaya, 12, 2752-2755 (1989)) in THF (3.5 mL) was added thereto, and the mixture was stirred at room temperature for 10 minutes until the iodine color disappeared. The remaining amount of the solution of 1-bromo-3-(cyclopropylmethoxy)benzene in THF was added thereto, and the mixture was stirred at room temperature for 1 hour until the magnesium disappeared. To the reaction mixture, a solution of 3-pentanone (1.02 g) in THF (3.0 mL) was added, and the mixture was stirred at room temperature for 2 hours. To the reaction mixture, an aqueous saturated ammonium chloride solution (10 ml) was added at 0° C., and the aqueous layer was extracted with ethyl acetate (20 mL×2). The organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30% ethyl acetate/hexane). The obtained compound was dissolved in chloroform (20 mL). To the solution, sodium azide (1.7 g) was added. To the reaction mixture, trifluoroacetic acid (3.2 mL) was added dropwise at 0° C., and the mixture was then stirred at room temperature for 1 hour. To the reaction mixture, water (20 mL) was added, and the resultant mixture was then extracted with chloroform (20 mL). The organic layer was washed with an aqueous saturated sodium bicarbonate solution (20 mL), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10% ethyl acetate/hexane). The obtained compound was dissolved in methanol (10 mL). To the solution, 10% palladium-carbon (260 mg) was added, and the reaction mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere. The precipitate was removed by filtration through a pad of Celite and washed with methanol (100 mL). Then, the combined filtrate was concentrated under reduced pressure to obtain the title compound (1.70 g) as a crude product.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[CH:5][C:6]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:3]=1[OH:16].[CH2:17](N(CC)CC)C.O1CCCC1.[P:29]([S:35][CH2:36][CH3:37])(=[S:34])(Cl)[O:30][CH2:31][CH3:32]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[P:29]([S:35][CH2:36][CH3:37])(=[S:34])([O:16][C:3]1[C:4]2[C:13](=[CH:12][C:11]3[C:6]([CH:5]=2)=[CH:7][CH:8]=[C:9]([CH3:17])[CH:10]=3)[CH:14]=[CH:15][C:2]=1[Br:1])[O:30][CH2:31][CH3:32]
Reactant: CCN(CC)CC
Reactant: CCOP(=S)(Cl)SCC
Reactant: Oc1c(Br)ccc2cc3ccccc3cc12
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOP(=S)(Oc1c(Br)ccc2cc3cc(C)ccc3cc12)SCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-Bromo-1-anthrol (0.01 mole), triethylamine (0.01 mole), tetrahydrofuran (25 ml) and toluene (25 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The mixture is cooled to a temperature of about 0° C. and O,S-diethyl phosphorochloridodithioate (0.01 mole) dissolved in toluene (25 ml) is added with stirring over a period of about 30 minutes. After the addition is completed the reaction mixture is allowed to warm to room temperature and stirring is continued for a period of about 16 hours. After this time the reaction mixture is filtered to remove triethylamine hydrochloride. The filtrate is then washed with water, dried over anhydrous magnesium sulfate and stripped of solvents leaving a residue. This residue is subjected to flash chromatography using ethyl acetate as the eluant to yield the desired product O,S-diethyl O-(2-bromo-6-methyl-1-anthryl) phosphorodithioate.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].[C:5]1(=O)[CH:10]=[CH:9][C:8](=[O:11])[CH:7]=[CH:6]1>C(O)C.Cl>[NH2:1][C:2]1[S:3][C:10]2[CH:9]=[C:8]([OH:11])[CH:7]=[CH:6][C:5]=2[N:4]=1
Reactant: NC(N)=S
Reactant: O=C1C=CC(=O)C=C1
Agent: Cl
Solvent: CCO
Product: Nc1nc2ccc(O)cc2s1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The intermediate 2-amino-1,3-benzothiazol-6-ol was prepared according to a slightly modified literature procedure by Lau and Gompf: J. Org. Chem. 1970, 35, 4103-4108. To a stirred solution of thiourea (7.6 g, 0.10 mol) in a mixture of 200 mL ethanol and 9 mL concentrated hydrochloric acid was added a solution of 1,4-benzoquinone (21.6 g, 0.20 mol) in 400 mL of hot ethanol. The reaction was stirred for 24 hours at room temperature and then concentrated to dryness. The residue was triturated with hot acetonitrile and the resulting solid was filtered and dried.