Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][C@@:7]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:11]([C:12](=[O:17])[C@H:13]([O:15][CH3:16])[CH3:14])[N:10]=[C:9]([C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[F:25])[S:8]1)=[N+]=[N-].NCCC[C@]1(C2C=CC=CC=2)N(C(=O)[C@@H](OC)C)N=C(C2C=C(F)C=CC=2F)S1.NCCC[C@@]1(C2C=CC=CC=2)N(C(=O)[C@@H](OC)C)N=C(C2C=C(F)C=CC=2F)S1>>[NH2:1][CH2:4][CH2:5][CH2:6][C@@:7]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:11]([C:12](=[O:17])[C@H:13]([O:15][CH3:16])[CH3:14])[N:10]=[C:9]([C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[F:25])[S:8]1
Reactant: CO[C@H](C)C(=O)N1N=C(c2cc(F)ccc2F)S[C@]1(CCCN=[N+]=[N-])c1ccccc1
Agent: CO[C@@H](C)C(=O)N1N=C(c2cc(F)ccc2F)S[C@@]1(CCCN)c1ccccc1
Agent: CO[C@@H](C)C(=O)N1N=C(c2cc(F)ccc2F)S[C@]1(CCCN)c1ccccc1
Product: CO[C@H](C)C(=O)N1N=C(c2cc(F)ccc2F)S[C@]1(CCCN)c1ccccc1

Procedure:
Prepared as previously described in Example 75 using (R)-1-((R)-2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one. MS ESI (+) m/z 420 (M+1) detected; 1H NMR (400 MHz, CDCl3) δ 7.52 (m, 1H), 7.44 (d, 2H, J=7 Hz), 7.35 (t, 2H, J=8 Hz), 7.29 (t, 1H, J=7 Hz), 7.13 (m, 2H), 4.68 (q, 1H, J=6 Hz), 3.41 (s, 3H), 3.24 (m, 1H), 2.85 (m, 2H), 2.43 (m, 1H), 1.95 (m, 1H), 1.54 (br, 3H), 1.46 (d, 3H, J=6 Hz). Stereochemistry was assigned by comparison to (S)-1-((S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one and (S)-1-((R)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:20]1([CH2:23][N:24]([CH2:37][CH2:38][OH:39])[C:25]2[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[C:27]([C:33]([F:36])([F:35])[F:34])[CH:26]=2)[CH2:22][CH2:21]1.[C:40]([C:44]1[CH:49]=[CH:48][C:47](O)=[CH:46][CH:45]=1)([CH3:43])([CH3:42])[CH3:41].C1C=CC(COC(/N=N/C(OCC2C=CC=CC=2)=O)=O)=CC=1.C(=O)([O-])[O-]>C(Cl)Cl>[CH:20]1([CH2:23][N:24]([CH2:37][CH2:38][O:39][C:47]2[CH:48]=[CH:49][C:44]([C:40]([CH3:43])([CH3:42])[CH3:41])=[CH:45][CH:46]=2)[C:25]2[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[C:27]([C:33]([F:35])([F:36])[F:34])[CH:26]=2)[CH2:21][CH2:22]1
Reactant: N#Cc1ccc(N(CCO)CC2CC2)cc1C(F)(F)F
Reactant: CC(C)(C)c1ccc(O)cc1
Agent: O=C(/N=N/C(=O)OCc1ccccc1)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)c1ccc(OCCN(CC2CC2)c2ccc(C#N)c(C(F)(F)F)c2)cc1
Reaction time: 0.17 h
Yield: 58.1 %

Procedure:
To a slurry of polymer-supported triphenylphosphine (0.23 g, ca. 3 mmol/g, ca. 0.70 mmol) in CH2Cl2 was added 4-[(cyclopropylmethyl)(2-hydroxyethyl)amino]-2-(trifluoromethyl)benzonitrile (0.100 g, 0.35 mmol) and 4-tert-butylphenol (0.105 g, 0.70 mmol). The mixture was shaken for 10 min, a solution of DBAD (0.121 g, 0.525 mmol) in CH2Cl2 (0.5 mL) was added, and shaking was continued overnight. Solids were removed by filtration and the filtrate was shaken with polymer-supported carbonate (0.50 g, ca. 2.9 mmol/g, ca. 1.5 mmol CO32−) for 4 h. Solids were removed by filtration, the filtrate was treated with TFA (1 mL) for 1 h and concentrated in vacuo. The residue was purified by flash chromatography (EtOAc/hexanes), affording 0.0847 g of the title compound as a colorless gum: 1H NMR (300 MHz, CDCl3) δ 7.58 (d, J=8.8 Hz, 1H), 7.29 (app. d, J=8.8 Hz, 2H), 7.11 (d, J=2.4 Hz, 1H), 6.90 (dd, J=8.8, 2.5 Hz, 1H), 6.78 (app. d, J=8.7 Hz, 2H), 4.14 (t, J=5.8 Hz, 2H), 3.89 (t, J=5.6 Hz, 2H), 3.39 (d, J=6.2 Hz, 2H), 1.29 (s, 9H), 1.14-0.99 (m, 1H), 0.69-0.59 (m, 2H), 0.36-0.27 (m, 2H); MS (APCI) m/z 417 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[C:10]1(=[O:17])[CH2:15][CH2:14][CH2:13][C:12](=O)[CH2:11]1.[CH2:18]([O:20][C:21](=[O:26])[CH2:22][C:23](=[NH:25])[NH2:24])[CH3:19]>C(O)C>[CH2:18]([O:20][C:21]([C:22]1[CH:5]([C:4]2[CH:7]=[CH:8][CH:9]=[C:2]([Br:1])[CH:3]=2)[C:11]2[C:10](=[O:17])[CH2:15][CH2:14][CH2:13][C:12]=2[NH:24][C:23]=1[NH2:25])=[O:26])[CH3:19]
Reactant: CCOC(=O)CC(=N)N
Reactant: O=Cc1cccc(Br)c1
Reactant: O=C1CCCC(=O)C1
Solvent: CCO
Product: CCOC(=O)C1=C(N)NC2=C(C(=O)CCC2)C1c1cccc(Br)c1
Yield: 44 %

Procedure:
Upon heating a solution of 9.3 g of 3-bromobenzaldehyde, 5.6 g of cyclohexane-1,3-dione and 6.5 g of amidinoacetic acid ethyl ester in 100 ml of ethanol for 8 hours, 2-amino-4-(3-bromophenyl)-1,4,5,6,7,8-hexahydro-5-oxoquinoline-3-carboxylic acid ethyl ester of melting point 255°C (ethanol) is obtained.
Reaction SMILES: [CH3:1][N:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][OH:17])[CH2:10][CH2:9]2)=[CH:6][C:5](=[O:18])[N:4]([CH3:19])[C:3]1=[O:20].C(N(CC)CC)C.[Cl:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1>O1CCOCC1>[ClH:28].[CH3:1][N:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][O:17][C:33](=[O:34])[C:32]3[CH:36]=[CH:37][C:29]([Cl:28])=[CH:30][CH:31]=3)[CH2:10][CH2:9]2)=[CH:6][C:5](=[O:18])[N:4]([CH3:19])[C:3]1=[O:20]
Reactant: Cn1c(N2CCN(CCCO)CC2)cc(=O)n(C)c1=O
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Cl
Product: Cn1c(N2CCN(CCCOC(=O)c3ccc(Cl)cc3)CC2)cc(=O)n(C)c1=O
Reaction time: 2 h
Yield: 88.2 %

Procedure:
In 50 ml of dioxane were dissolved 1.45 g of 1,3-dimethyl-6-[4-(3-hydroxypropyl)piperazin-1-yl]-2,4(1H,3H)-pyrimidinedione and 1.5 ml of triethylamine, and 10 ml of a dioxane solution containing 1.05 g of 4-chlorobenzoyl chloride was further added dropwise. The solution was stirred at 50°-60° C. for 2 hours, and the solvent was then distilled off. Afterward, the resultant residue was dissolved in chloroform, washed with water, and then concentrated to dryness. The residue was purified through a silica gel column chromatograph (chloroform/methanol=100/1 to 100/3 in volume ratio), thereby obtaining 1.21 g of the crystals of 1,3-dimethyl-6-[4-(3-[4-chlorobenzoyloxy]propyl)piperazin-1-yl]-2,4(1H,3H)-pyrimidinedione.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[C:5]([O:12][CH3:13])[CH:4]=1.[NH:14]1[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:13][O:12][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][C:6]=1[N+:9]([O-:11])=[O:10])[CH2:2][N:14]1[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16][CH2:15]1
Reactant: COc1cc(CBr)ccc1[N+](=O)[O-]
Reactant: OC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(CN2CCC(O)CC2)ccc1[N+](=O)[O-]
Temperature: 80 °C

Procedure:
Into a 8-dram vial, 4-Bromomethyl-2-methoxy-1-nitro-benzene (2.44 g, 9.93 mmol), Piperidin-4-ol (2.01 g, 19.9 mmol), Potassium carbonate (5.49 g, 39.7 mmol), and N,N-Dimethylformamide (25 ml) were added. The reaction mixture was heated at 80° C. overnight. The reaction was partitioned with water and EtOAc. The organic was separated, washed with Brine and dried over Na2SO4. The solid was filtered and washed with DCM. The solvent was removed under vacuum. The reaction mixture was purified via ISCO column chromatography with hexane and EtOAc as eluant (0 to 100% EtOAc). The collected fractions afforded 1-(3-Methoxy-4-nitro-benzyl)-piperidin-4-ol as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[NH:12][C:11](=[O:13])[O:10][C:8](=[O:9])[C:7]=12.[H-].[Na+].[H][H].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C=O)C>[CH2:18]([C:7]12[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][CH:6]1[NH:12][C:11](=[O:13])[O:10][C:8]2=[O:9])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: [H][H]
Reactant: Cc1cccc2[nH]c(=O)oc(=O)c12
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1=CC=CC2NC(=O)OC(=O)C12Cc1ccccc1
Reaction time: 1 h

Procedure:
A solution of 6-methyl-isatoic anhydride (4.5 gm) in DMF (30 ml) was added dropwise to a stirred suspension of 60% sodium hydride (1.0 gm) in DMF (20 ml) under nitrogen atmosphere. The reaction was then warmed to 45° and stirred until hydrogen evolution ceased. It was then cooled and a solution of benzyl bromide (4.4 gm) in DMF (10 ml) was added slowly. Stirring was continued for one hour at room temperature and the solution was then evaporated under reduced pressure at 45° C. The resulting solid was suspended in methylene chloride, the insoluble inorganic solid was removed by filtration and the filtrate was evaporated to afford the title compound as a crystalline solid.
Reaction SMILES: [CH2:1]([NH:4][CH2:5][CH:6]=[CH2:7])[CH:2]=[CH2:3].[CH2:8]([S:12](Cl)(=[O:14])=[O:13])[CH:9]([CH3:11])[CH3:10]>C1C=CC=CC=1>[CH2:1]([N:4]([CH2:5][CH:6]=[CH2:7])[S:12]([CH2:8][CH:9]([CH3:11])[CH3:10])(=[O:14])=[O:13])[CH:2]=[CH2:3]
Reactant: C=CCNCC=C
Reactant: CC(C)CS(=O)(=O)Cl
Solvent: c1ccccc1
Product: C=CCN(CC=C)S(=O)(=O)CC(C)C

Procedure:
A solution was formed containing 19.4 g of diallylamine n 100 ml. of benzene. Then, 15.7 g. of isobutylsulfonyl chloride was added at such a rate that the temperature did not exceed 45° C. The mixture was stirred and refluxed for ten minutes, cooled, washed with 100 ml. of dilute hydrochloric acid and then with H2O. It was then dried over magnesium sulfate, filtered and evaporated to give 20.1 g. (02% of theory) of the product, a liquid, nD30 = 1.4697.
Reaction SMILES: C([C:3]1[CH:8]=[CH:7][C:6](C2C=CC=CC=2)=[CH:5][C:4]=1[CH2:15][NH:16][C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=O.[C:25]1([CH3:31])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[CH2:32]([OH:35])[CH2:33][OH:34]>C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[O:34]1[CH2:33][CH2:32][O:35][CH:31]1[C:25]1[CH:30]=[CH:29][C:28]([C:6]2[CH:7]=[CH:8][CH:3]=[C:4]([CH2:15][NH:16][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:5]=2)=[CH:27][CH:26]=1
Reactant: Cc1ccccc1
Reactant: O=Cc1ccc(-c2ccccc2)cc1CNC(=O)c1ccccc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: O=C(NCc1cccc(-c2ccc(C3OCCO3)cc2)c1)c1ccccc1
Yield: 100 %

Procedure:
3.2 g (10 mmol) of N-(4-formylbiphenyl-3-yl-methyl)benzamide, 50 ml of toluene, 2.8 ml (50 mmol) of ethylene glycol and 38 mg (0.2 mmol) of para-toluenesulfonic acid are introduced into a three-necked flask under a stream of nitrogen. The reaction medium is refluxed for 3 hours and the water formed is separated off using Dean-stark apparatus. The reaction medium is extracted with dichloromethane and washed with water, and the organic phase is separated out after settling of the phases has taken place. The organic phase is dried over magnesium sulfate and filtered. 3.7 g (100%) of the desired product are obtained.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[N:7][C:8]#[N:9])[S:5][CH3:6])[CH3:2].[CH:10]1(N)CC[CH2:11]1.C(N)C>>[CH:1]1([NH:3][C:4](=[N:7][C:8]#[N:9])[S:5][CH3:6])[CH2:11][CH2:10][CH2:2]1
Reactant: NC1CCC1
Reactant: CCNC(=NC#N)SC
Agent: CCN
Product: CSC(=NC#N)NC1CCC1

Procedure:
1-Cyclobutyl-2-methyl-3-cyanoisothiourea was prepared following the same procedure as for 1-ethyl-2-methyl-3-cyanoisothiourea (see EXAMPLE 250) except that cyclobutylamine was used in lieu of ethylamine. 1H NMR (CDCl3) δ 1.62-1.79 (m, 2H), 1.92-2.08 (m, 2H), 2.29-2.45 (m, 5H), 4.11 (br s, 1H), 6.74 (br s, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:30]=[CH:29][C:8]([CH2:9][N:10]2[C:18]3[C:13](=[CH:14][C:15]([NH:19][S:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)(=[O:22])=[O:21])=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:33][O:34][C:35](=[O:38])[CH2:36]Br.CCCCCC>CN(C=O)C.CCOC(C)=O>[CH3:33][O:34][C:35](=[O:38])[CH2:36][N:19]([S:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:21])=[O:22])[C:15]1[CH:14]=[C:13]2[C:18](=[CH:17][CH:16]=1)[N:10]([CH2:9][C:8]1[CH:29]=[CH:30][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:6][CH:7]=1)[CH:11]=[CH:12]2
Reactant: COC(=O)CBr
Reactant: CC(C)(C)c1ccc(Cn2ccc3cc(NS(=O)(=O)c4ccccc4)ccc32)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)CN(c1ccc2c(ccn2Cc2ccc(C(C)(C)C)cc2)c1)S(=O)(=O)c1ccccc1
Reaction time: 1.5 h
Yield: 72 %

Procedure:
To N-[1-(4-tert-butyl-benzyl)-1H-indol-5-yl]-benzenesulfonamide (0.20 g, 0.48 mmol) in DMF (5 ml) at room temperature under a nitrogen atmosphere was added sodium hydride (60% dispersion in mineral oil, 0.03 g, 0.72 mmol) in one portion. The resulting brown mixture was stirred 10 minutes upon which bromo-acetic acid methyl ester was added (0.19 g, 0.96 mmol). After 90 minutes total reaction time, the reaction was quenched with water (2 ml). The brown solution was partitioned between EtOAc (15 ml) and H2O (10 ml) and the layers were separated. The aqueous layer was extracted with EtOAc (5 ml). All organics were combined, extracted with brine (3×10 ml), dried with MgSO4, filtered and concentrated in vacuo to afford a brown powder. Gradient SiO2 chromatography (Hexane:EtOAc) afforded {benzenesulfonyl-[1-(4-tert-butyl-benzyl)-1H-indol-5-yl]-amino}-acetic acid methyl ester as a pale red powder (0.18 g, 72% yield): MS (ESI) m/z 533.
Reaction SMILES: [N:1]1([CH2:7][C:8]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:9])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[ClH:15].[CH3:16][O:17][C:18]1[C:26]2[O:25][C:24](C)(C)C[C:22]=2[C:21]([C:29]2[C@@H:38]3[C@@H:33]([CH2:34][CH:35]=[CH:36][CH2:37]3)[C:32](=[O:39])[N:31]([C:40]3[CH:45]=[CH:44][C:43]([C:46](N4CCN(C/C=C/C5C=CC=CC=5)CC4)=[O:47])=[CH:42][CH:41]=3)[N:30]=2)=[CH:20][CH:19]=1>>[ClH:15].[CH3:24][O:25][C:26]1[CH:22]=[C:21]([C:29]2[C@@H:38]3[C@@H:33]([CH2:34][CH:35]=[CH:36][CH2:37]3)[C:32](=[O:39])[N:31]([C:40]3[CH:41]=[CH:42][C:43]([C:46]([N:4]4[CH2:3][CH2:2][N:1]([CH2:7][C:8](=[O:9])[N:10]5[CH2:11][CH2:12][CH2:13][CH2:14]5)[CH2:6][CH2:5]4)=[O:47])=[CH:44][CH:45]=3)[N:30]=2)[CH:20]=[CH:19][C:18]=1[O:17][CH3:16]
Reactant: COc1ccc(C2=NN(c3ccc(C(=O)N4CCN(C/C=C/c5ccccc5)CC4)cc3)C(=O)[C@@H]3CC=CC[C@H]23)c2c1OC(C)(C)C2
Reactant: O=C(CN1CCNCC1)N1CCCC1
Agent: Cl
Product: COc1ccc(C2=NN(c3ccc(C(=O)N4CCN(CC(=O)N5CCCC5)CC4)cc3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OC

Procedure:
Prepared from intermediate product A6 and 2-piperazin-1-yl-1-pyrrolidin-1-yl-ethanone as described for compound 8. M.p. 160–161° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N+:23]([O-:25])=[O:24])(=[O:16])=[O:15])[CH:5]=[C:6]([CH:12]=1)[O:7][CH2:8][CH2:9][CH2:10][OH:11].C(N(CC)C(C)C)(C)C.CS(C)=O>ClCCl>[CH3:1][C:2]1[CH:3]=[C:4]([O:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N+:23]([O-:25])=[O:24])(=[O:16])=[O:15])[CH:5]=[C:6]([CH:12]=1)[O:7][CH2:8][CH2:9][CH:10]=[O:11]
Reactant: Cc1cc(OCCCO)cc(OS(=O)(=O)c2ccccc2[N+](=O)[O-])c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cc1cc(OCCC=O)cc(OS(=O)(=O)c2ccccc2[N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.4 %

Procedure:
Sulfur trioxide pyridine complex (1.12 mg, 7.0 mmol) was added to a solution of 3-[5-methyl-3-(2-nitrophenylsulfonyloxy)phenoxy]propanol (920 mg, 2.5 mmol), as prepared in the preceding step, N,N-diisopropylethylamine (0.7 mL, 5.5 mmol) and anhydrous dimethyl sulfoxide (0.4 mL, 5.6 mmol) in anhydrous dichloromethane (20 mL). The reaction mixture was stirred at ambient temperature for 1 hour and then quenched with 10% aqueous citric acid (50 mL). The mixture was extracted into dichloromethane (3×50 mL), and the dichloromethane solution was washed with 10% aqueous citric acid (40 mL) and dried over Na2SO4. After removing the solvent in vacuo, the residue was purified by flash column chromatography (dichloromethane) to give the title compound as a pale yellow oil (780 mg, 85%). 1H-NMR (300 MHz, CDCl3) δ 9.84 (s, 1H), 7.99 (d, J=7.6 Hz, 1H), 7.85 (m, 2H), 7.70 (m, 1H), 6.64 (s, 2H), 6.57 (s, 1H), 4.22 (t, J=6.0 Hz, 2H), 2.88 (t, J=6.0 Hz, 2H), 2.27 (s, 3H).
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][CH:4]=1)=[CH2:2].C(C1C=C(O)C(=CC=1)O)(C)(C)C.C(Cl)(Cl)[Cl:25].C(Cl)(=O)C(Cl)=O>CN(C)C=O>[CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([Cl:25])=[O:8])=[CH:5][CH:4]=1)=[CH2:2]
Reactant: ClC(Cl)Cl
Reactant: C=Cc1ccc(C(=O)O)cc1
Agent: CC(C)(C)c1ccc(O)c(O)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: C=Cc1ccc(C(=O)Cl)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Into a reaction vessel fitted with a cooling pipe, a stirrer, a thermometer and a nitrogen feed pipe, 20 parts of formula-(21) 4-vinylbenzoic acid, 0.6 part of 4-tert-butylcatechol and 225 parts of chloroform were fed, and then cooled to 15° C. or below. While keeping the liquid temperature at 15° C. or below, 2.8 parts of dehydrated N,N-dimethylformamide was added, and then 87.4 parts of oxalyl chloride was dropwise added thereto. After its addition made dropwise, the liquid temperature was raised to room temperature, followed by stirring for 20 hours. After the reaction was completed, the solvent was evaporated off under reduced pressure, and then 340 parts of n-heptane was added. The organic layer formed was washed with ion-exchanged water, and this organic layer was dried with magnesium sulfuric anhydride, followed by evaporation of the solvent under reduced pressure to obtain a crude product of formula-(22) 4-vinylbenzoic acid chloride (21.8 parts).
Reaction SMILES: CS(OCC[N:8]1[C:12]2=[N:13][CH:14]=[N:15][C:16]([NH2:17])=[C:11]2[C:10]([C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]3[N:28]([CH3:36])[C:29]4[C:34]([CH:35]=3)=[CH:33][CH:32]=[CH:31][CH:30]=4)=[O:26])=[C:20]([O:37][CH3:38])[CH:19]=2)=[N:9]1)(=O)=O.[CH2:39]([CH2:41][NH2:42])[OH:40].[CH2:43](N(CC)CC)[CH3:44].[I-].[Na+]>CN(C=O)C>[NH2:17][C:16]1[N:15]=[CH:14][N:13]=[C:12]2[N:8]([CH2:43][CH2:44][NH:42][CH2:41][CH2:39][OH:40])[N:9]=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]4[N:28]([CH3:36])[C:29]5[C:34]([CH:35]=4)=[CH:33][CH:32]=[CH:31][CH:30]=5)=[O:26])=[C:20]([O:37][CH3:38])[CH:19]=3)[C:11]=12
Reactant: NCCO
Reactant: CCN(CC)CC
Reactant: COc1cc(-c2nn(CCOS(C)(=O)=O)c3ncnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(-c2nn(CCNCCO)c3ncnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 70 °C
Yield: 13.3 %

Procedure:
A mixture of 2-[4-amino-3-(3-methoxy-4-{[(1-methyl-1H-2-indolyl)carbonyl]amino}phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl methanesulfonate (Intermediate 4) (0.080 g, 0.15 mmol), ethanolamine (0.05 mL, 0.82 mmol), triethylamine (0.021 mL, 0.15 mmol), and sodium iodide (0.021 g, 0.15 mmol) in DMF (2.5 mL) was heated at 70° C. for 15 h. The reaction mixture was cooled to ambient temperature and concentrated; water (5 mL) was added and the resulting precipitate was collected by filtration and rinsed with water (5 mL). The crude solid was purified by silica gel column chromatography (elution with 20% MeOH—CH2Cl2). The appropriate fractions were combined and the solvent removed in vacuo to afford N2-[4-(4-amino-1-{2-[(2-hydroxyethyl)amino]ethyl}-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methoxyphenyl]-1-methyl-1H-2-indolecarboxamide as a white solid (0.009 g, 0.02 mmol). RP-HPLC (Hypersil C18, 5 μm, 100 Å, 15 cm; 5%-100% acetonitrile-0.1 M ammonium acetate over 15 min, 1 mL/min). Rt 9.39 min. MS: M+ 501.3.
Reaction SMILES: Cl[C:2]1C=CC=C(C(OO)=[O:9])[CH:3]=1.[CH2:12]([S:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[N:30]=[C:29]([NH:31][CH2:32][CH2:33][CH3:34])[C:28]2[C:23](=[CH:24][C:25]([C:35]([F:38])([F:37])[F:36])=[CH:26][CH:27]=2)[N:22]=1)[CH3:13].[S:39]([O-:43])([O-])(=[O:41])=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH2:12]([S:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[N:30]=[C:29]([NH:31][CH2:32][CH2:33][CH3:34])[C:28]2[C:23](=[CH:24][C:25]([C:35]([F:38])([F:37])[F:36])=[CH:26][CH:27]=2)[N:22]=1)=[O:9])[CH3:13].[CH2:2]([S:39]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[N:30]=[C:29]([NH:31][CH2:32][CH2:33][CH3:34])[C:28]2[C:23](=[CH:24][C:25]([C:35]([F:38])([F:37])[F:36])=[CH:26][CH:27]=2)[N:22]=1)(=[O:43])=[O:41])[CH3:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=S([O-])([O-])=S
Reactant: CCCNc1nc(-c2ccccc2SCC)nc2cc(C(F)(F)F)ccc12
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCCNc1nc(-c2ccccc2S(=O)(=O)CC)nc2cc(C(F)(F)F)ccc12
Product: CCCNc1nc(-c2ccccc2S(=O)CC)nc2cc(C(F)(F)F)ccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
281 mg of 3-chloroperbenzoic acid (purity of 65% or more) was added to a mixture of 305 mg of 2-(2-ethylsulfanylphenyl)-4-propylamino-7-trifluoromethylquinazoline and 4 ml of chloroform, under ice cooling, and the mixture was stirred at room temperature for 4 hours. A 10% aqueous sodium thiosulfate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was applied to a silica gel column chromatography to obtain 174 mg of 2-(2-ethylsulfinylphenyl)-4-propylamino-7-trifluoromethylquinazoline (Compound of Present Invention 9) and 100 mg of 2-(2-ethylsulfonylphenyl)-4-propylamino-7-trifluoromethylquinazoline (Compound of Present Invention 10).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=1)/[C:6]([CH3:20])=[C:5]2[CH2:21][CH2:22]O.C(Br)(Br)(Br)[Br:25].C1(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:25][CH2:22][CH2:21][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=2)/[C:7](=[CH:11]\[C:12]2[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=2)/[C:6]=1[CH3:20]
Reactant: CSc1ccc(/C=C2/C(C)=C(CCO)c3cc(F)ccc32)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(CCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CSc1ccc(/C=C2/C(C)=C(CCBr)c3cc(F)ccc32)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of the alcohol from Step 1 (4.8 g, 14.7 mmol) and carbon tetrabromide (6.34 g, 19.1 mmol) in methylene chloride (100 mL) at 0° C. there was added, in portions, 1,2-bis(diphenylphosphino)ethane (6.34 g, 17.3 mmol). The mixture was stirred at 0° C. for 1 hour, and the solvent was evaporated. The residue was stirred in a mixture of ethyl acetate and water (150 mL each) for 30 minutes. After filtration, the organic portion of the filtrate was evaporated down and the crude product purified by column chromatography on silica gel using 10% ethyl acetate in hexane as eluent to afford pure title compound as a yellow oil which solidified on standing.
Reaction SMILES: [P:1]([O-:5])([O-:4])([O-:3])=[O:2].[Na+:6].[Na+].[Na+].[S:9](=[O:13])(=[O:12])([OH:11])[OH:10]>>[P:1]([OH:5])([O-:4])([O-:3])=[O:2].[Na+:6].[Na+:6].[S:9]([O-:13])([O-:12])(=[O:11])=[O:10].[Na+:6].[Na+:6]
Reactant: O=S(=O)(O)O
Reactant: O=P([O-])([O-])[O-]
Agent: [Na+]
Product: O=P([O-])([O-])O
Product: O=S(=O)([O-])[O-]

Procedure:
In a third form of the invention trisodium orthophosphate is acidified with sufficient sulphuric acid in solution to form disodium orthophosphate and sodium sulphate. The two compounds were separated by crystallization and the disodium orthophosphate heat treated to give tetrasodium pyrophosphate.