Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(=O)(O)[O-].[Na+].C(#N)C.[Cl:17][CH2:18][C:19](Cl)=[O:20]>CO.O>[Cl:17][CH2:18][C:19]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8])=[O:20]
Reactant: O=C(Cl)CCl
Reactant: Nc1ccccc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: CO
Product: O=C(CCl)Nc1ccccc1O
Temperature: 10 °C
Reaction time: 3 h

Procedure:
109.1 g (1 mol) of 2-aminophenol, 84.1 g (1 mol) of sodium bicarbonate, 900 mL of acetonitrile and 100 mL of water were added under room temperature into a 2 L flask with four inlets and attached with a stirrer and a thermometer. The internal temperature was cool down to 10° C. and 112.9 g (1 mol) of chloroacetyl chloride was added to the solution over a period of 3 hours and stirred for 3 hours at room temperature. Following to the completion of the reaction, 10 mL of methanol was added, and then acetonitrile was distilled out under reduced pressure and the resultant residue was subjected to recrystallization with toluene. Then, salt was taken out in a cleaning process using water to obtain 2-chloroacetyl-2-hydroxyaniline.
Reaction SMILES: [C:1]1([S:7][CH:8](SC2C=CC=CC=2)[CH:9]2[CH2:18][CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[N:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N12CCCN=C1CCCCC2.ClCCl.O>C1(C)C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[F:26][C:23]1[CH:22]=[CH:21][C:20]([N:19]=[C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:17][CH2:18]/[C:9]/2=[CH:8]\[S:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:25][CH:24]=1
Reactant: Fc1ccc(N=C2c3ccccc3CCC2C(Sc2ccccc2)Sc2ccccc2)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O
Product: Fc1ccc(N=C2/C(=C/Sc3ccccc3)CCc3ccccc32)cc1
Reaction time: 1 h
Yield: 41.7 %

Procedure:
266 mg (0.56 mmol) of N-{2-[bis(phenylsulphanyl)methyl]-3,4-dihydronaphthalen-1(2H)-ylidene}-4-fluoroaniline are dissolved in 50 ml of toluene, 0.26 ml (0.26 mmol of a titanium(IV) tetrachloride solution (1 M in dichloromethane) is added a little at a time at 25° C. and the mixture is stirred for 1 h. 431 mg (2.83 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene and 5 ml of dichloromethane are added, and this mixture is poured into water and extracted with ethyl acetate. After washing with saturated aqueous sodium chloride solution, the organic phase is dried over sodium sulphate and concentrated under reduced pressure. Purification of the residue by column chromatography on RP18 (mobile phase: acetonitrile/water) gives 84 mg of 4-fluoro-N-[(2E)-2-[(phenylsulphanyl)methylene]-3,4-dihydronaphthalen-1(2H)-ylidene]aniline.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:18][CH:19]1[CH2:21][CH2:20]1.Cl>CC#N.CCOC(C)=O>[CH:19]1([CH2:18][O:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])[CH2:21][CH2:20]1
Reactant: O=[N+]([O-])c1ccccc1O
Reactant: BrCC1CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=[N+]([O-])c1ccccc1OCC1CC1
Temperature: 85 °C
Yield: 97 %

Procedure:
A mixture of 2-nitrophenol (1 g, 7.19 mmol), K2CO3 (1.192 g, 8.63 mmol), and (bromomethyl)cyclopropane (0.837 ml, 8.63 mmol) in CH3CN (40 ml) was heated to 85° C. overnight. The mixture was portioned between EtOAc and HCl 1N. The organic phase was dried over Na2SO4 and the solvent was removed. 1-(cyclopropylmethoxy)-2-nitrobenzene was obtained as a crude (1.352 g, 7.00 mmol, 97% yield) and used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:17]([O:19][CH3:20])=[O:18])[C:5]2[C:6]([CH:15]=O)=[CH:7][N:8]([CH:11]([CH2:13][CH3:14])[CH3:12])[C:9]=2[CH:10]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.S1(CCCC1)(=O)=O.C([BH3-])#N.[Na+]>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([C:17]([O:19][CH3:20])=[O:18])[C:5]2[C:6]([CH3:15])=[CH:7][N:8]([CH:11]([CH2:13][CH3:14])[CH3:12])[C:9]=2[CH:10]=1
Reactant: CCC(C)n1cc(C=O)c2c(C(=O)OC)cc(Br)cc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: O=S1(=O)CCCC1
Product: CCC(C)n1cc(C)c2c(C(=O)OC)cc(Br)cc21
Temperature: 100 °C
Reaction time: 1 h
Yield: 54.5 %

Procedure:
To a stirred solution of methyl 6-bromo-1-sec-butyl-3-formyl-1H-indole-4-carboxylate (15 g, 44.6 mmol) in DMF (115 mL) was added p-toluenesulfonic acid mono hydrate (1.1 g, 5.8 mmol), p-toluenesulfonyl hydrazide (10.8 g, 58 mmol) followed by sulfolane (115 mL) at RT and the reaction mixture was stirred at 100° C. for 1 h. The reaction mixture was cooled to room temperature, treated with sodium cyanoborohydride (11.9 g, 178.5 mmol) portion wise over a period of 5 min and stirred at 100° C. for 2 h. The reaction mixture was cooled to room temperature and stirred at the same temperature for 16 h. The reaction mixture was diluted with water and extracted with 30% EtOAc: Pet ether. The organic layer was washed with cold water (100 mL), brine (100 mL) and dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude, which was purified by column chromatography over silica gel (100-200 mesh) using 5% EtOAc: Pet ether as eluent to afford title compound methyl 6-bromo-1-sec-butyl-3-methyl-1H-indole-4-carboxylate (7.88 g, 54.6%) as pale yellow gum. 1H NMR (CDCl3, 400 MHz): δ 0.804-0.841 (t, J=7.4 Hz, 3H), 1.454-1.470 (d, J=6.4 Hz, 3H), 1.865-1.884 (m, 2H), 2.363 (s, 3H), 3.950 (s, 3H), 4.265-4.316 (m, 1H), 7.038 (s, 1H), 7.609 (d, J=1.2 Hz, 1H), 7.671 (d, J=2 Hz, 1H). MS (ES+): 324.19 [M+H] ion present.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].[Cl:7][C:8]1[CH:9]=[C:10]([CH:26]=[C:27]([Cl:29])[CH:28]=1)[CH2:11][N:12]1[CH:16]=[CH:15][N:14]=[C:13]1[CH2:17][O:18][C:19]1[CH:20]=[C:21]([NH2:25])[CH:22]=[CH:23][CH:24]=1.C(O)C(N)(CO)CO>C(Cl)Cl>[Cl:7][C:8]1[CH:9]=[C:10]([CH:26]=[C:27]([Cl:29])[CH:28]=1)[CH2:11][N:12]1[CH:16]=[CH:15][N:14]=[C:13]1[CH2:17][O:18][C:19]1[CH:20]=[C:21]([NH:25][C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])[CH:22]=[CH:23][CH:24]=1
Reactant: CC(C)C(=O)Cl
Reactant: Nc1cccc(OCc2nccn2Cc2cc(Cl)cc(Cl)c2)c1
Agent: NC(CO)(CO)CO
Solvent: ClCCl
Product: CC(C)C(=O)Nc1cccc(OCc2nccn2Cc2cc(Cl)cc(Cl)c2)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Isobutyryl chloride (11 mg, 0.1 mmol) was added to a solution of 3-[1-(3,5-dichloro-benzyl)-1H-imidazol-2-ylmethoxy]-phenylamine (see Example 21) (30 mg, 0.09 mmol) in CH2Cl2 (1 mL). The reaction was shaken at room temperature. After 72 h, trisamine resin (79 mg, 0.1 mmol) was added and the reaction was shaken for another 4 h. The reaction was filtered and the resin was washed with CH2Cl2 (2 mL). The filtrates were combined and concentrated in vacuo. Preparative TLC (silica, 20:1 CH2Cl2:MeOH, Rf=0.4) provided N-{3-[1-(3,5-dichloro-benzyl)-1H-imidazol-2-ylmethoxy]-phenyl}-isobutyramide, 24a as a white solid (15 mg, 40%); MS m/z 418 [C21H21Cl2N3O2+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH2:9][CH2:10][CH2:11]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:32]N1C(=O)CCC1=O>C(Cl)Cl>[Br:32][CH2:11][CH2:10][CH2:9][C:3]1[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=1[F:1]
Reactant: Cc1ccc(F)c(CCCO)c1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1ccc(F)c(CCCBr)c1
Reaction time: 5 h
Yield: 49.7 %

Procedure:
Compound 45-3 (5.54 g) was dissolved in methylene chloride (30 ml), triphenylphosphine (9.49 g) and N-bromosuccinimide (6.44 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 2 hr, and at room temperature for 5 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (100 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (3.78 g) as a pale-yellow oil.
Reaction SMILES: [CH:1]1([C:7]([OH:9])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)(Cl)=O.C1(C(Cl)=O)CCCCC1.Cl.Cl.[CH3:25][N:26]1[CH:31]2[CH2:32][CH2:33][CH:27]1[CH2:28][NH:29][CH2:30]2.[OH-].[Na+].Cl>O.C(Cl)(Cl)Cl>[CH:1]1([C:7]([N:29]2[CH2:30][CH:31]3[N:26]([CH3:25])[CH:27]([CH2:33][CH2:32]3)[CH2:28]2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)C1CCCCC1
Reactant: CN1C2CCC1CNC2
Agent: Cl
Agent: O=C(Cl)C1CCCCC1
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: CN1C2CCC1CN(C(=O)C1CCCCC1)C2
Temperature: 0 °C
Reaction time: 1 h
Yield: 66.8 %

Procedure:
Cyclohexane carboxylic acid (1.29 g, 0.010 mole) and 1.2 g (0.010 mole) thionyl chloride were heated in a dry atmosphere at 90° C for 1 hour. To this cyclohexane carboxylic acid chloride, at 0° C, was added a mixture of 2.0 g (0.010 mole) 8-methyl-3,8-diazabicyclo[3.2.1]octane dihydrochloride (prepared as described in Example 1), 1.6 g sodium hydroxide dissolved in 16 ml water, and 16 ml chloroform which had been stirred vigorously at room temperature and then chilled to 0° C. The reaction was stirred at 0° C for 1 hour. The crude product was isolated as a yellow oil by extraction of the aqueous phase with chloroform. Purification by chromatography on alumina followed by treatment with ethanolic hydrogen chloride yielded 1.58 g (58% yield) of the desired product as a white monohydrochloride, melting point 263°-268° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][N:8]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[C:5]2=[N:6][CH:7]=1.[Li]CCCC.C[O:27]B(OC)OC.O>O1CCCC1>[CH:12]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[N:8]1[C:5]2=[N:6][CH:7]=[C:2]([OH:27])[CH:3]=[C:4]2[CH:10]=[CH:9]1)([CH3:14])[CH3:13]
Reactant: COB(OC)OC
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(Br)cnc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(O)cnc21
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
To a mixture of EXAMPLE 277F (24.3 g) in tetrahydrofuran (500 mL) at −78° C. was added 2.5M BuLi (30.3 mL). After 2 minutes, trimethylborate (11.5 mL) was added, and the mixture was allowed to warm to room temperature over 1 hour. The reaction was poured into water, extracted thee times with ethyl acetate, and the combined extracts were washed with brine and concentrated. The crude product was taken up in tetrahydrofuran (200 mL) at 0° C., and 1M NaOH (69 mL) was added, followed by 30% H2O2 (8.43 mL), and the solution was stirred for 1 hour. Na2S2O3 (10 g) was added, and the pH was adjusted to 4-5 with concentrated HCl and solid NaH2PO4. The solution was extracted twice with ethyl acetate, and the combined extracts were washed with brine, dried (Na2SO4), filtered, and concentrated. The crude product was chromatographed on silica gel with 5-25% ethyl acetate/hexanes.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]([NH2:14])[N:6]=1.[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[C:23]1[N:28]=[C:27](NCCNC2C=CC([N+]([O-])=O)=CN=2)[CH:26]=[CH:25][C:24]=1[C:42]1[NH:43][CH:44]=[CH:45][N:46]=1>>[NH2:14][C:7]1[N:6]=[C:5]([NH:4][CH2:3][CH2:2][NH:1][C:27]2[CH:26]=[CH:25][C:24]([C:42]3[NH:46][CH:45]=[CH:44][N:43]=3)=[C:23]([C:17]3[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:16]=3[Cl:15])[N:28]=2)[CH:10]=[CH:9][C:8]=1[N+:11]([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1ccc(NCCNc2ccc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)nc1
Reactant: NCCNc1ccc([N+](=O)[O-])c(N)n1
Product: Nc1nc(NCCNc2ccc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]

Procedure:
{2-[(6-amino-5-nitro(2-pyridyl))amino]ethyl}[6-(2,4-dichlorophenyl)-5-imidazol-2-yl(2-pyridyl)]amine was prepared from (2-aminoethyl)(6-amino-5-nitro(2-pyridyl))amine using the general method for [6-(2,4-dichlorophenyl)-5-imidazol-2-yl(2-pyridyl)]{2-[(5-nitro(2-pyridyl))amino]ethyl}amine.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6](N)=[C:5]([CH3:10])[C:4]=1[Cl:11].N([O-])=O.[Na+]>CCO>[Br:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:10])[C:4]=1[Cl:11]
Reactant: Cc1c(N)ccc(Br)c1Cl
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cccc(Br)c1Cl
Temperature: 70 °C

Procedure:
Concentrated HCl was added to a solution of 4-bromo-3-chloro-2-methyl-phenylamine (4.98 g, 22.60 mmol) in EtOH. NaNO2 (3.00 g, 43.50 mmol) was added and the resulting mixture was heated to 70° C. for 2 hours. Ethanol was distilled off and the residue was purified by column chromatography using hexanes as the eluant to afford the title compound. Spectroscopic data: 1H NMR (300 MHz, CDCl3) δ 2.43 (s, 3H), 7.01 (t, J=7.91 Hz, 1H), 7.18 (d, J=7.62 Hz, 1H), 7.47 (d, J=7.91 Hz, 1H).
Reaction SMILES: [Na+:1].[Na+].[Na+].[NH2:4][C:5]1[CH:6]=[C:7]([S:23]([O-:26])(=[O:25])=[O:24])[CH:8]=[C:9]2[C:14]=1[C:13]([S:15]([O-:18])(=[O:17])=[O:16])=[CH:12][C:11]([S:19]([O-:22])(=[O:21])=[O:20])=[CH:10]2.O.O.O.C([O-])(=O)C.[Na+].[N+](C1C=CC(C([O:44][C:45](=O)[C:46]2[CH:51]=[CH:50][C:49]([N+:52]([O-:54])=[O:53])=[CH:48][C:47]=2[S:55]([OH:58])(=[O:57])=[O:56])=O)=C(S(O)(=O)=O)C=1)([O-])=O>O>[Na+:1].[Na+:1].[Na+:1].[Na+:1].[N+:52]([C:49]1[CH:50]=[CH:51][C:46]([C:45]([NH:4][C:5]2[CH:6]=[C:7]([S:23]([O-:26])(=[O:25])=[O:24])[CH:8]=[C:9]3[C:14]=2[C:13]([S:15]([O-:18])(=[O:17])=[O:16])=[CH:12][C:11]([S:19]([O-:22])(=[O:20])=[O:21])=[CH:10]3)=[O:44])=[C:47]([S:55]([OH:58])(=[O:56])=[O:57])[CH:48]=1)([O-:54])=[O:53]
Reactant: O=C(OC(=O)c1ccc([N+](=O)[O-])cc1S(=O)(=O)O)c1ccc([N+](=O)[O-])cc1S(=O)(=O)O
Reactant: Nc1cc(S(=O)(=O)[O-])cc2cc(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])c12
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: O=C(Nc1cc(S(=O)(=O)[O-])cc2cc(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])c12)c1ccc([N+](=O)[O-])cc1S(=O)(=O)O
Reaction time: 0.17 h
Yield: 296.2 %

Procedure:
To an ice bath cooled solution (5° C.) of 16.0 g of 8-amino-1,3,6-naphthalenetrisulfonic acid trisodium salt and 6.7 g of sodium acetate trihydrate in 100 ml of water is added 8.8 g of 4-nitro-2-sulfobenzoic acid anhydride. The mixture is stirred vigorously for 10 minutes and is filtered. The filtrate is cooled in an ice bath and diluted with 500 ml of cold ethanol. The mixture is filtered and the product is washed with ethanol and ether and then is dried. The product is dissolved in 50 ml of warm water and is stirred for 10 minutes after the addition of one ml of acetone. The mixture is treated with activated charcoal, filtered through diatomaceous earth and is washed with 20 ml of water. The filtrate is cooled in an ice bath and acidified with 1.5 ml of concentrated hydrochloric acid. The solution is diluted with 500 ml of cold ethanol and the precipitated material is filtered, washed with ethanol followed by ether and dried. The above purification process is repeated without acidification. The product obtained is dried overnight at 110° C. to give 18.5 g of 8-(4-nitro-2-sulfobenzamido)-1,3,6-naphthalenetrisulfonic acid tetrasodium salt.
Reaction SMILES: Cl.[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]1[N:12]=[C:13]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[N:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH2:20])[C:15]=12.C(N(CC)C(C)C)(C)C.[CH3:36][N:37]([CH3:41])[C:38](Cl)=[O:39]>CN(C=O)C>[NH2:20][C:16]1[C:15]2[N:14]([C:13]([CH:21]3[CH2:26][CH2:25][N:24]([C:38]([N:37]([CH3:41])[CH3:36])=[O:39])[CH2:23][CH2:22]3)=[N:12][C:11]=2[C:3]2[NH:2][C:10]3[C:5]([CH:4]=2)=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:19]=[CH:18][N:17]=1
Reactant: Nc1nccn2c(C3CCNCC3)nc(-c3cc4ccccc4[nH]3)c12
Reactant: CN(C)C(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)C(=O)N1CCC(c2nc(-c3cc4ccccc4[nH]3)c3c(N)nccn23)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 1-(1H-indol-2-yl)-3-piperidin-4-ylimidazo[1,5-α]pyrazin-8-amine hydrochloride (30.0 mg, 0.0679 mmol),N,N-diisopropylethylamine (59.1 μL, 0.340 mmol) and DMF (1.00 mL) was treated with N,N-dimethylcarbamoyl chloride (6-23 μL, 0.0679 mmol) and stirred at rt for 1 h prior to semi-preparative HPLC to afford the isolated title compound. 1H NMR (400 CD3OD) ppm: 8.32 (br. s., 1H), 7.59-7.66 (m, 2H), 7.46 (d, 1H, J=8.3 Hz), 7.15-7.22 (m, 1H), 7.01-7.10 (m, 2H), 6.74 (s, 1H), 3.82 (d, 2H, J=12.6 Hz), 3.34-3.42 (m, 1H), 2.97-3.09 (m, 2H), 2.87 (s, 6H), 1.95-2.09 (m, 4H); MS (ES+): m/z 404.14 [MH+].
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:8]2[N:13]=[C:12]3[N:14]([CH2:17][C:18]4[CH:27]=[CH:26][CH:25]=[CH:24][C:19]=4[C:20]([O:22]C)=[O:21])[N:15]=[CH:16][C:11]3=[CH:10][N:9]=2)[CH:4]=[N:3]1.[OH-].[Na+].Cl>C1COCC1>[CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:8]2[N:13]=[C:12]3[N:14]([CH2:17][C:18]4[CH:27]=[CH:26][CH:25]=[CH:24][C:19]=4[C:20]([OH:22])=[O:21])[N:15]=[CH:16][C:11]3=[CH:10][N:9]=2)[CH:4]=[N:3]1
Reactant: COC(=O)c1ccccc1Cn1ncc2cnc(Nc3cnn(C)c3)nc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cn1cc(Nc2ncc3cnn(Cc4ccccc4C(=O)O)c3n2)cn1

Procedure:
A solution of methyl 2-((6-(1-methyl-1H-pyrazol-4-ylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)benzoate (15 mg, 0.04 mmol) and sodium hydroxide (1 mL, 4M aqueous solution) in THF (3 mL) was stirred at rt for 2 h. The mixture was then acidified with HCl (2M) and extracted into EtOAc. The organic phase was collected, dried (MgSO4) and concentrated in vacuo to give the title product. 1H NMR (d6-DMSO) δ 9.86 (s, 1H), 8.94 (s, 1H), 8.11 (s, 1H), 7.93 (d, 1H), 7.89 (s, 1H), 7.47 (s, 1H), 7.36-7.41 (m, 2H), 6.79 (s, 1H), 5.95 (s, 2H), 3.78 (s, 3H); LC-MS method B, (ES+) 350.0, RT=6.91 min.
Reaction SMILES: [Br:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][CH:7]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=2)[C:8]([CH3:13])([CH3:12])[CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1.N1C=CN=C1.CN(C)C=O.[CH:34]([Si:37](Cl)([CH:41]([CH3:43])[CH3:42])[CH:38]([CH3:40])[CH3:39])([CH3:36])[CH3:35]>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([Br:21])=[CH:19][CH:20]=2)[C:8]([CH3:13])([CH3:12])[CH2:9][CH2:10][O:11][Si:37]([CH:41]([CH3:43])[CH3:42])([CH:38]([CH3:40])[CH3:39])[CH:34]([CH3:36])[CH3:35])=[CH:22][CH:23]=1
Reactant: CC(C)(CCO)C(Cc1ccc(Br)cc1)Cc1ccc(Br)cc1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)[Si](OCCC(C)(C)C(Cc1ccc(Br)cc1)Cc1ccc(Br)cc1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.9 %

Procedure:
A mixture of 4-(4-bromobenzyl)-5-(4-bromophenyl)-3,3-dimethylpentan-1-ol (0.974 g, 2.34 mmol) and 1,3-diaza-2,4-cyclopentadiene (0.351 g, 5.15 mmol) in a reaction container was deaerated, and the air inside the reaction container was replaced with argon. N,N-dimethylformamide (12 mL) and triisopropylsilyl chloride (0.68 g, 3.51 mmol) were then added to the mixed liquid. The thus obtained mixed liquid was stirred overnight at room temperature, and a sufficient amount of water was added to halt the reaction. The organic layer was separated from the mixed liquid, and the water layer was extracted with diethyl ether. The thus obtained organic layer was washed with a saturated saline solution and then dried using anhydrous magnesium sulfate. The organic layer was then filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:diethyl ether=50:1), yielding the title compound (4j) (1.16 g, 1.94 mmol) as a light yellow liquid in a yield of 83%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][CH:34]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([C:24]4[O:28][C:27]([CH:29]=O)=[CH:26][CH:25]=4)[CH:22]=3)[N:17]=[CH:16][N:15]=2)=[CH:9][C:8]=1[Cl:31].[CH3:35][P:36]([CH2:39][NH2:40])([CH3:38])=[O:37].[P].[S].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C>[CH3:35][P:36]([CH2:39][NH:40][CH2:29][C:27]1[O:28][C:24]([C:21]2[CH:22]=[C:23]3[C:18](=[CH:19][CH:20]=2)[N:17]=[CH:16][N:15]=[C:14]3[NH:13][C:10]2[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]3[CH:32]=[CH:33][CH:34]=[C:2]([F:1])[CH:3]=3)=[C:8]([Cl:31])[CH:9]=2)=[CH:25][CH:26]=1)([CH3:38])=[O:37]
Reactant: CP(C)(=O)CN
Reactant: O=Cc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c3c2)o1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [P]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CP(C)(=O)CNCc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c3c2)o1
Temperature: 25 °C

Procedure:
5-(4-(4-(3-fluorobenzyloxy)-3-chlorophenylamino)quinazolin-6-yl)furan-2-carbaldehyde (compound 1.7) and (dimethylphosphinoyl)methanamine (preparation: Maier, Ludwig Phosphorus, Sulfur and Silicon and the Related Elements, 53(1-4), 43-67; 1990) were suspended in dichloromethane (20 mL). Sequentially, acetic acid (3 drops) and sodium triacetoxyborohydride (2 equiv.) were added at room temperature. The mixture was stirred at room temperature until the starting material disappeared. The reaction was quenched with 2N NaOH aqueous solution and extracted with dichloromethane. The combined organic layer and extracts were dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography, eluting with 20% methanol in dichloromethane to give the desired product as yellow crystalline solid. LCMS ESI(+) m/z: 566 (M+1). 1H NMR (300 MHz, CD3OD) δ 8.65 (s, 1H), 8.46 (s, 1H), 8.15 (m, 1H), 7.91 (d, 1H), 7.75 (m, 1H), 7.62 (m, 1H), 7.40 (m, 1H), 7.29 (m, 1H), 7.26 (m, 1H), 7.13 (m, 1H), 7.08 (m, 1H), 6.93 (d, 1H), 6.47 (d, 1H), 5.20 (s, 2H), 3.97 (s, 2H), 3.08 (m, 2H), 2.85 (m, 1H), 1.57 (m, 6H).
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:4])[CH:2]=[CH2:3].[Cl:15][S:16](O)(=[O:18])=[O:17]>ClCCl.C(OCC)(=O)C.[Cl-].[Na+].O>[C:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([S:16]([Cl:15])(=[O:18])=[O:17])=[CH:13][CH:14]=1)(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)OCCOc1ccccc1
Reactant: O=S(=O)(O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: C=CC(=O)OCCOc1ccc(S(=O)(=O)Cl)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 2-(phenyloxy)ethyl 2-propenoate (5 g, 26.0 mmol) in dichloromethane (50 mL), was cooled to 0° C. Chlorosulfonic acid (5.21 mL, 78 mmol) was added dropwise over 15 minutes at 0° C. then the mixture was allowed to warm to room temperate over 30 minutes. The reaction mixture was stirred overnight (16 hours) at room temperature. The solution was then poured onto ice and extracted with dichloromethane (3×50 mL). Resulting emulsion was diluted with ethyl acetate (200 mL) and brine (50 mL) in order to achieve separation of phases. The aqueous layer was further extracted with ethyl acetate (100 mL). The combined organic fractions were dried with magnesium sulphate then evaporated in vacuo to give an oily solid, which was dried under high vacuum overnight. After drying, a sticky solid was isolated (3.2 g) and this was taken on to the next step without further purification. LCMS [LCMS1] Rt 0.47 min, m/z (ES−) 272 (M−Cl+OH).
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:4])([CH3:3])[CH3:2].S(Cl)(Cl)=O.[CH2:18]([NH:20][CH2:21][CH3:22])[CH3:19]>C(Cl)Cl>[CH2:18]([N:20]([CH2:21][CH3:22])[C:7](=[O:9])[C:6]1[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=1[C:1]([CH3:2])([CH3:3])[CH3:4])[CH3:19]
Reactant: CCNCC
Reactant: CC(C)(C)c1ccccc1C(=O)O
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CCN(CC)C(=O)c1ccccc1C(C)(C)C
Temperature: 0 °C

Procedure:
A solution of 2-tert-butylbenzoic acid (4.0 g, 22.5 mmol) in thionyl chloride (8.2 mL, 112 mmol) was stirred at RT for 2 h, then was concentrated three times from carbon tetrachloride to remove all traces of excess thionyl chloride. A solution of diethylamine (4.93 g, 67.4 mmol) in CH2Cl2 (10 mL) was added dropwise over 10 min to an ice water-cooled solution of the crude acid chloride in CH2Cl2 (35 mL). Ten min after addition was complete, the reaction was partitioned between ether and 10% HCl. The ether phase was then washed with sat aq NaHCO3, then was dried (MgSO4), and concentrated to afford a quantitative yield of N,N-diethyl-2-tert-butylbenzamide as an off-white solid. m.p. 38.5-40.5° C.