Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8](B(O)O)=[CH:7][CH:6]=[CH:5][N:4]=1.FC(F)(F)S(O[C:18]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:19]=1[CH2:20][C@H:21]([N:28]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:22][O:23]2)(=O)=O>>[CH2:36]([N:28]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C@H:21]1[CH2:20][C:19]2[C:24](=[CH:25][CH:26]=[CH:27][C:18]=2[C:8]2[C:3]([O:2][CH3:1])=[N:4][CH:5]=[CH:6][CH:7]=2)[O:23][CH2:22]1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: O=S(=O)(Oc1cccc2c1C[C@H](N(Cc1ccccc1)Cc1ccccc1)CO2)C(F)(F)F
Reactant: COc1ncccc1B(O)O
Product: COc1ncccc1-c1cccc2c1C[C@H](N(Cc1ccccc1)Cc1ccccc1)CO2
Yield: 93 %

Procedure:
The title compound was synthesized as described for Intermediate example I-2 in 93% yield, starting from 2-methoxypyridine-3-boronic acid and (3S)-3-(dibenzylamino)-3,4-dihydro-2H-chromen-5-yl trifluoromethanesulfonate. The reaction mixture was irradiated in a microwave at 150° C. for 1 h; 1H NMR (400 MHz, DMSO-d6) δ ppm 7.52 (dd, 1 H), 7.25-7.34 (m, 9 H), 7.16-7.24 (m, 2 H), 7.04-7.14 (m, 2 H), 6.76 (d, 1 H), 6.68 (d, 1 H), 4.25-4.35 (m, 1 H), 4.05 (t, 1 H), 3.80 (s, 3 H), 3.55-3.70 (m, 4 H), 2.93-3.04 (m, 1 H), 2.55-2.84 (m, 1 H), 2.27-2.38 (m, 1 H); MS (ESI) m/z 437[M+H+].
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Cl:8][C:9]1[C:14]([C:15]2[C:20]([F:21])=[CH:19][C:18]([F:22])=[CH:17][C:16]=2[F:23])=[C:13](Cl)[N:12]2[N:25]=[CH:26][CH:27]=[C:11]2[N:10]=1>C1COCC1.[Cu](I)I>[Cl:8][C:9]1[C:14]([C:15]2[C:20]([F:21])=[CH:19][C:18]([F:22])=[CH:17][C:16]=2[F:23])=[C:13]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[N:12]2[N:25]=[CH:26][CH:27]=[C:11]2[N:10]=1
Reactant: Fc1cc(F)c(-c2c(Cl)nc3ccnn3c2Cl)c(F)c1
Reactant: [Li]CCCCCC
Agent: I[Cu]I
Solvent: C1CCOC1
Product: CCCCCCc1c(-c2c(F)cc(F)cc2F)c(Cl)nc2ccnn12
Temperature: -70 °C
Reaction time: 0.75 h

Procedure:
Copper iodide (5 mmol) was suspended in THF (25 ml) under an inert gas atmosphere. The suspension was cooled to −70° C. and n-hexyllithium (5 ml,2M in hexanes) was added by syringe. The mixture was stirred for 45 minutes and 5,7-dichloro-6-(2,4,6-trifluorophenyl)-pyrazolo[1,5-α]pyrimidine (5 mmol, obtained from Example 3) was added as a solution in THF (10 min). The reaction mixture was stirred for 15 minutes at −70° C. The reaction mixture was then quenched with a mixture of aqueous saturated ammonium chloride/concentrated ammonia (9:1). The two phase mixture was separated. An oil was isolated from the organic layer which was subjected to chromatographic purification which yields the product as a crystalline residue.
Reaction SMILES: [CH3:1][O-:2].[Na+].[CH3:4][OH:5]>>[CH2:4]([OH:5])[C@@H:1]([C@H:4]([C@@H:1]([C@@H:4]([CH2:1][OH:2])[OH:5])[OH:2])[OH:5])[OH:2]
Reactant: CO
Reactant: C[O-]
Agent: [Na+]
Product: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(1S)-2,3,4,6-Tetra-0-acetyl-1,5-anhydro-1-[5-(1-benzothiophene-2-ylmethyl)-2-(cyclopentyloxy)phenyl]-D-glucitol (381 mg) was dissolved in methanol (10 ml). Sodium methoxide (32 mg) was added to the solution, and the mixture was stirred for three hours at room temperature. The reaction mixture was neutralized with acid ion-exchange resin, and the resin was separated by filtration. The filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform-methanol) to obtain (1S)-1,5-anhydro-1-[5-(1-benzothien-2-yl)methyl]-2-(cyclopentyloxy)phenyl]-D-glucitol (215 mg).
Reaction SMILES: CC[Mg+].[Br-].[Br:5][C:6]1[N:7]=[C:8]([CH2:20][O:21][CH2:22][CH2:23][O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[N:9]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:10]=1Br.CN([CH:35]=[O:36])C>C(OCC)C.C1COCC1>[Br:5][C:6]1[N:7]=[C:8]([CH2:20][O:21][CH2:22][CH2:23][O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[N:9]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:10]=1[CH:35]=[O:36]
Reactant: CN(C)C=O
Reactant: CC(C)(C)[Si](C)(C)OCCOCc1nc(Br)c(Br)n1COCC[Si](C)(C)C
Agent: CC[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)OCCOCc1nc(Br)c(C=O)n1COCC[Si](C)(C)C
Reaction time: 3 h
Yield: 69 %

Procedure:
3N EtMgBr (0.086 mL of a 3N solution in diethyl ether, 0.26 mmol) was added to a solution of 4,5-dibromo-2-{[(2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}ethyl)oxy]methyl}-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole (0.12 g, 0.21 mmol) in THF (2 mL). The reaction mixture was stirred for 3 h, DMF was added (0.5 mL, 4.9 mmol), and stirring was continued overnight. The solution was quenched by addition of sat'd NH4Cl and extracted with EtOAc and CH2Cl2. The organic phase was dried (Na2SO4), filtered, and purified by silica gel chromatography (0-30% EtOAc/hex) to afford the title compound (0.073 g, 69%) as a clear oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.77 (s, 1H), 5.84 (s, 2H), 5.27-5.47 (m, 1H), 4.60-4.77 (m, 1H), 3.74 (ddd, J=9.16, 4.85, 4.67 Hz, 2H), 3.47-3.62 (m, 4H), 0.83-0.95 (m, 11H), 0.04 (s, 6H), −0.06-0.01 (m, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH3:11][NH:12][CH3:13].N1C=CC=CC=1.Cl>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:12]([CH3:13])[CH3:11])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CNC
Agent: Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CN(C)C(=O)c1ccc(Cl)cc1

Procedure:
The procedure of Example 13 is followed, but the endcapper is 4-chloro-N,N-dimethylbenzamide (0.20 g, 1.09 mmol) to yield the amido-functionalized macromonomer. 4-Chloro-N,N-dimethylbenzamide is prepared by reacting 4-chlorobenzoyl chloride with dimethylamine in toluene with some pyridine (1 mol equivalent per acid chloride) to trap the HCl that is evolved. After aqueous extraction of the pyridinium salt and any excess starting materials, the product is crystallized from the toluene solution.
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH2:7][C:8]([NH:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.Br[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[F:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[CH2:15][O:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]([NH:10][CH3:11])=[O:9])=[CH:12][CH:13]=1
Reactant: CNC(=O)COc1ccc(O)cc1
Reactant: Fc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CNC(=O)COc1ccc(OCc2cccc(F)c2)cc1

Procedure:
In analogy to the procedure described in Example 3b), the alkylation of 2-(4-hydroxy-phenoxy)-N-methyl-acetamide [Example 3a)] with 1-bromomethyl-3-fluoro-benzene in 2-butanone using potassium carbonate as the base yielded the 2-[4-(3-fluoro-benzyloxy)-phenoxy]-N-methyl-acetamide as white crystals; MS: m/e=290 (M+H)+.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][CH3:13])[CH:5]=1)([CH3:3])[CH3:2].[CH3:14][S:15]([OH:18])(=O)=[O:16].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>>[OH:10][C:7]1[CH:8]=[CH:9][C:14]([S:15]([C:5]2[C:6]([O:12][CH3:13])=[C:7]([O:10][CH3:11])[CH:8]=[CH:9][C:4]=2[CH:1]([CH3:3])[CH3:2])(=[O:18])=[O:16])=[CH:5][CH:6]=1
Reactant: CS(=O)(=O)O
Reactant: COc1ccc(C(C)C)cc1OC
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: COc1ccc(C(C)C)c(S(=O)(=O)c2ccc(O)cc2)c1OC
Temperature: 50 °C
Reaction time: 5 h

Procedure:
A mixture of 2 g (0.011 mole) of 1-isopropyl 3,4-dimethoxy benzene, 3.4 g (0.011 mole) of sodium 4-benzyloxy benzenesulfonate, 45 ml of anhydrous methanesulfonic acid and 4.5 g of phosphoric anhydride is stirred at 50° C. for 5 hours. It is poured into an ice/water mixture, the product is filtered off and washed on the filter with water. The still moist solid is taken up in 20 ml of ethanol and 5 ml of a 30% sodium hydroxide solution. It is heated at 60° C. for about 2 h until dissolution is complete, the solution is diluted with water, filtered and acidified with acetic acid. The product is filtered off and washed on the filter with water. It is then purified by chromatography on a column of silica using a dichloroethane/ethyl acetate mixture 95/5.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:26]([O:28][CH2:29][CH3:30])=[O:27])[O:10][C:9]2[CH:11]=[CH:12][C:13]([CH2:15][C@H:16]([NH:18]C(OC(C)(C)C)=O)[CH3:17])=[CH:14][C:8]=2[O:7]1)=[O:5])[CH3:2].C(OCC)C.[ClH:36]>C(OCC)(=O)C>[ClH:36].[NH2:18][C@H:16]([CH3:17])[CH2:15][C:13]1[CH:12]=[CH:11][C:9]2[O:10][C:6]([C:26]([O:28][CH2:29][CH3:30])=[O:27])([C:4]([O:3][CH2:1][CH3:2])=[O:5])[O:7][C:8]=2[CH:14]=1
Reactant: CCOC(=O)C1(C(=O)OCC)Oc2ccc(C[C@@H](C)NC(=O)OC(C)(C)C)cc2O1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCOC(=O)C1(C(=O)OCC)Oc2ccc(C[C@@H](C)N)cc2O1

Procedure:
A solution of (R)-5-[N-(t-butyloxycarbonyl)-2-aminopropyl]-1,3-benzodioxole-2,2-dicarboxylic acid diethyl ester (3.0 g, 7 mMol) in ethyl acetate (40 ml) and hydrogen chloride solution in diethyl ether (1M, 56 ml, 56 mMol) was stirred at ambient temperature under an argon atmosphere for 48 hours. The solvent was evaporated and the residue was dried giving the title compound as a glass.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[C:7](=[O:12])[CH:6]([CH2:13][CH2:14][CH2:15][CH3:16])[CH2:5]2.[Cl:17]N1C(=O)CCC1=O>CN(C)C=O>[NH2:1][C:2]1[C:3]([Cl:17])=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[C:7](=[O:12])[CH:6]([CH2:13][CH2:14][CH2:15][CH3:16])[CH2:5]2
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCCCC1Cc2cc(N)c(F)cc2C1=O
Solvent: CN(C)C=O
Product: CCCCC1Cc2c(cc(F)c(N)c2Cl)C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.7 %

Procedure:
A solution of 5-amino-2-butyl-6-fluoro-1-indanone (5.14 g, 23.2 mmol) in N,N-dimethylformamide (23 mL) was placed under a nitrogen atmosphere and treated with N-chlorosuccinimide (3.2 g, 24 mmol). After stirring at room temperature for 3 hours, the reaction mixture was partitioned between EtOAc and water. The organic portion was washed with water and brine, dried over MgSO4, filtered, and evaporated under vacuum to an orange solid (6.5 g). The crude product was purified by flash chromatography on a Biotage 40M KP-Sil column, eluting with 9:1 hexanes-EtOAc. The product containing fractions were evaporated under vacuum to afford 5-amino-2-butyl-4-chloro-6-fluoro-1-indanone (5.2 g, 88%) as a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]([O:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:5]=1)([O-])=O.[H][H]>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:14][CH:15]=1
Reactant: [H][H]
Reactant: COC(=O)COc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)COc1ccc(N)cc1
Yield: 97.6 %

Procedure:
A solution of 30.8 g of methyl 4-nitrophenoxyacetate [prepared as described in step (a) above] in 500 ml of methanol was shaken in an atmosphere of hydrogen and in the presence of 5.0 g of 10% w/w palladium-on-charcoal for 6 hours. At the end of this time, the reaction mixture was filtered and the filtrate was concentrated by evaporation under reduced pressure, to give 25.8 g of the title compound having an Rf value=0.79 (on thin layer chromatography on silica gel; developing solvent: ethyl acetate).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C@@H:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]#[N:21])[CH:15]=2)[C@@H:11]([NH2:13])[CH3:12])=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.Cl[C:32]1[CH:37]=[CH:36][C:35]([C:38](=O)[C:39]([CH3:42])([OH:41])[CH3:40])=[CH:34][CH:33]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C@@H:10]([C:14]2[CH:15]=[C:16]([CH:17]=[CH:18][CH:19]=2)[C:20]#[N:21])[C@@H:11]([NH:13][CH:38]([C:35]2[CH:36]=[CH:37][CH:32]=[CH:33][CH:34]=2)[C:39]([OH:41])([CH3:42])[CH3:40])[CH3:12])=[CH:5][CH:4]=1
Reactant: C[C@H](N)[C@@H](Cc1ccc(Cl)cc1)c1cccc(C#N)c1
Reactant: CC(C)(O)C(=O)c1ccc(Cl)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](NC(c1ccccc1)C(C)(C)O)[C@@H](Cc1ccc(Cl)cc1)c1cccc(C#N)c1
Reaction time: 0.08 h

Procedure:
To a solution of 100 mg (0.31 mmol) of 3-(4-chlorophenyl)-2(S)-(3-cyanophenyl)-1(S)-methyl-propylamine hydrochloride in 2 mL of CH2Cl2, 54 μL (0.31 mmol) of diisopropylethylamine and 62 mg (0.31 mmol) of 1-(4-chlorophenyl)-2-methyl-2-hydroxy-propan-1-one were added. After 5 min, 99 mg (0.47 mmol) of sodium triacetoxyborohydride was added and stirred for 3 hr. The reaction was quenched with water and the layers were separated. The organic layer was dried and concentrated. The residue was purified on a prep TLC plate using 30% EtOAc/hexane as an eluant to isolate two products. The higher Rf band gave 3-(1(S)-(4-chlorobenzyl)-2(S)-((2-hydroxy-2-methyl-1-phenylpropyl)amino)propyl)benzonitrile (diastereomer A) and the lower Rf band gave 3-(1(S)-4-chlorobenzyl)-2(S)-((2-hydroxy-2-methyl-1-phenylpropyl)amino)propyl)benzonitrile (diastereomer B). Diastereomer A, LC-MS: m/e=467 (M+1), 469 (M+3) (3.28 min). Diastereomer B, LC-MS: m/e=467 (M+1), 469 (M+3) (3.28 min).
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:5]([C:6]#[N:7])[C:4]=1[NH2:12].[CH3:13][C:14]1([CH3:22])[CH2:21][C:19](=O)[CH2:18][C:16](=[O:17])[CH2:15]1>C1COCC1>[ClH:1].[CH3:13][C:14]1([CH3:22])[CH2:21][C:19]([NH:12][C:4]2[C:3]([CH3:2])=[CH:10][CH:9]=[C:8]([CH3:11])[C:5]=2[C:6]#[N:7])=[CH:18][C:16](=[O:17])[CH2:15]1
Reactant: Cc1ccc(C)c(C#N)c1N
Reactant: CC1(C)CC(=O)CC(=O)C1
Agent: Cl
Solvent: C1CCOC1
Product: Cc1ccc(C)c(NC2=CC(=O)CC(C)(C)C2)c1C#N
Reaction time: 14 h

Procedure:
6 ml of concentrated hydrochloric acid were added to a solution of 5.84 g (0.04 mol) of 3,6-dimethylanthranilonitrile (Ib) in 80 ml of THF with stirring, after 15 min 5.6 g (0.04 mol) of dimedone (II) were added, the mixture was heated under reflux with stirring for 14 h, the precipitate was filtered off, washed with acetone and dried. The mother liquor was concentrated to 1/4 of the initial volume, the precipitate was filtered off, washed with acetone and dried. Precipitates were combined to give 10.5 g (87%) of IIId, m.p. 208-209 (i-PrOH).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([CH:29]=O)=[CH:21]1>>[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([CH2:29][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)=[CH:21]1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: O=Cc1c[nH]c2ccccc12
Product: FC(F)(F)c1nnc2ccc(N3CCN(Cc4c[nH]c5ccccc45)CC3)nn12

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 1H-indole-3-carbaldehyde was carried out according to General Synthetic Method 5. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-(1H-indol-3-ylmethyl)piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].CN[C@@H]1CCCC[C@H]1NC.Cl.[OH2:23]>CN[C@@H]1CCCC[C@H]1NC>[OH:23][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Cc1ccc(C(=O)O)c(Cl)c1
Reactant: O
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: Cl
Product: Cc1ccc(C(=O)O)c(O)c1
Temperature: 85 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
Under nitrogen, 1.86 g (10.0 mmol) of 2-chloro-4-methylbenzoic acid was combined with 10 g of H2O. 1.11 g (15 mmol) of Ca(OH)2 was then added. The mixture was heated at 85° C. under stirring for 60 min, remaining under a nitrogen atmosphere. Separately, 43 mg of CuBr and 94 mg of rac-trans-N,N′-dimethylcyclohexane-1,2-diamine (Ligand F) were combined with 1 mL deionized water under nitrogen. The resulting mixture was stirred under an air atmosphere until the CuBr was dissolved to give a blue solution. This solution was added to the stirred reaction mixture via syringe at 80° C. under nitrogen and stirred for 24 h at 80° C. After cooling to 25° C., the reaction mixture was acidified with 15% HCl, producing a white precipitate. The white precipitate was filtered and washed with water. After drying, a total of 1.45 g (9.5 mmol, 95% yield) of 2-hydroxy-4-methylbenzoic acid was collected. The purity was determined by 1H NMR to be >99%.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[C:12]([N:14]3[CH:23]([CH3:24])[CH2:22][C:21]4[C:16](=[CH:17][C:18]([C:25]5[CH:29]=[CH:28][NH:27][N:26]=5)=[CH:19][CH:20]=4)[CH2:15]3)[N:11]=[C:10]([NH2:30])[N:9]=2)[CH2:4][CH2:3]1.[C:31](#[N:34])[CH:32]=[CH2:33].N12CCCN=C1CCCCC2>C(#N)C>[NH2:30][C:10]1[N:11]=[C:12]([N:14]2[CH:23]([CH3:24])[CH2:22][C:21]3[C:16](=[CH:17][C:18]([C:25]4[CH:29]=[CH:28][N:27]([CH2:33][CH2:32][C:31]#[N:34])[N:26]=4)=[CH:19][CH:20]=3)[CH2:15]2)[CH:13]=[C:8]([N:5]2[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]2)[N:9]=1
Reactant: CC1Cc2ccc(-c3cc[nH]n3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Reactant: C=CC#N
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC1Cc2ccc(-c3ccn(CCC#N)n3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Temperature: 50 °C

Procedure:
A mixture of 4-(4-methylpiperazin-1-yl)-6-[3-methyl-7-(1H-pyrazol-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl]pyrimidin-2-amine (10.0 mg, 0.0247 mmol), 2-propenenitrile (50.0 uL, 0.761 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (5.0 uL, 0.033 mmol) in acetonitrile (0.15 mL) was heated at 50° C. for 2 h. The mixture was purified by RP-HPLC (pH=10) to afford the desired product. LCMS (M+H)+: m/z=458.3.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]=[C:15]2[CH:23]([F:25])[F:24])[N:3]=1.[NH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.O>O1CCOCC1>[F:24][CH:23]([F:25])[C:15]1[N:14]([C:4]2[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=[C:2]([NH:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:3]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=1
Reactant: FC(F)c1nc2ccccc2n1-c1nc(Cl)nc(N2CCOCC2)n1
Reactant: Nc1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: FC(F)c1nc2ccccc2n1-c1nc(Nc2ccccc2)nc(N2CCOCC2)n1
Yield: 49.1 %

Procedure:
A mixture of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-1H-benzimidazole (92 mg, 0.25 mmol) and aniline (58 mg, 0.625 mmol) in dioxane (5 mL) was heated under reflux for 1 hr and cooled. Dilution with water gave a white precipitate, which was recrystallised from MeOH to give 52 mg (49% yield) of 4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-N-phenyl-1,3,5-triazin-2-amine: mp 171-174° C.; 1H NMR (CDCl3) δ 8.40 (m, 1H), 7.89 (m, 1H), 7.58 (t, JHF=54.7 Hz, 1H), 7.55 (d, J=7.5 Hz, 1H), 7.43-7.38 (m, 4H), 7.20 (t, J=7.3 Hz, 1H), 7.09 (br, exchangeable with D2O, 1H), 3.93 (m, 4H), 3.81 (m, 4H); Anal. Calc. for C21H19F2N7O: C, 59.6; H, 4.5; N, 23.2. Found: C, 59.6; H, 4.5; N, 23.3%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([CH3:27])[CH:21]=2)[C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].Cl.[Cl:35][CH2:36][CH2:37][N:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1.Cl>C1C=CC=CC=1.CC(C)=O>[ClH:35].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:36][CH2:37][N:38]3[CH2:42][CH2:41][CH2:40][CH2:39]3)=[C:22]([CH3:27])[CH:21]=2)[C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1
Reactant: ClCCN1CCCC1
Reactant: COc1ccc(C(c2ccc(O)c(C)c2)c2cccc3ccccc23)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: CC(C)=O
Product: COc1ccc(C(c2ccc(OCCN3CCCC3)c(C)c2)c2cccc3ccccc23)cc1

Procedure:
A mixture of (4-methoxyphenyl)-(3-methyl-4-hydroxyphenyl)-naphth-1-yl-methane (0.3 gm, 0.008 mol), anhydrous K2CO3 (2.0 gm), 1-(2-chloroethyl)pyrrolidine hydrochloride (0.3 gm, 0.0017 mol) and anhydrous acetone (25 ml) was refluxed for 10 hrs, K2CO3 was filtered off, acetone was distilled off, and the residue was diluted with water. The reaction mixture was extracted with ethyl acetate washed with water, dried over Na2SO4 and concentrated to give an oil. This oil was passed through basic alumina using benzene as eluent. Solvent was distilled off. The oil thus obtained was treated with ethanolic HCl. The solvent was evaporated and compound was crystallized with absolute alcohol and anhydrous ether to give the title compound as a salt of general formula I. Yield 170 mg(46%).
Reaction SMILES: [O-]S([O-])(=O)=O.[Mg+2].OS(O)(=O)=O.[Br:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][C:14]=1[O:22][CH3:23].[CH3:24][C:25](O)([CH3:27])[CH3:26]>C(Cl)Cl>[Br:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([O:19][C:25]([CH3:27])([CH3:26])[CH3:24])=[O:18])=[CH:15][C:14]=1[O:22][CH3:23]
Reactant: COc1cc(C(=O)O)ccc1Br
Reactant: CC(C)(C)O
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: COc1cc(C(=O)OC(C)(C)C)ccc1Br
Reaction time: 0.5 h
Yield: 13.9 %

Procedure:
To MgSO4 (4.8 g, 1.8 mL, 40 mmol) in DCM (40 mL) was added H2SO4 (1.0 g, 533 μL, 10 mmol) at 0° C. and the reaction mixture was allowed to stir for 30 minutes. 4-Bromo-3-methoxy-benzoic acid (2.3 g, 10 mmol) was added followed by 2-methylpropan-2-ol (3.7 g, 4.8 mL, 50 mmol). The reaction mixture was allowed to stir at room temperature for 16 hours. MgSO4 was removed by filtration and 1N NaOH solution was added until pH 9 was achieved. The layers were separated and the organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to yield tert-butyl 4-bromo-3-methoxy-benzoate (0.4 g, 14%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=1.S(Cl)([Cl:20])=O>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([Cl:20])=[O:14])=[CH:11][CH:10]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(OCCCCCCBr)cc1
Product: O=C(Cl)c1ccc(OCCCCCCBr)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 452 g of 4-(6-bromohexyloxy)benzoic acid and 1000 g of thionyl chloride was stirred at room temperature for about 20 hours. The reaction mixture was concentrated in vacuo and residual thionyl chloride removed by repeated addition of toluene and concentration in vacuo. The oily product comprising 4-(6-bromohexyloxy)benzoyl chloride (450 ml) was used directly in the next reaction.
Reaction SMILES: [NH2:1][C:2]([CH3:15])([CH3:14])[CH2:3][C:4]1[N:8]([CH2:9][CH3:10])[N:7]=[C:6]([C:11]#[N:12])[C:5]=1[Br:13].[CH:16]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH2:17]>C1(C)C=CC=CC=1>[Br:13][C:5]1[C:6]([C:11]#[N:12])=[N:7][N:8]([CH2:9][CH3:10])[C:4]=1[CH2:3][C:2]([CH3:14])([NH:1][CH2:17][CH2:16][S:18]([CH3:21])(=[O:20])=[O:19])[CH3:15]
Reactant: CCn1nc(C#N)c(Br)c1CC(C)(C)N
Reactant: C=CS(C)(=O)=O
Solvent: Cc1ccccc1
Product: CCn1nc(C#N)c(Br)c1CC(C)(C)NCCS(C)(=O)=O
Temperature: 25 °C
Yield: 48.3 %

Procedure:
A solution of 5-(2-amino-2-methylpropyl)-4-bromo-1-ethyl-1H-pyrazole-3-carbonitrile (4.1 g, 15.1 mmol) and methyl vinyl sulfone (3.2 g, 30.2 mmol) in toluene (30 mL) was heated at reflux for 15 hours, allowed to cool to room temperature, and concentrated under reduced pressure. The crude product was purified twice by column chromatography on silica gel (eluting first with 5% methanol in dichloromethane and secondly with ethyl acetate) to provide 2.75 g of 4-bromo-1-ethyl-5-(2-methyl-2-{[2-(methylsulfonyl)ethyl]amino}propyl)-1H-pyrazole-3-carbonitrile as a colorless oil.