Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[CH:7]=[O:8].[F:11][C:12]([F:21])([F:20])[C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>CN(C)C(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][C:16]2[CH:17]=[CH:18][C:13]([C:12]([F:11])([F:20])[F:21])=[CH:14][CH:15]=2)=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: O=Cc1cc(Br)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: O=Cc1cc(Br)ccc1Oc1ccc(C(F)(F)F)cc1
Yield: 65.1 %

Procedure:
In a manner similar to the method described in Example 50a, 5-bromo-2-fluorobenzaldehyde (2.1 g, 11 mmol) (Alfa) was reacted with 4-trifluoromethylphenol (1.9 g, 12 mmol)(Aldrich) and K2CO3 in N,N-dimethylacetamide to give 5-bromo-2-(4-trifluoromethyl-phenoxy)-benzaldehyde as a yellow solid (Yield 2.47 g, 68%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[CH3:18][C:19]([C:21]1[C:26]([NH2:27])=[CH:25][C:24]([O:28][CH3:29])=[C:23]([O:30][CH3:31])[CH:22]=1)=[O:20]>>[C:19]([C:21]1[CH:22]=[C:23]([O:30][CH3:31])[C:24]([O:28][CH3:29])=[CH:25][C:26]=1[NH:27][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1)(=[O:20])[CH3:18]
Reactant: COc1cc(N)c(C(C)=O)cc1OC
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Product: COc1cc(Nc2cc(C(F)(F)F)nc(-c3cccnc3)n2)c(C(C)=O)cc1OC

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 2-amino-4,5-dimethoxyacetophenone (56 mg, 0.290 mmol) similar to Example 117 and isolated as a tan solid (24 mg, 30%). 1H NMR (CDCl3): 12.49 (s, 1H), 9.65–9.64 (m, 1H), 8.86 (s, 1H), 8.74–8.70 (m, 2H), 7.45–7.41 (m, 1H), 7.35 (s, 1H), 6.99 (s, 1H), 4.12 (s, 3H), 3.95 (s, 3H), 2.68 (s, 3H).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(OC([NH:32][CH2:33][C:34]1([C:49]([OH:51])=O)[CH2:39][CH2:38][N:37]([C:40]2[C:41]3[CH:48]=[CH:47][NH:46][C:42]=3[N:43]=[CH:44][N:45]=2)[CH2:36][CH2:35]1)=O)(C)(C)C.C(N(CC)C(C)C)(C)C.[NH2:61][CH:62]([C:66]1[CH:71]=[CH:70][C:69]([Cl:72])=[CH:68][CH:67]=1)[CH2:63][CH2:64][OH:65].Cl>CN1C(=O)CCC1.O1CCOCC1>[NH2:32][CH2:33][C:34]1([C:49]([NH:61][CH:62]([C:66]2[CH:67]=[CH:68][C:69]([Cl:72])=[CH:70][CH:71]=2)[CH2:63][CH2:64][OH:65])=[O:51])[CH2:39][CH2:38][N:37]([C:40]2[C:41]3[CH:48]=[CH:47][NH:46][C:42]=3[N:43]=[CH:44][N:45]=2)[CH2:36][CH2:35]1
Reactant: NC(CCO)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)NCC1(C(=O)O)CCN(c2ncnc3[nH]ccc23)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: CN1CCCC1=O
Product: NCC1(C(=O)NC(CCO)c2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 79.4 %

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (106 mg, 0.28 mmol) was added to 4-((tert-butoxycarbonylamino)methyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (Intermediate 12) (100 mg, 0.27 mmol) and N,N-diisopropylethylamine (0.055 mL, 0.32 mmol) in NMP (5 mL) at 22° C. The resulting solution was stirred at 50° C. for 10 minutes then cooled to ambient temperature. 3-Amino-3-(4-chlorophenyl)propan-1-ol (Intermediate 29) (49.5 mg, 0.27 mmol) was added as a solution in NMP (2 mL) and the mixture was stirred at 22° C. for 16 hours. 4M HCl in dioxane (1 mL) was added and the mixture was stirred at 22° C. for a further 24 hours. The mixture was concentrated and the residue was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 30% (2M NH3 in MeOH) in DCM and pure fractions were evaporated to dryness to afford crude product. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford 4-(aminomethyl)-N-(1-(4-chlorophenyl)-3-hydroxypropyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (0.095 g, 81%) as a white solid.
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([CH3:12])=[CH:7][CH:8]=2)[NH:3]1.C([O:15][CH:16]=[C:17]([C:23](OCC)=O)[C:18]([O:20][CH2:21][CH3:22])=[O:19])C>>[CH3:1][CH:2]1[N:3]2[C:4]3[C:5](=[C:6]([CH3:12])[CH:7]=[CH:8][C:9]=3[CH2:10][CH2:11]1)[C:16](=[O:15])[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:23]2
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Cc1ccc2c(c1)NC(C)CC2
Product: CCOC(=O)c1cn2c3c(ccc(C)c3c1=O)CCC2C

Procedure:
Using the procedure of Example 25, 2,7-dimethyltetrahydroquinoline and diethyl ethoxymethylenemalonate are reacted to give solid ethyl 6,7-dihydro-5,10-dimethyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylate, m.p. 106-108° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:13]=[C:12]([CH3:21])[C:11]=2[CH:22]=[O:23])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[BH4-].[Na+].O>CO>[Cl:8][C:6]1[CH:5]=[C:4]([S:9][C:10]2[N:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:13]=[C:12]([CH3:21])[C:11]=2[CH2:22][OH:23])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: Cc1nn(-c2ccccc2)c(Sc2cc(Cl)cc(Cl)c2)c1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1nn(-c2ccccc2)c(Sc2cc(Cl)cc(Cl)c2)c1CO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.4 %

Procedure:
A mixture of 1.35 g of 5-(3,5-dichlorophenylthio)-3-methyl-1-phenyl-1H-pyrazole-4-carboxaldehyde and 0.84 g of sodium borohydride in 10 ml of methanol was stirred at room temperature for 30 minutes. Water (10 ml) was added and the mixture was extracted four times with 15 ml of diethyl ether. Combined extracts were dried over magnesium sulphate, filtered and evaporated to leave 670 mg of [5-(3,5-dichloro-phenylsulphanyl)-3-methyl-1-phenyl-1H-pyrazol-4-yl]-methanol as a grey paste which was used without further purification. Mass spectrum (ES) m/z 365 [M+H]+, 406 [M+H+CH3CN]+.
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][N:5]1[C:9]2[C:10]([C:14]([O:16][CH3:17])=[O:15])=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][S:6]1(=[O:19])=[O:18].O.FC(F)(F)C(O)=O>C(Cl)Cl>[O:2]=[CH:3][CH2:4][N:5]1[C:9]2[C:10]([C:14]([O:16][CH3:17])=[O:15])=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][S:6]1(=[O:18])=[O:19]
Reactant: COC(=O)c1cccc2c1N(CC(OC)OC)S(=O)(=O)N2
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cccc2c1N(CC=O)S(=O)(=O)N2
Yield: 148 %

Procedure:
The solution of methyl 3-(2,2-dimethoxyethyl)-1,3-dihydro-2,1,3-benzothiadiazole-4-carboxylate 2,2-dioxide (0.2 g, 0.5 mmol) from Step D above in methylene chloride (10 mL) with water (1 mL) and trifluoroacetic acid (0.5 mL) was stirred at room temperature for 3.5 h. The reaction mixture was concentrated under reduced pressure and dried overnight under high vacuum to remove the excess trifluoroacetic acid, providing methyl 3-(2-oxoethyl)-1,3-dihydro-2,1,3-benzothiadiazole-4-carboxylate 2,2-dioxide (0.2 g): 1H NMR (500 MHz, DMSO-d6) δ 9.56 (s, 1H), 7.42 (dd, J=7.5, 1.5 Hz, 1H), 7.19-6.99 (m, 2H), 4.71 (s, 2H), 3.78 (s, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=2)[C:11](O)=[O:12])=[CH:3][CH:2]=1.[NH3:17]>>[N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=2)[C:11]([NH2:17])=[O:12])=[CH:3][CH:2]=1
Reactant: N
Reactant: O=C(O)c1cccc(Nc2ccncc2)c1
Product: NC(=O)c1cccc(Nc2ccncc2)c1
Yield: 50 %

Procedure:
3-(4-Pyridinylamino)benzamide was prepared from 3-(4-pyridinylamino)benzoic acid and ammonia according to the procedure of Example 48, part (b), and was obtained in 50% yield as a colorless powder, m.p. 201°-203° C. when recrystallized from methanol.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2[CH:7]=[C:8]([OH:11])[CH:9]=[CH:10][C:4]=2[C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:29][CH2:30][O:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][O:33]1>CN(C)C=O>[CH3:1][C:2]1[S:6][C:5]2[CH:7]=[C:8]([O:11][CH2:29][CH2:30][O:31][CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][O:33]3)[CH:9]=[CH:10][C:4]=2[C:3]=1[C:12]1[CH:13]=[CH:14][C:15]([C:18]([F:21])([F:19])[F:20])=[CH:16][CH:17]=1
Reactant: BrCCOC1CCCCO1
Reactant: Cc1sc2cc(O)ccc2c1-c1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1sc2cc(OCCOC3CCCCO3)ccc2c1-c1ccc(C(F)(F)F)cc1
Temperature: 120 °C
Reaction time: 3 h
Yield: 101.5 %

Procedure:
4.0 g (13.0 mmol) 2-Methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-ol (example 26.5) dissolved in 30 ml N,N-dimethylformamide were treated with 2.69 g (19.5 mmol, 1.5 eq) K2CO3 and 3.06 ml (19.5 mmol, 1.5 eq) 2-(2-Bromo-ethoxy)-tetrahydro-pyran. The reaction mixture was stirred at 120° C. for 3 hours, cooled to room temperature, poured into 100 ml of ice-water and extracted 3 times with 50 ml of ether. The combined ether phases were washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue formed was filtered over silica gel with dichloromethane as the eluent giving 5.76 g crude 2-{2-[2-Methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yloxy]-ethoxy}-tetrahydro-pyran. This crude product was subsequently dissolved in 70 ml of 2N HCl in methanol and the reaction mixture stirred for 1 hour at room temperature. Subsequently, it was poured into a diluted sodium hydroxide/ice solution and extracted 3 times with 150 ml of dichloromethane. The combined dichloromethane phases were washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue formed was chromatographed on silica gel with dichloromethane as the eluent giving 4.3 g (93%) 2-[2-Methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yloxy]-ethanol as colorless solid, MS: 352 (M+).
Reaction SMILES: [C:1]([C:9]1[CH:38]=[C:37]([Br:39])[CH:36]=[CH:35][C:10]=1[C:11]([N:13]([CH2:25][CH:26]([OH:34])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=1)=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.O.Cl>CS(C)=O>[C:1]([C:9]1[CH:38]=[C:37]([Br:39])[CH:36]=[CH:35][C:10]=1[C:11]([N:13]([CH2:14][C:15]1[CH:16]=[CH:17][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:19][CH:20]=1)[CH2:25][C:26](=[O:34])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:12])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(CN(CC(O)Cc2ccccc2)C(=O)c2ccc(Br)cc2C(=O)c2ccccc2)cc1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: CS(=O)(=O)c1ccc(CN(CC(=O)Cc2ccccc2)C(=O)c2ccc(Br)cc2C(=O)c2ccccc2)cc1
Reaction time: 1 h
Yield: 72.2 %

Procedure:
[Step 2] To a solution (10 ml) of 2-benzoyl-4-bromo-N-(2-hydroxy-3-phenylpropyl)-N-(4-methanesulfonylbenzyl)benzamide (1.0 g) in DMSO was added triethylamine (2 ml), and pyridine sulfur trioxide complex (1.1 g) was added at room temperature. The mixture was stirred for 1 hr. and the reaction mixture was added to water. 10% Hydrochloric acid was added to acidify the aqueous layer, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium hydrogen carbonate, water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-hexane:ethyl acetate=1:2) to give 2-benzoyl-4-bromo-N-(4-methanesulfonylbenzyl)-N-(2-oxo-3-phenylpropyl)benzamide (0.72 g). [Step 3] To a solution (6 ml) of 2-benzoyl-4-bromo-N-(4-methanesulfonylbenzyl)-N-(2-oxo-3-phenylpropyl)benzamide (0.3 g) in ethanol was added 1,8-diazabicyclo[5.4.0]undeca-7-ene (0.15 g), and the mixture was stirred at 80° C. for 12 hrs. The reaction mixture was concentrated under reduced pressure, water and 10% hydrochloric acid were added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium hydrogen carbonate, water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel thin layer chromatography (hexane:ethyl acetate=2:1) and recrystallized (ethyl acetate-hexane) to give the title compound (4 mg).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[C:17]([C:18]2[N:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[CH:16][CH:15]=[C:14]([CH3:24])[N:13]=1)=[O:11].Br[C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][N:27]=1>>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([NH:1][CH2:2][C@@H:3]2[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]2[C:10]([C:12]2[C:17]([C:18]3[N:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[CH:16][CH:15]=[C:14]([CH3:24])[N:13]=2)=[O:11])=[N:27][CH:28]=1
Reactant: Clc1ccc(Br)nc1
Reactant: Cc1ccc(-c2ncccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)n1
Product: Cc1ccc(-c2ncccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(Cl)cn2)n1

Procedure:
The title compound was prepared following the same general protocol as described for Example A44 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl)methanone and 2-bromo-5-chloropyridine. ESI-MS (m/z): 437 [M+1]+.
Reaction SMILES: [Br:1][C:2]([Cl:13])([C:9]([F:12])([F:11])[F:10])[CH:3]([OH:8])[CH:4]=[C:5]([CH3:7])[CH3:6].[C:14](OC)([O:18][CH3:19])([O:16][CH3:17])[CH3:15].C(O)(=O)C(C)C>>[Br:1][C:2]([Cl:13])([C:9]([F:10])([F:11])[F:12])[CH:3]([O:8][C:14]([O:18][CH3:19])([O:16][CH3:17])[CH3:15])[CH:4]=[C:5]([CH3:7])[CH3:6]
Reactant: COC(C)(OC)OC
Reactant: CC(C)=CC(O)C(Cl)(Br)C(F)(F)F
Solvent: CC(C)C(=O)O
Product: COC(C)(OC)OC(C=C(C)C)C(Cl)(Br)C(F)(F)F
Temperature: 111 °C

Procedure:
5-Bromo-5-chloro-4-hydroxy-2-methyl-6,6,6-trifluorohex-2-ene (10.0 g), trimethyl orthoacetate (48.0 g) and isobutyric acid (0.29 g) were charged to a round-bottomed flask fitted with: nitrogen inlet/bubbler, thermometer and Dean and Stark received packed with 5A molecular seives. The mixture was heated with agitation to reflux and distillates collected until reaction mass temperature increased to 111° C. (ca. 1 hr). Once the reaction was complete, the residual trimethyl orthoacetate was removed by distillation under vacuum (ca. 50° C. @ 50 mmHg) to give the product, 5-bromo-5-chloro-4-(1,1-dimethoxyethoxy)-2-methyl-6,6,6-trifluorohex-2-ene, as an orange oil (10.9 g, 85% yield).
Reaction SMILES: C[O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[C:15]([CH2:16][OH:17])=[CH:14][N:13]=[CH:12]2)=[CH:6][CH:5]=1.C(O[K])(C)(C)C.Cl[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:29][CH:28]=1>C1COCC1.CN(C=O)C>[C:30]1([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:29]=[CH:28][C:27]([CH2:26][O:17][CH2:16][C:15]2[N:11]([CH2:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:2])=[O:18])=[CH:5][CH:6]=3)[CH:12]=[N:13][CH:14]=2)=[CH:32][CH:31]=1
Reactant: ClCc1ccc(-c2ccccc2)cc1
Reactant: COC(=O)c1ccc(Cn2cncc2CO)cc1
Agent: CC(C)(C)O[K]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(Cn2cncc2COCc2ccc(-c3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 11.4 %

Procedure:
To a solution of 4-(5-hydroxymethylimidazol-1-ylmethyl)benzoic acid methyl ester of Example A2 (0.11 g, 0.44 mmol) in THF (4 ml), DMF (1 ml) was added portionwise tBuOK (50 mg, 0.44 mmol). The reaction mixture was stirred at room temperature for 1.5 h, then 4-chloromethylbiphenyl (90 mg, 0.44 mmol) in THF (1 ml) was added and the reaction was stirred overnight. The solvent was removed under reduced pressure, then water (10 ml) was added and the mixture was extracted with AcOEt. The organic phase was dried over MgSO4 and the resulting oil was purified by flash chromatography on silica gel (CH2Cl2/MeOH: 95/05) to give a yellow solid (20 mg).
Reaction SMILES: Cl[C:2]1[N:13]=[CH:12][CH:11]=[CH:10][C:3]=1[C:4]([NH:6][CH2:7][C:8]#[CH:9])=[O:5].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:20]=[C:21]([O:25][CH3:26])[C:22]=1[O:23][CH3:24])[NH2:19]>C(O)CO>[CH2:7]([NH:6][C:4](=[O:5])[C:3]1[CH:10]=[CH:11][CH:12]=[N:13][C:2]=1[NH:19][C:18]1[CH:20]=[C:21]([O:25][CH3:26])[C:22]([O:23][CH3:24])=[C:16]([O:15][CH3:14])[CH:17]=1)[C:8]#[CH:9]
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: C#CCNC(=O)c1cccnc1Cl
Solvent: OCCO
Product: C#CCNC(=O)c1cccnc1Nc1cc(OC)c(OC)c(OC)c1
Temperature: 140 °C

Procedure:
Compound 8 (194 mg, 1 mmol) and 3,4,5-trimethoxyaniline (9j, 183 mg, 1 mmol) were taken in ethylene glycol and heated at 140° C. for 6 h. Then the reaction mixture was cooled and extracted with ethyl acetate from the aqueous layer and concentrated in vacuum. The compound was further purified by column chromatography using 60-120 silica gel to obtain N-(prop-2-ynyl)-2-(3,4,5-trimethoxyphenylamino)nicotinamide 10j as pure product. To a solution of N-(prop-2-ynyl)-2-(3,4,5-trimethoxyphenylamino)nicotinamide (10j, 150 mg, 0.41 mmol) and 1-(azidomethyl)-3-phenoxybenzene (12a, 102 mg, 0.45 mmol), in 2:1 mixture of water and tert-butyl alcohol, sodium ascorbate (0.06 mmol) and copper (II) sulphate (0.004 mmol) were added sequentially. The reaction was stirred at room temperature for 10 h, TLC analysis indicated completion of reaction. The reaction mixture was concentrated under vacuum and extracted with EtOAc to give crude product. The crude was purified by column chromatography to afford pure product 1j (186 mg, 75%); mp: 142-144° C.; 1H NMR (300 MHz, CDCl3) δ 10.42 (s, 1H), 8.27 (d, J=7.5, Hz, 1H), 7.85 (d, J=7.5 Hz 2H), 7.75 (brs, 1H), 7.60 (s, 1H), 7.39-7.27 (m, 3H), 7.11 (t, J=7.5 Hz, 1H), 6.99-6.83 (m, 7H), 6.65 (m, 1H), 5.47 (s, 2H), 4.66 (d, J=5.28 Hz, 2H), 3.85 (s, 6H), 3.81 ppm (s, 3H); MS (ESI m/z): 567 [M+H]+. Yield: 75%
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH:9]2[CH2:13][CH2:12][O:11][CH2:10]2)[C:5]([Cl:14])=[CH:4][N:3]=1.[NH3:15]>>[Cl:14][C:5]1[C:6]([O:8][CH:9]2[CH2:13][CH2:12][O:11][CH2:10]2)=[N:7][C:2]([NH2:15])=[N:3][CH:4]=1
Reactant: N
Reactant: Clc1ncc(Cl)c(OC2CCOC2)n1
Product: Nc1ncc(Cl)c(OC2CCOC2)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 2,5-dichloro-4-((tetrahydrofuran-3-yl)oxy)pyrimidine (intermediate 31,100 mg, 0.425 mmol) in NH3 (7 M in MeOH, 608 μl, 4.25 mmol) was heated to 70° C. and stirred for 16 h. The reaction mixture was cooled to room temperature and concentrated. The crude material was purified by normal phase chromatography (4 g silica gel cartridge, heptanes/EtOAc 100:0 to 0:100) to give the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.04 (s, 1H), 6.78 (br. s, 2H), 5.47-5.54 (m, 1H), 3.72-3.94 (m, 4H), 2.18-2.29 (m, 1H), 1.95-2.04 (m, 1H).
Reaction SMILES: [C:1]1([CH:7]([CH3:11])[C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:12]O>OS(O)(=O)=O>[C:1]1([CH:7]([CH3:11])[C:8]([O:10][CH3:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CO
Reactant: CC(C(=O)O)c1ccccc1
Agent: O=S(=O)(O)O
Product: COC(=O)C(C)c1ccccc1
Temperature: 25 °C

Procedure:
2-Phenylpropionic acid (8.4 g, 56 mmol) in methanol (180 ml) and concentrated H2SO4 (2 ml) were heated at reflux for 4 hours. The reaction was cooled down to room temperature and concentrated in vacuo (~30 ml), which was poured into ice water (~100 ml). The products were extracted with Et2O (150 ml×3), which was washed with saturated NaHCO3, H2O and dried over MgSO4. Filtration and evaporation of solvent yielded a yellow oil (8.9 g), which was distilled to give a colorless oil (8.34 g, 51 mmol, 91%, b.p. 73° C./1.5 mm Hg).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH2:8][CH:9]([C:10]#N)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[OH-:12].[K+].[OH2:14]>CCO>[Cl:1][C:2]1[C:7]2[CH2:8][CH:9]([C:10]([OH:14])=[O:12])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O
Reactant: N#CC1Cc2c(Cl)cccc21
Reactant: [OH-]
Agent: [K+]
Solvent: CCO
Product: O=C(O)C1Cc2c(Cl)cccc21
Yield: 85 %

Procedure:
A solution of 3-chloro-1,2-dihydrocyclobutabenzene-1-carbonitrile (196 mmol, 32 g) and potassium hydroxide (978 mmol, 54.9 g) in EtOH (500 ml)/water (100 ml) was stirred at reflux for 2 h. After evaporation of the organic solvent, the aqueous residue was washed with Et2O. The organic layer was extracted with 2N NaOH aq. and combined aqueous layers were acidified with 5 N HCl and extracted with Et2O. The extracts were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was washed with heptane/Et2O (5/1) to afford 3-chloro-1,2-dihydrocyclobutabenzene-1-carboxylic acid (85% yield, 30.3 g).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:39][CH3:40])=[C:17]([O:20][CH2:21][CH2:22][CH2:23][N:24]4[CH2:28][CH:27]5[CH2:29][N:30](C(OC(C)(C)C)=O)[CH2:31][CH:26]5[CH2:25]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1)#[CH:2].Cl>C(Cl)Cl.CCOC(C)=O>[C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:39][CH3:40])=[C:17]([O:20][CH2:21][CH2:22][CH2:23][N:24]4[CH2:25][CH:26]5[CH:27]([CH2:29][NH:30][CH2:31]5)[CH2:28]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1)#[CH:2]
Reactant: C#Cc1cccc(Nc2ncnc3cc(OC)c(OCCCN4CC5CN(C(=O)OC(C)(C)C)CC5C4)cc23)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C#Cc1cccc(Nc2ncnc3cc(OC)c(OCCCN4CC5CNCC5C4)cc23)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 91.4 %

Procedure:
To a solution of tert-butyl 5-(3-((4-((3-ethynylphenyl)amino)-7-methoxyquinazolin-6-yl)oxy) propyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (1.22 g) in DCM (30 mL) was added a solution of HCl in EtOAc at room temperature. The reaction mixture was stirred for 6 h at room temperature and filtered to give crude product. The crude product was recrystallized from a mixture of MeOH and EA to give the title compound as a white solid (0.91 g, 90.50%), HPLC: 94.65%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 444.2 (M+1); 1H NMR (400 MHz, CDCl3) δ: 1.84-1.89 (m, 4H), 2.38-2.44 (m, 6H), 2.69-2.76 (m, 4H), 3.95 (s, 3H), 4.03 (s, 1H), 4.14 (t, J=7.2 Hz, 2H), 7.13 (s, 1H), 7.25 (s, 1H), 7.43 (s, 1H), 7.55-7.60 (m, 1H), 7.90-7.93 (m, 1H), 8.68 (s, 1H) ppm.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[C:20]3[CH2:19][CH2:18][CH2:17][C:16](=[O:21])[C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][C:13]=3[C:22]([O:24][CH3:25])=[O:23])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].C1(S(OC)=O)C=CC=CC=1>O1CCOCC1.C(O)(=O)C.C(OCC)(=O)C>[C:1]1([CH2:7][N:8]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([OH:21])[C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][C:13]=3[C:22]([O:24][CH3:25])=[O:23])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1cccc2c1c1c(n2Cc2ccccc2)CCCC1=O
Agent: COS(=O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: COC(=O)c1cccc2c1c1c(O)cccc1n2Cc1ccccc1
Reaction time: 0.13 h
Yield: 81 %

Procedure:
To a solution of the 9-[(phenyl)methyl]-5-carbomethoxy-1,2-dihydrocarbazol-4(3H)-one (2.87 g, 8.61 mM) in 29 ml dioxane was added 60% sodium hydride in mineral oil (0.79 g, 19.8 mM). The reaction was stirred 8 minutes, then methyl benzenesulfinate (1.80 ml, 13.8 mM) was added. The reaction was stirred an additional 1.5 hours, then diluted with 43 ml dioxane and 1.13 ml acetic acid. The mixture was refluxed 1 hour, diluted with ethyl acetate, and extracted with saturated NaHCO3 two times, then with brine. After drying (NaSO4), evaporation in vacuo afforded 4.90 g. The mixture was purified by column chromatography on silica gel (elution with toluene/methylene chloride) to afford 2.31 g (81%) of the 9-[(phenyl)methyl]-4-hydroxy-5-carbomethoxy carbazole. 1H NMR (DMSO-d6) δ 10.25 (s, 1H), 7.7 (d, 1H, J=8 Hz), 7.4 (t, 1H, J=8 Hz), 7.4-7.0 (m, 8H), 6.6 (d, 1H, J=8 Hz), 5.6 (s, 2H), and 3.8 (s, 3H). IR (CHCl3, cm−1) 1723, 1685, 1621, 1597, 1568, 1496, 1453, 1442, 1392, 1286, 1267, 1156, and 1138. MS (ES) m/e 330, 332.