Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C@H:16]([OH:25])[CH2:17][CH2:18][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C(O)(=O)C1C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[C:66]([OH:71])(=[O:70])[C:67]([OH:69])=[O:68]>CCOCC>[C:66]([OH:71])(=[O:70])[C:67]([OH:69])=[O:68].[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][C@@H:16]([OH:25])[CH2:17][CH2:18][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)=[CH:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O[C@@H](CCc1ccc(-c2cccc(Cl)c2)cc1)CCc1cccnc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: O=C(O)C(=O)O
Agent: O=C(O)c1ccccc1
Solvent: CCOCC
Product: O[C@H](CCc1ccc(-c2cccc(Cl)c2)cc1)CCc1cccnc1
Reaction time: 2 h

Procedure:
Prepared according to the method described in Example 27 from (3S)-1-(3'-chlorobiphenyl-4-yl)-5-(3-pyridyl)-3-pentanol (0.137 g, Example 86), benzoic acid (0.061 g), triphenylphosphine (0.131 g) and diethyl azodicarboxylate (0.061 ml). The mixture was concentrated under reduced pressure and the residue redissolved in methanol (8 ml) and water (2 ml). Solid sodium hydroxide (0.2 g) was added and the reaction stirred for 2 hours before being poured into a solution of saturated aqueous sodium hydrogen carbonate. The mixture was extracted with ethyl acetate, the combined organic extracts dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give an oil which was converted to the oxalate salt upon treatment with oxalic acid in ether (excess) to give the title compound as a solid (0.033 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:9][C@@H:10]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:11]([OH:13])=O)=[CH:4][CH:3]=1.CN(C(O[N:32]1N=[N:39][C:34]2C=CC=N[C:33]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.Cl.NCC#N.C(=O)(O)[O-].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[O:9][C@@H:10]([CH2:14][CH:15]([CH3:16])[CH3:17])[C:11]([NH:39][CH2:34][C:33]#[N:32])=[O:13])=[CH:6][CH:7]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)C[C@H](O[C@H](c1ccccc1)c1ccc(Br)cc1)C(=O)O
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: N#CCN
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)C[C@H](O[C@H](c1ccccc1)c1ccc(Br)cc1)C(=O)NCC#N
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(2S)-2-{[(R)-(4-bromophenyl)(phenyl)methyl]oxy}-4-methylpentanoic acid (46.5 g, 123 mmol) was dissolved in DMF (200 mL). To this mixture was added HATU (56.7 g, 149 mmol, 1.2 eg), Et3N (57.7 g, 570 mmol, 4.6 eg), then added at 0° C. aminoacetonitrile hydrochloride (13.5 g, 146 mmol, 1.19 eg). The resulting reaction mixture was stirred at room temperature for 3 hours; then poured into 1 L of half saturated sodium bicarbonate. The aqueous phase was extracted with EtOAc (2×500 mL). Organic fraction was washed with brine (200 mL), IN HCl (200 mL), brine (200 mL), 0.5 N NaOH (300 mL), brine (200 mL). Solvent was evaporated under reduced pressure and the resulting dark red oil which was chromatographed with 20% EA/hexane to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20])[C:4]=1[CH2:21]/[CH:22]=[C:23](\[CH3:26])/[CH2:24]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:46]N1C(=O)CCC1=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20])[C:4]=1[CH2:21]/[CH:22]=[C:23](\[CH3:26])/[CH2:24][Br:46]
Reactant: O=C1CCC(=O)N1Br
Reactant: COCCOCOc1c(C/C=C(\C)CO)c(OC)c(C)c2c1C(=O)OC2
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COCCOCOc1c(C/C=C(\C)CBr)c(OC)c(C)c2c1C(=O)OC2

Procedure:
To a solution of (E)-4-(1,3-dihydro-6-methoxy-4-methoxyethoxymethoxy-7-methyl-3-oxoisobenzofuran-5-yl)-2-methylbut-2-en-1-ol (4.6 g) in methylene chloride (100 ml) at 0° C. was added triphenylphosphine (3.64 g) then N-bromosuccinimide (2.48 g). After 15 minutes the solution was washed with 10% aqueous sodium bisulphite, water, aqueous sodium bicarbonate, then dried and evaporated. The residue was chromatographed on silica gel, eluting with 4:1 hexane: ethyl acetate, to give (E)-4-(1,3-dihydro-6-methoxy-4-methoxyethoxymethoxy-7-methyl-3-oxoisobenzofuran-5-yl) -2-methylbut-2-enyl bromide, mp 74°-75° C. (hexane).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH:13][C@H:14]1[C:18]2[N:19]=[CH:20][N:21]=[C:22]([N:23]3[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]3)[C:17]=2[C@H:16]([CH3:36])[CH2:15]1.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:36][C@H:16]1[C:17]2[C:22]([N:23]3[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]3)=[N:21][CH:20]=[N:19][C:18]=2[C@H:14]([O:13][C:8](=[O:9])[C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)[CH2:15]1
Reactant: C[C@@H]1C[C@@H](O)c2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H]1C[C@@H](OC(=O)c2ccc([N+](=O)[O-])cc2)c2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.6 %

Procedure:
4-Nitrobenzoyl chloride (4.27 g, 23.0 mmol) was added to a 0° C. solution of tert-butyl 4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (7.0 g, 20.9 mmol) and triethylamine (4.38 mL, 31.4 mmol) in DCM (110 mL). The reaction mixture was stirred at room temperature overnight, after which saturated NaHCO3 was added. The mixture was stirred 10 minutes, and then extracted with DCM. The combined extracts were dried (Na2SO4), filtered, and concentrated. The crude was flashed on Biotage 65M (3:1 hexanes:ethyl acetate loaded crude, then 2:1 hexanes:ethyl acetate eluted tert-butyl 4-((5R,7R)-5-methyl-7-(4-nitrobenzoyloxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate and a few mixed fractions). Then tert-butyl 4-((5R,7S)-5-methyl-7-(4-nitrobenzoyloxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate was eluted using 1:2 hexanes:ethyl acetate. The fractions with product were concentrated by rotary evaporation to give tert-butyl 4-((5R,7R)-5-methyl-7-(4-nitrobenzoyloxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (8.55 g, 84.5% yield) as a foam. LC/MS (APCI+) m/z 484 [M+H]+. 1H NMR (CDCl3) shows single diastereomer). The fractions with other diastereomer were concentrated by rotary evaporation to give tert-butyl 4-((5R,7S)-5-methyl-7-(4-nitrobenzoyloxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (0.356 g, 3.52% yield) as a foam. LC/MS (APCI+) m/z 484 [M+H]+.
Reaction SMILES: ClC1C(C(OO)=[O:9])=CC=CC=1.[CH2:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:13]=[CH2:14]>C(Cl)Cl.CCOCC>[CH2:12]([CH:13]1[O:9][CH2:14]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(OO)c1ccccc1Cl
Reactant: C=CCc1ccccc1
Solvent: ClCCl
Solvent: CCOCC
Product: c1ccc(CC2CO2)cc1
Reaction time: 5 h
Yield: 74.5 %

Procedure:
A solution of m chloroperbenzoic acid (mCPBA; 17 g, 0.1 mol) in 120 mL of methylene chloride was added (at ambient temperature) dropwise to a solution of allyl benzene (10 g, 85 mmol) in 200 mL of methylene chloride. After the reaction mixture was stirred for 5 h with a mechanical stirrer, 5 additional qrams of m CPBA were added and the reaction mixture stirred for another 2 h. The reaction mixture was then diluted with 200 mL of ether, washed with 2×100 mL of aqueous sodium bisulfite solution, 1×100 mL of aqueous sodium bicarbonate solution and 1×100 mL of brine. The organic solution was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by bulb-to-bulb distillation (60° C., 0.1 mm) to give 8.5 g (77% yield) of 1-benzyl ethylene oxide as a clear colorless liquid.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].Cl.CN(C)CCCN=C=NCC.[C:24](O)([CH3:27])([CH3:26])[CH3:25]>CN(C)C1C=CN=CC=1.ClCCl.C(OCC)(=O)C>[C:24]([O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([I:1])[CH:3]=[CH:4][C:5]=1[CH3:11])([CH3:27])([CH3:26])[CH3:25]
Reactant: Cc1ccc(I)cc1C(=O)O
Reactant: CC(C)(C)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1ccc(I)cc1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
A mixture of 5-iodo-2-methylbenzoic acid (760 mg, 2.9 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (670 mg, 3.5 mmol), 4-dimethylaminopyridine (425 mg, 3.5 mmol), and t-butanol (1.07 g, 14.5 mmol) in dichloromethane (10 ml) was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (25 ml) and washed with 5% NaHCO3, 1M HCl, water and, brine. The organic phase was dried and evaporated to give a pale yellow solid 600 mg 65%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][CH2:8][C:9]1[CH:24]=[CH:23][C:12]2[N:13]([CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])[C:14]([CH2:16]O)=[N:15][C:11]=2[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].S(Cl)([Cl:28])=O>C(Cl)Cl>[C:1]([O:5][C:6](=[O:25])[NH:7][CH2:8][C:9]1[CH:24]=[CH:23][C:12]2[N:13]([CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])[C:14]([CH2:16][Cl:28])=[N:15][C:11]=2[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(C)CCn1c(CO)nc2cc(CNC(=O)OC(C)(C)C)ccc21
Solvent: ClCCl
Product: CC(C)CCn1c(CCl)nc2cc(CNC(=O)OC(C)(C)C)ccc21
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a cooled (0° C.) solution of [2-hydroxymethyl-1-(3-methyl-butyl)-1H-benzoimidazol-5-ylmethyl]-carbamic acid tert-butyl ester (146 mg, 0.42 mmol) in DCM (5 mL) was added thionyl chloride (46 μL, 0.63 mmol). The solution was stirred at 0° C. for 15 min. and concentrated in vacuo to give [2-chloromethyl-1-(3-methyl-butyl)-1H-benzoimidazol-5-ylmethyl]-carbamic acid tert-butyl ester; HCl salt (176 mg, 100%) as a white solid, which was used without further purification.
Reaction SMILES: [CH2:1]1[CH:8]2[N:4]([C:5](=[O:9])[CH2:6][CH2:7]2)[C:3](=[O:10])[CH2:2]1.Cl.[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16][OH:17]>C(OCC)C>[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16][O:17][C:5](=[O:9])[CH2:6][CH2:7][CH:8]1[CH2:1][CH2:2][C:3](=[O:10])[NH:4]1
Reactant: O=C1CCC2CCC(=O)N12
Reactant: OCc1cccc(Cl)c1
Agent: Cl
Solvent: CCOCC
Product: O=C1CCC(CCC(=O)OCc2cccc(Cl)c2)N1
Temperature: 100 °C

Procedure:
Two hundred and eighty eight milligrams of dihydro-1H-pyrrolizine-3,5(2H,6H)-dione (III) are dissolved in 600 mg of m-chlorobenzyl alcohol and 0.2 ml of concentrated hydrochloric acid is added. The solution is heated at 100° C. for 40 hours. The mixture is cooled and is dissolved in 50 ml of anhydrous diethylether. The filtrate is cooled to induce crystallization and the resulting crystals are isolated by filtration. Recrystallization from toluene-petroleum ether yields 5-oxo-2-pyrrolidinepropanic acid m-chlorobenzyl ester with a melting point of 90°-91° C.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH2:12][NH:13][C:14]([C:16]1[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[O:18][C:17]=1[CH2:25][CH2:26][CH2:27][CH3:28])=[O:15])[CH:6]=[CH:5]2.Br[CH2:37][C:38]#[N:39].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[C:38]([CH2:37][O:1][C:2]1[C:3]([C:29]2[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH2:12][NH:13][C:14]([C:16]1[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[O:18][C:17]=1[CH2:25][CH2:26][CH2:27][CH3:28])=[O:15])[CH:6]=[CH:5]2)#[N:39]
Reactant: N#CCBr
Reactant: CCCCc1oc2ccccc2c1C(=O)NCc1ccc2c(-c3ccc(C)cc3)c(O)ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCc1oc2ccccc2c1C(=O)NCc1ccc2c(-c3ccc(C)cc3)c(OCC#N)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.1 %

Procedure:
A mixture of 2-butyl-benzofuran-3-carboxylic acid (6-hydroxy-5-p-tolyl-naphthalen-2-ylmethyl)-amide (252 mg, 0.54 mmol), prepared in the previous step, bromoacetonitrile (55 μL, 0.81 mmol) and potassium carbonate (378 mg, 2.73 mmol) in 15 mL of DMF was stirred under nitrogen at room temperature for 19 h (overnight). The reaction was diluted with ethyl acetate, extracted multiple times with water, dried (MgSO4) and the solvent removed under reduced presure to give 2-butyl-benzofuran-3-carboxylic acid (6-cyanomethoxy-5-p-tolyl-naphthalen-2-ylmethyl)-amide (269 mg, 99%) as a light brown solid, mp 114-117° C.
Reaction SMILES: N1C=CC=CC=1.[CH3:7][O:8][CH2:9][O:10][C:11]1[CH:12]=[C:13]([CH2:30][OH:31])[CH:14]=[C:15]([O:26][CH2:27][O:28][CH3:29])[C:16]=1[CH2:17]/[CH:18]=[CH:19]/[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)Cl>[CH3:29][O:28][CH2:27][O:26][C:15]1[CH:14]=[C:13]([CH:12]=[C:11]([O:10][CH2:9][O:8][CH3:7])[C:16]=1[CH2:17]/[CH:18]=[CH:19]/[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH:30]=[O:31]
Reactant: COCOc1cc(CO)cc(OCOC)c1C/C=C/c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COCOc1cc(C=O)cc(OCOC)c1C/C=C/c1ccccc1
Reaction time: 0.17 h
Yield: 101.1 %

Procedure:
To a solution of pyridine (62 g, 0.78 mol) in CH2Cl2 (500 mL) were added CrO3 (39 g, 0.39 mol) and Silica gel (40 g) in several portions at 0° C. After stirring for 10 min, [3,5-bis-methoxymethoxy-4-((E)-3-phenyl-allyl)-phenyl]-methanol (220e) (45 g, 0.13 mol) was added in one portion. The mixture was stirred at room temperature overnight. TLC (EtOAc/petroleum ether=1/2) indicated that the reaction was complete. The reaction mixture was filtered and the filter cake was washed with Et2O. The combined filtrates were concentrated. The residue was suspended in Et2O and filtered again. The filtrate was concentrated under vacuum to give the crude title compound (45 g, 100% yield) as a yellow oil, which was used directly in the next step without further purification. 1H NMR (400 MHz, CDCl3): δ 9.89 (s, 1H), 7.16-7.41 (m, 5H), 6.25˜6.44 (m, 2H), 5.36 (s, 4H), 3.66 (d, 2H), 3.47 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([C:15]([OH:17])=O)[CH2:6][C:5]2=1.C1N=C[N:20](C(N2C=NC=C2)=O)C=1>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([C:15]([NH2:20])=[O:17])[CH2:6][C:5]2=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)C1CCc2[nH]c3ccc(Cl)cc3c2C1
Solvent: C1CCOC1
Product: NC(=O)C1CCc2[nH]c3ccc(Cl)cc3c2C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid (7c, 5.67 g, 22.71 mmole) dissolved THF (70 ml). N,N-carbonyldiimidazole (5.52 g, 44.81 mmole) was added. The reaction was stirred at ambient temperature for 3 hours. Ammonia was bubbled in for 1½ hours. The solid was filtered and discarded. Ethyl acetate (50 ml) was added to the filtrate and washed with citric acid 2 times, then the ethyl acetate phase was washed with 5% sodium bicarbonate and brine. The organic phase was concentrated in vacuo. The product was crystallized from the solution and filtered yielding a white solid, 4.39 g, 78%; mp. 247-248° C.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH:9][C:10]2[N:15]=[C:14]3[N:16](COCC[Si](C)(C)C)[N:17]=[C:18]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([NH:25][CH2:26][C:27]5[CH:31]=[CH:30][S:29][CH:28]=5)[CH:20]=4)[C:13]3=[CH:12][N:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>ClCCl>[N:1]1([CH2:7][CH2:8][NH:9][C:10]2[N:15]=[C:14]3[NH:16][N:17]=[C:18]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([NH:25][CH2:26][C:27]5[CH:31]=[CH:30][S:29][CH:28]=5)[CH:20]=4)[C:13]3=[CH:12][N:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)CCOCn1nc(-c2cccc(NCc3ccsc3)c2)c2cnc(NCCN3CCOCC3)nc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1cc(NCc2ccsc2)cc(-c2n[nH]c3nc(NCCN4CCOCC4)ncc23)c1
Reaction time: 2 h

Procedure:
To the stirred solution of (2-morpholin-4-yl-ethyl)-[3-{3-[(thiophen-3-ylmethyl)-amino]-phenyl}-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-amine (150 mg, 0.265 mmol) in dichloromethane (3 mL) was added TFA (3 mL) at room temperature. The resulting mixture was stirred for another two hours at this temperature. The solvent was then evaporated under reduced pressure and the pH of the residue was adjusted to 8 with saturated NaHCO3. The resulting mixture was extracted with EtOAc (10 mL). The organic layer was dried and concentrated. It was purified by prep-HPLC to give (2-morpholin-4-yl-ethyl)-(3-{3-[(thiophen-3-ylmethyl)-amino]-phenyl}-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-amine. (Yield 70 mg, 61%).
Reaction SMILES: C[O-].[Na+].[N:4]([CH2:7][C:8]([O:10][CH2:11]C)=[O:9])=[N+]=[N-].[F:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[C:16]([O:22][CH3:23])[CH:15]=1>CO>[CH3:11][O:10][C:8]([C:7]1[NH:4][C:20]2[C:17]([CH:18]=1)=[C:16]([O:22][CH3:23])[CH:15]=[C:14]([F:13])[CH:21]=2)=[O:9]
Reactant: COc1cc(F)ccc1C=O
Reactant: CCOC(=O)CN=[N+]=[N-]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc2c(OC)cc(F)cc2[nH]1
Temperature: -20 °C
Reaction time: 3.5 h

Procedure:
Sodium methoxide solution (25% by weight in methanol, 22.25 mL) and methanol (52 mL) were added to a flask and cooled to −20° C. using an acetonitrile/dry ice bath. Ethyl 2-azidoacetate (25% by weight in ethanol, 50.3 g) and 4-fluoro-2-methoxybenzaldehyde (5.00 g, dissolved in ethyl 2-azidoacetate solution) were added drop-wise to the stirring sodium methoxide solution at −20° C. The solution was then stirred at −20° C. for 3.5 hours, then at 0° C. for one hour. The solution was poured over ice, vacuum filtered, and washed with water. The filtered solid was taken up in xylenes (100 mL), washed twice with brine, and dried using anhydrous sodium sulfate and filtered. In a separate flask xylenes (50 mL) was brought to reflux. The xylene solution containing the filtered material was added drop-wise to the refluxing xylenes. The solution was then refluxed for five hours, cooled, and placed in a freezer for 16 hours. The precipitate was filtered out. The volume of the filtrate was reduced on vacuum to generate a second crop of precipitate, which was washed with hexanes, then 5% ethyl acetate in hexanes and combined with material from the first filtration.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3](=[O:11])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Br:14]Br>C(OCC)C>[Br:14][CH:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:3](=[O:11])[C:2]([F:12])([F:13])[F:1]
Reactant: O=C(Cc1ccccc1)C(F)(F)F
Reactant: BrBr
Solvent: CCOCC
Product: O=C(C(Br)c1ccccc1)C(F)(F)F
Temperature: 0 °C
Reaction time: 18 h

Procedure:
1,1,1-trifluoro-3-phenylpropanone (0.50 mL, 3.2 mmol) was dissolved in 5 mL of diethyl ether and the mixture was cooled to 0° C. Bromine (0.16 mL, 3.2 mmoL) was added and the mixture was stirred for 18 h and allowed to warm to rt. The solvent was removed to provide a 2:1 mixture of Example A176a as a starting material which was used in the subsequent reaction without further purification.
Reaction SMILES: [O:1]1[CH:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:2]1.[CH3:14][C:15]([NH2:26])([CH3:25])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1>>[OH:1][CH:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:2][NH:26][C:15]([CH3:25])([CH3:14])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1
Reactant: COc1ccc(CC(C)(C)N)cc1
Reactant: CCCCCCCCCCC1CO1
Product: CCCCCCCCCCC(O)CNC(C)(C)Cc1ccc(OC)cc1
Yield: 18.7 %

Procedure:
Using the method of Example 5, supra, 1,2-epoxydodecane (240 μL, 1.0 mmol) and 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine (197 mg, 1.1 mmol) were used to prepare 68 mg of the title compound as a clear, colorless oil: GC/EI-MS, m/z (rel. int.) 363 (M+1, 0.2), 348 (2), 242 (100), 224 (8), 163 (7), 121 (20); 1H-NMR (CDCl3) δ7.08 (2H, d, J=8.4), 6.83 (2H, d, J=8.4), 3.79 (3H, s), 3.50 (1H, m), 2.78 (1H, dd, J=11.8 and 3.1), 2.66 (2H, s), 2.41 (1H, dd, J=11.5 and 9.3), 1.26 (18H, m), 1.07 (6H, s), 0.88 (3H, t, J=6.5); 13C-NMR (CDCl3) δ158.2, 131.4, 129.9, 113.4, 76.9, 70.0, 55.2, 53.6, 47.8, 46.6, 35.1, 31.9, 29.7, 29.6, 29.3, 26.7, 26.5, 25.7, 22.7, 14.1; FT-IR (film) cm−1 3386, 1612, 1512, 1246, 1039, 824.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[NH:5]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:15]3[C:16]4[S:23][C:22]([C:24]5[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=5)=[CH:21][C:17]=4[N:18]=[CH:19][N:20]=3)=[CH:11][CH:12]=2)[CH:7]=[CH:6]1>>[CH:1]1([NH:4][CH2:28][C:27]2[CH:26]=[CH:25][C:24]([C:22]3[S:23][C:16]4[C:15]([NH:14][C:10]5[CH:9]=[C:8]6[C:13](=[CH:12][CH:11]=5)[NH:5][CH:6]=[CH:7]6)=[N:20][CH:19]=[N:18][C:17]=4[CH:21]=3)=[CH:31][CH:30]=2)[CH2:3][CH2:2]1
Reactant: O=Cc1ccc(-c2cc3ncnc(Nc4ccc5[nH]ccc5c4)c3s2)cc1
Reactant: NC1CC1
Product: c1nc(Nc2ccc3[nH]ccc3c2)c2sc(-c3ccc(CNC4CC4)cc3)cc2n1

Procedure:
The title compound was prepared from cyclopropylamine and 4-[4-(1H-indol-5-ylamino)-thieno[3,2-d]pyrimidin-6-yl]-benzaldehyde by a procedure analogous to example 17. M.P. 176-180° C.; LC-MS: 412 (MH+); HPLC RT: 4.10 minutes.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]2[NH:8][C:7]3[C:12]4[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=4[O:14][C:6]=3[C:5]=2[CH:4]=1.Cl.Cl[CH2:21][C:22]1[CH:35]=[CH:34][C:25]([O:26][CH2:27][CH2:28][N:29]([CH2:32][CH3:33])[CH2:30][CH3:31])=[CH:24][CH:23]=1>>[CH2:32]([N:29]([CH2:30][CH3:31])[CH2:28][CH2:27][O:26][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][N:8]2[C:9]3[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[C:6]3[O:14][C:13]4[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=4[C:7]2=3)=[CH:35][CH:34]=1)[CH3:33]
Reactant: CCN(CC)CCOc1ccc(CCl)cc1
Reactant: COc1ccc2[nH]c3c4ccccc4oc3c2c1
Agent: Cl
Product: CCN(CC)CCOc1ccc(Cn2c3ccc(OC)cc3c3oc4ccccc4c32)cc1

Procedure:
Following the procedure described in Example 102, using 3-methoxy-10H-benzo[4,5]furo[3,2-b]indole (405 mg, 1.517 mmol) and [2-(4-chloromethyl-phenoxy)-ethyl]-diethyl-amine hydrochloride salt as a starting material, the title compound was prepared as a brown solid.