Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[O:3][CH:4](OOC)[CH2:5][Br:6].C1(C)C=CC(S(O)(=O)=O)=CC=1.O[C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH2:28])=S)=CC=1>C(O)C>[Br:6][CH2:5][C@@H:4]([C:30]1[CH:22]=[N:28][CH:26]=[CH:25][CH:29]=1)[OH:3]
Reactant: NC(=S)c1ccc(O)cc1
Reactant: COOC(CBr)OOC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: O[C@@H](CBr)c1cccnc1
Yield: 53.8 %

Procedure:
In a round-bottomed flask, bromoacetaldehyde dimethoxyacetal (123 μl, 1.04 mmol), p-toluenesulfonic acid (199 mg, 1.04 mmol), and 4-hydroxy-thiobenzamide (160 mg, 1.04 mmol) were dissolved in ethanol (10 ml) and the resulting solution was heated to reflux for about twenty-four hours. The reaction mixture was then concentrated to an oil which was redissolved in ethyl acetate, and extracted with saturated aqueous sodium carbonate. The combined organic extracts were then washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to an oil. The crude product was purified by column chromatography (hexanes to 10% ethyl acetate/hexanes) to furnish the title compound as a white solid (113 mg, 61% yield). LRMS ([M+H+])=177.8. Preparation of Intermediate 1-(4-Methoxy-phenyl)-1H-pyrazole:
Reaction SMILES: O=S(Cl)[Cl:3].[C:5]([O:16][CH3:17])(=[O:15])[C:6]1[CH:14]=[CH:13][CH:12]=[C:8]([C:9]([O-])=[O:10])[CH:7]=1>CN(C=O)C>[CH3:17][O:16][C:5](=[O:15])[C:6]1[CH:14]=[CH:13][CH:12]=[C:8]([C:9]([Cl:3])=[O:10])[CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: COC(=O)c1cccc(C(=O)[O-])c1
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(C(=O)Cl)c1
Temperature: 80 °C

Procedure:
SOCl2 (15 mL) and dry DMF (2 drops) were added to monomethyl isophthalate (5 g, 17.7 mmol), and the reaction mixture was refluxed at 80° C. for 6 hr. The SOCl2 was removed in vacuo, and a colorless oil was obtained and used directly in the next step.
Reaction SMILES: N1C=CC=CC=1.[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]#[C:15][C:16]1[C:17]([O:26][CH3:27])=[CH:18][C:19]([O:24][CH3:25])=[C:20]([CH:23]=1)[CH:21]=[O:22].[C:28](Cl)(=[O:30])[CH3:29]>C(Cl)Cl>[CH:21]([C:20]1[C:19]([O:24][CH3:25])=[CH:18][C:17]([O:26][CH3:27])=[C:16]([C:15]#[C:14][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:28](=[O:30])[CH3:29])[CH:23]=1)=[O:22]
Reactant: CC(=O)Cl
Reactant: COc1cc(OC)c(C=O)cc1C#Cc1ccccc1N
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(OC)c(C=O)cc1C#Cc1ccccc1NC(C)=O
Temperature: 0 °C
Yield: 77.7 %

Procedure:
Pyridine (453 μL, 5.61 mmol) was added to a suspension of 5-(2-amino-phenylethynyl)-2,4-dimethoxybenzaldehyde (Ex-35C, 750 mg, 2.67 mmol) in anhydrous methylene chloride (20 mL) and chilled to 0° C. The reaction mixture was treated dropwise with acetyl chloride (9.25 mL, 75.1 mmol). Upon completion the reaction was quenched with IN HCl (10 mL) and the layers were separated. The organic layer was washed with brine, dried over sodium sulfate, and concentrated to dryness. The crude solid was purified by silica gel chromatography (5% MeOH/CH2Cl2) to yield 671 mg (78%) of N-[2-(5-formyl-2,4-dimethoxyphenylethynyl)phenyl]acetamide as an off-white solid. 1H-NMR (300 MHz, DMSO-d6) 10.15 (s, 1H), 9.23 (br s, 1H), 7.82 (m, 2H), 7.80 (s, 1H), 7.50 (dd, 1H, J=0.9, 7.8 Hz), 7.35 (dt, 1H, J=1.8, 9.3 Hz), 7.12 (t, 1H, J=7.8 Hz), 6.82 (s, 1H), 4.00 (s, 3.99 (s, 3H), 2.10 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:3]=1[CH2:4][N:5]1[C:17]2[CH:16]=[N:15][C:14]([C:18]([NH:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[O:19])=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2.C[Li].[CH2:36]([O:38]CC)C.C1(C(C)C)C=CC=CC=1.C(=O)=O.CC(C)=O.CN(C=O)C>C1COCC1>[Cl:1][C:2]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:3]=1[CH2:4][N:5]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=2[C:12]2[C:13]3[CH:36]([OH:38])[N:20]([CH2:21][CH2:22][N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[C:18](=[O:19])[C:14]=3[N:15]=[CH:16][C:17]1=2
Reactant: CCOCC
Reactant: O=C(NCCN1CCOCC1)c1cc2c3ccccc3n(Cc3cc(Cl)ccc3Cl)c2cn1
Agent: O=C=O
Agent: [Li]C
Solvent: CN(C)C=O
Solvent: CC(C)c1ccccc1
Solvent: C1CCOC1
Product: O=C1c2ncc3c(c2C(O)N1CCN1CCOCC1)c1ccccc1n3Cc1cc(Cl)ccc1Cl
Temperature: -78 °C
Reaction time: 2 h

Procedure:
6-(2,5-Dichlorobenzyl)-1-hydroxy-2-[2-(4-morpholinyl)ethyl]-1,6-dihydropyrrolo[3′,4′:5,6]-pyrido[3,4-b]indol-3(2H)-one was prepared by a slight modification of a reported procedure (Dodd et al., J Org. Chem. 1993, 58:7587): A solution of 9-(2,5-dichlorobenzyl)-N-[2-(4-morpholinyl)ethyl]-9H-β-carboline-3-carboxamide (400 mg, 0.83 mmol) in anhydrous THF (12 mL) was stirred and cooled to −78° C. under nitrogen. When an internal temperature of −78° C. was attained, a 1.0 M methyllithium in diethyl ether/cumene solution (4.2 mL, 4.2 mmol) was added by syringe over a period of 0.3 hours. The reaction mixture developed a very dark blue color after complete addition of methyllithium. The solution was stirred at −78° C. for 2 hours, and the dry ice-acetone bath was then replaced with an ice-water bath. After 0.5 hour, anhydrous DMF (3070 mg, 4.2 mmol) was added dropwise, and the reaction mixture was stirred at room temperature for another 15 hours. The solution was cooled to 0° C., and distilled water was slowly added while maintaining the internal temperature of the reaction mixture at 0-5° C. The solution was concentrated to about 10 mL under reduced pressure, excess CH2Cl2 was added, and the mixture was washed with water. The organic phase was dried (Na2SO4), and the solvents were removed in vacuo. The resulting crude residue was washed several times with ether. Purification of the crude material by column chromatography on silica with 4% 2M MH3—CH3OH in CH2Cl2 as eluent furnished the lactam (106 mg, 25%) as a pale yellow solid. A 241 mg portion (60%) of unreacted starting material was recovered by evaporating combined ether layers and chromatography fractions. 1H NMR (CDCl3) δ8.76 (s, 1H), 8.48 (d, J=7.6 Hz, 1H), 7.66 (td, J=8.2 Hz, 0.91 Hz, I H), 7.46 (t,J=7.4 Hz, 1H), 7.35-7.40 (4-line multiplet, 2H), 7.18 (dd, J=8.5 Hz, 2.4 Hz, 1H), 6.42 (d,J=2.3 Hz, 1H), 6.17 (s, 1H), 5.56 (s, 2H), 4.46 (dt, J=9.6, 2.7 Hz, 1H), 3.83 (t, J=4.3 Hz, 4H), 3.47 (td,J=9.8, 1.5 Hz, 1H), 2.78-2.86 (m, 3H), 2.51-2.64 (m, 3H), 1.50-2.30 (v. br. s, 1H); MS (APCI; (M+H)+) m/z 511.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[CH2:12][C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:14]=3[C@:5]3([C@@H:10]2[CH2:9][CH2:8][CH2:7][CH2:6]3)[CH2:4][CH2:3]1.[CH:20]1[CH:25]=[CH:24][C:23]([C:26]2[N:35]=[C:34](Cl)[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]=2)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[C:23]1([C:26]2[N:35]=[C:34]([O:19][C:16]3[CH:17]=[CH:18][C:13]4[CH2:12][C@H:11]5[N:2]([CH3:1])[CH2:3][CH2:4][C@@:5]6([C:14]=4[CH:15]=3)[C@H:10]5[CH2:9][CH2:8][CH2:7][CH2:6]6)[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]=2)[CH:22]=[CH:21][CH:20]=[CH:25][CH:24]=1
Reactant: Clc1nc(-c2ccccc2)nc2ccccc12
Reactant: CN1CC[C@@]23CCCC[C@@H]2[C@@H]1Cc1ccc(O)cc13
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CN1CC[C@]23CCCC[C@H]2[C@H]1Cc1ccc(Oc2nc(-c4ccccc4)nc4ccccc24)cc13
Yield: 95.7 %

Procedure:
The O-demethylation procedure described in Steroids 11:151 [1968] was modified for this synthesis. First, 16.1 g (62.3 mmol) of dextrorphan, 2, were dissolved in 500 mL hot acetone, to which 15.5 g (64.4 mmol) AM-ex-OL (Aldrich) and 17.13 g (123.9 mmol) potassium carbonate were added. The reaction mixture was stirred at reflux overnight under an atmosphere of argon. After cooling, the reaction mixture was poured into a separatory funnel to which 500 mL water were added. Extraction with 1×500 and 2×250 mL benzene was followed by washing the combined organics with 1×250 mL water and removing the solvent in vacuo to give 27.51 g (96%) product as a white glass which was homogeneous by TLC. Recrystallization in ethyl acetate gave pure 3 as white crystals, mp 138°-139° C. EIMS m/z 461. Anal. (C31H31N3) C, H, N.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]2[N:10](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15](F)[N:14]=3)[C:5]=12)[CH3:2].[CH2:39]([C@H:43]1[CH2:48][NH:47][CH2:46][CH2:45][N:44]1C(OC(C)(C)C)=O)[CH:40]([CH3:42])[CH3:41].CCN(C(C)C)C(C)C.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>CS(C)=O.O.C(Cl)Cl>[CH2:1]([O:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]2[NH:10][N:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([N:47]4[CH2:46][CH2:45][NH:44][CH:43]([CH2:39][CH:40]([CH3:42])[CH3:41])[CH2:48]4)[N:14]=3)[C:5]=12)[CH3:2]
Reactant: CCOc1ncnc2c1c(-c1cccc(F)n1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)C[C@H]1CNCCN1C(=O)OC(C)(C)C
Agent: CC[SiH](CC)CC
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CCOc1ncnc2[nH]nc(-c3cccc(N4CCNC(CC(C)C)C4)n3)c12
Temperature: 150 °C
Reaction time: 18 h
Yield: 1.8 %

Procedure:
4-ethoxy-3-(6-fluoro-2-pyridyl)-1-trityl-pyrazolo[3,4-d]pyrimidine (139 mg, 0.27 mmol), (S)-tert-butyl 2-isobutylpiperazine-1-carboxylate (201.5 mg, 0.83 mmol) and DIPEA (214.9 mg, 289.6 μL, 1.66 mmol) were dissolved in DMSO (3.5 mL) and the reaction mixture was heated at 150° C. for 5 hours under microwave conditions. After this time, the reaction mixture was allowed to cool and DCM and water were added. The organic layer was separated dried (Na2SO4), filtered and concentrated in vacuo. The crude mixture was purified by column chromatography (ISCO Companion™, 40 g column, eluting with MeOH/DCM). The fractions were isolated and concentrated in vacuo. The residue was taken up in DCM (10 mL) and triethylsilane (128.8 mg, 176.9 μL, 1.11 mmol) and TFA (631.9 mg, 427.0 μL, 5.54 mmol) was added. The reaction mixture was stirred at ambient temperature for 18 hours. After this time the reaction mixture was concentrated in vacuo. The residue was purified by reverse phase preparative HPLC [Waters Sunfire C18, 5 mM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min] The fractions were isolated and freeze-dried to give the di-TFA salt of the title compound as a solid (1.9 mg, 1% Yield). H1 NMR (400 MHz, DMSO) δ 14.13 (brs, 1H), 8.98-8.60 (m, 2H), 8.58 (s, 1H), 7.83-7.67 (m, 1H), 7.31 (brs, 1H), 4.66-4.48 (m, 3H), 3.80-3.00 (m, 5H), 3.00-2.88 (m, 1H), 1.86-1.72 (m, 1H), 1.54-1.31 (m, 5H), 0.91 (d, J=6.5 Hz, 3H) and 0.85 (d, J=6.5 Hz, 3H) ppm; MS (ES+) 382.0.
Reaction SMILES: [CH3:1][C:2]1[NH:8][C:7]([NH2:9])=[N:6][C:4](=[O:5])[CH:3]=1.[C:10](N1C=CN=C1)([N:12]1[CH:16]=[CH:15][N:14]=[CH:13]1)=[O:11].CC(C)=O>CS(C)=O>[CH3:1][C:2]1[NH:8][C:7]([NH:9][C:10]([N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)=[O:11])=[N:6][C:4](=[O:5])[CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1cc(=O)nc(N)[nH]1
Solvent: CC(C)=O
Solvent: CS(C)=O
Product: Cc1cc(=O)nc(NC(=O)n2ccnc2)[nH]1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A mixture of 6-methylisocytosine (1 eq.) and carbonyldiimidazole (1.5 eq.) were combined in dimethylsulfoxide (DMSO) and the solution was stirred at 60° C. for 2 hours. The mixture was cooled to about room temperature and acetone added after which the desired product precipitated as a white powder that was collected by filtration. The procedure of A. T. Cate, P. Y. W. Dankers, H. Kooijman, A. L. Spek, R. P. Sijbesma, and E. W. Meijer, J. of Am. Chem. Soc., 2003, 125, 6860 was followed for this step. The product can be used without further purification.
Reaction SMILES: C(OC(=O)[NH:7][C:8]([C:10]1[S:11][C:12]([S:25][CH3:26])=[C:13]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20](Br)[CH:19]=2)(=[O:17])=[O:16])[CH:14]=1)=[NH:9])(C)(C)C.C([O:32][C:33](=[O:53])[CH2:34][O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([CH3:43])[C:38]=1B1OC(C)(C)C(C)(C)O1)(C)(C)C.C([O-])([O-])=O.[Na+].[Na+].[C:60]([OH:66])([C:62]([F:65])([F:64])[F:63])=[O:61].C(Cl)Cl>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1.C(O)C>[F:63][C:62]([F:65])([F:64])[C:60]([OH:66])=[O:61].[C:8]([C:10]1[S:11][C:12]([S:25][CH3:26])=[C:13]([S:15]([C:18]2[CH:19]=[C:20]([C:40]3[C:39]([CH3:43])=[CH:38][C:37]([CH2:36][O:35][CH2:34][C:33]([OH:53])=[O:32])=[CH:42][CH:41]=3)[CH:21]=[CH:22][CH:23]=2)(=[O:16])=[O:17])[CH:14]=1)(=[NH:9])[NH2:7]
Reactant: Cc1cccc(COCC(=O)OC(C)(C)C)c1B1OC(C)(C)C(C)(C)O1
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CSc1sc(C(=N)N)cc1S(=O)(=O)c1cccc(-c2ccc(COCC(=O)O)cc2C)c1
Yield: 22 %

Procedure:
The procedure used in Example 1: step c was followed using {[4-(3-bromo-benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester ((Example 27: step c) 123 mg, 0.25 mmol), [3-methyl-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyloxy]-acetic acid tert-butyl ester ((Example 299: step c) 270 mg, 0.75 mmol), Na2CO3 (2M, 1.5 mL, 3 mmol), Pd(PPh3)4 (66 mg, 0.06 mmol), ethanol (1.5 mL) and toluene (3 mL). Analogous aqueous workup yielded 417 mg of crude material which was treated with 1:1 TFA/DCM as described in Example 1: step d. Analogous purification by C18-HPLC yielded the title compound (26.8 mg, 22%) as a white solid. 1H-NMR (CD3OD): δ 8.35 (s, 1H), 8.07 (ddd, 1H, J=1.2, 1.9, 7.9 Hz), 7.86 (t, 1H, J=1.6 Hz), 7.71 (t, 1H, J=7.9 Hz), 7.10–7.43 (m, 3H), 4.25 (m, 2H), 4.07 (br s, 1H), 3.78 (br s, 1H), 2.73 (s, 3H), 2.35 (s, 3H), 2.02 (s, 3H). ESI-MS (m/z): Calcd. for C22H22N2O5S3 (M+H): 490.1; found: 490.1.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][O:7][C:8]([CH3:16])([C:10](OC)([O:12]C)[CH3:11])[CH3:9])=[CH:4][CH:3]=1.O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][O:7][C:8]([CH3:9])([CH3:16])[C:10](=[O:12])[CH3:11])=[CH:17][CH:18]=1
Reactant: COC(C)(OC)C(C)(C)OCc1ccc(Cl)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)C(C)(C)OCc1ccc(Cl)cc1
Yield: 86.5 %

Procedure:
134 g (0.5 mol) of 2-(4-chlorobenzyloxy)-3,3-di- methoxy-2-methyl-butane are stirred in 1 liter of toluene with 100 g of ion exchanger (Levatit SP C118) and 200 ml of water at 60° C. for 8 hours. After the ion exchanger has been filtered off with suction, the organic phase is separated off, washed with water and concentrated in vacuo. The residue is distilled. 98 g (87% of theory) of 3-(4-chlorobenzyloxy)-3-methyl-2-butanone of boiling point 95° C. to 100° C./0.03 mm Hg are obtained.
Reaction SMILES: [O:1]=[C:2]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([O:12][CH2:13][CH:14]2[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:20]3[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:11])[C:5](=[O:27])[N:4]2[C@H:28]([C:32]([O:34]C(C)(C)C)=[O:33])[CH2:29][CH2:30][CH2:31][N:3]12.C(N[C@@H]1C(=O)N2[C@H](C(O)=O)CCCN2C(=O)CC1)(=O)C1C=CC=CC=1.[K+].[Br-]>C(Cl)Cl>[O:1]=[C:2]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([O:12][CH2:13][CH:14]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=3[C:21]3[C:26]2=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:11])[C:5](=[O:27])[N:4]2[C@H:28]([C:32]([OH:34])=[O:33])[CH2:29][CH2:30][CH2:31][N:3]12
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN2C(=O)CC[C@H](NC(=O)OCC3c4ccccc4-c4ccccc43)C(=O)N12
Agent: O=C(N[C@H]1CCC(=O)N2CCC[C@@H](C(=O)O)N2C1=O)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Product: O=C(N[C@H]1CCC(=O)N2CCC[C@@H](C(=O)O)N2C1=O)OCC1c2ccccc2-c2ccccc21
Yield: 96 %

Procedure:
was prepared from 211f in 96% yield by the same method as for 212e: mp 120-126° C.; [α]D25 −72.5° (c 0.1, CH2Cl2). IR (KBr) 3406, 2950, 1725, 1670, 1526, 1449, 1421, 1272, 1248, 1223, 1175, 761, 741; 1H NMR (CDCl3) δ7.76 (2H, m), 7.62-7.26 (4H, m), 6.07, 5.76 (2H, brs, d, d, J=2.9), 5.46, 5.36 (1H, 2m), 4.79-4.54 (2H, m), 4.77 (2H, m), 4.21 (1H, m), 3.41 (1H, m), 2.89 (1H, m), 2.69 (1H, m), 2.35 (2H, m), 1.98, 1.73 (4H, 2m). MS (ES−, m/z) 462 (M+−1, 50%), 240 (100%).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:13]=[C:9]([C:10]([NH2:12])=[O:11])[C:8]([OH:14])=[CH:7][CH:6]=1)[OH:4].[CH3:15][N:16]([CH2:24][CH2:25][C:26](=O)[CH3:27])[C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1.[BH3-]C#N.[Na+]>CO>[CH3:23][C:20]1[CH:21]=[CH:22][C:17]([N:16]([CH2:24][CH2:25][CH:26]([NH:1][CH2:2][CH:3]([C:5]2[CH:13]=[C:9]([C:10]([NH2:12])=[O:11])[C:8]([OH:14])=[CH:7][CH:6]=2)[OH:4])[CH3:27])[CH3:15])=[CH:18][CH:19]=1
Reactant: NCC(O)c1ccc(O)c(C(N)=O)c1
Reactant: CC(=O)CCN(C)c1ccc(C)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(N(C)CCC(C)NCC(O)c2ccc(O)c(C(N)=O)c2)cc1
Reaction time: 20 h

Procedure:
To a solution of 20 mmol 5-(2-amino-1-hydroxyethyl)salicylamide and 5.7 g (30 mmol) 4-(N,4-dimethylanilino)-2-butanone [b.p. 93°-6°/0.1 mm, prepared by procedure of Craig, et al, J. Org. Chem., 29, 410 (1964)] in 150 ml methanol, add 1.9 g (30 mmol) NaCNBH3. After 20 hrs., concentrate, and partition between EtOAc and 1.0 N NaHCO3 solution. Dry and concentrate. Warm the foam with EtOAc to give a white solid, m.p. 123°-6°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5](Br)=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH3:12])[CH2:7]2.[CH3:14][N:15](C=O)C>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH3:12])[CH2:7][C:6]=2[C:5]([C:14]#[N:15])=[CH:4][CH:3]=1
Reactant: CN1Cc2c(Br)ccc(N)c2C1=O
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CN1Cc2c(C#N)ccc(N)c2C1=O
Temperature: 150 °C
Yield: 64.4 %

Procedure:
A mixture of 7-Amino-4-bromo-2-methyl-2,3-dihydro-1H-isoindol-1-one (100.0 mg, 0.4148 mmol), zinc cyanide (48.71 mg, 0.4148 mmol) and Pd(PPh3)4 (71.90 mg, 0.06222 mmol) in DMF (1.5 mL, 19 mmol) was evacuated and purged with N2 three times. The mixture was heated in microwave at 150° C. for 5 minutes. The crude mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was evaporated and purified on an ISCO Combiflash unit to isolate the title compound (50.0 mg, 64% yield). MS (ES+): m/z 188.14 (100) [MH+]; HPLC: tR=1.00 min (UPLC, analytical).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C.[Cl-].[Na+].O>[CH2:17]([N:8]([C:5]1[CH:4]=[CH:3][C:2]([I:1])=[CH:7][CH:6]=1)[C:9]1[N:10]=[CH:11][CH:12]=[CH:13][N:14]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: Ic1ccc(Nc2ncccn2)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Ic1ccc(N(Cc2ccccc2)c2ncccn2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under an argon atmosphere, N-(4-iodophenyl)pyrimidin-2-amine (75 mg) was added to a suspension of sodium hydride (16 mg) in anhydrous DMF (3 ml), and the resulting mixture was stirred at room temperature for 30 minutes. The reaction solution was cooled to 0° C. and benzyl bromide (0.039 ml) was added thereto, followed by stirring the resulting mixture at room temperature for 1 hour. Saturated brine was added to the reaction solution and the resulting mixture was extracted 3 times with ethyl acetate. Organic layers were washed 3 times with water and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was purified by column chromatography (silica gel, eluent: ethyl acetate/hexane=1/15) to obtain N-benzyl-N-(4-iodophenyl)pyrimidin-2-amine (67 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:23])[C:5]([CH3:22])=[C:6]([CH2:12][C:13]2[CH:14]=C(C=CC=2)C(O)=O)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[NH:24]1CC[S:27][CH2:26][CH2:25]1>>[CH3:1][O:2][C:3]1[C:4](=[O:23])[C:5]([CH3:22])=[C:6]([CH2:12][CH:13]2[CH2:14][S:27][CH2:26][CH2:25][NH:24]2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2cccc(C(=O)O)c2)=C(C)C1=O
Reactant: C1CSCCN1
Product: COC1=C(OC)C(=O)C(CC2CSCCN2)=C(C)C1=O
Yield: 55.6 %

Procedure:
3-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)benzoic acid (85 mg, 0.27 mmol) obtained in Example 41 and thiomorpholine (0.041 ml, 0.41 mmol) were used, and a method similar to that described in Example 42 was employed to obtain the title compound (61 mg, 0.15 mmol, yield 54%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][C:8]=1[CH2:17][O:18][C:19]1[CH:28]=[C:27]2[C:22]([CH2:23][CH2:24][CH2:25][C:26]2=[O:29])=[CH:21][CH:20]=1>O1CCCC1>[N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][C:8]=1[CH2:17][O:18][C:19]1[CH:28]=[C:27]2[C:22]([CH2:23][CH2:24][CH2:25][CH:26]2[OH:29])=[CH:21][CH:20]=1
Reactant: O=C1CCCc2ccc(OCc3ccc4ccccc4n3)cc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OC1CCCc2ccc(OCc3ccc4ccccc4n3)cc21
Yield: 61.6 %

Procedure:
To a solution of 0.62 g (16.33 mmol) lithium aluminum hydride in 80 mL tetrahydrofuran under nitrogen at 0° C. is added dropwise with stirring a solution of 5.0 g (16.48 mmol) of 3,4-dihydro-7-(2-quinolinylmethoxy)-1(2H)-naphthalenone over 1 minute. The ice bath is removed and after 1 hour the reaction is worked up according to Micovic and Mihailovic1. The crude product is recrystallized from ethylacetate/hexane and affords 3.1 g (62%) of white crystals, m.p. 113°-115° C.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:20]=[C:19]3[C:14]([C@H:15]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]#[C:31][Si](C)(C)C)[CH:25]=4)[CH2:16][N:17]4[CH2:23][CH2:22][CH2:21][C@H:18]43)=[CH:13][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+]>CO>[C:30]([C:26]1[CH:25]=[C:24]([C@H:15]2[C:14]3[C:19](=[CH:20][C:11]([O:10][CH2:9][CH2:8][CH2:7][N:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)=[CH:12][CH:13]=3)[C@@H:18]3[CH2:21][CH2:22][CH2:23][N:17]3[CH2:16]2)[CH:29]=[CH:28][CH:27]=1)#[CH:31]
Reactant: C[Si](C)(C)C#Cc1cccc([C@@H]2CN3CCC[C@H]3c3cc(OCCCN4CCCCC4)ccc32)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1cccc([C@@H]2CN3CCC[C@H]3c3cc(OCCCN4CCCCC4)ccc32)c1
Yield: 55.9 %

Procedure:
A solution of cis-9-(3-piperidin-1-yl-propoxy)-6-(3-trimethylsilanylethynyl-phenyl)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline (Example 33, 40.0 mg, 0.082 mmol) and K2CO3 (2.0 mg, 0.008 mmol) in MeOH (4.1 mL, 0.2 M) was stirred for 2 h at rt. The crude reaction mixture was purified directly after filtration by reverse-phase HPLC to give 19.0 mg (36%) of the desired product as a TFA salt. MS: exact mass calcd for C28H34N2O, 414.3; m/z found, 415.5 [M+H]+. 1H NMR (acetone-d6): 7.45 (m, 4H), 6.96 (m, 1H), 6.79 (dd, J=3.2, 10.9, 1H), 6.64 (d, J=10.9, 1H), 4.92 (m, 1H), 4.62 (m, 1H), 4.12 (t, J=7.5, 2H), 3.93 (m, 1H), 3.66 (m, 4H), 3.51 (m, 1H), 3.39 (m, 1H), 3.31 (m, 2H), 2.93 (m, 3H), 2.32 (m, 5H), 1.89 (m, 5H), 1.51 (m, 1H).