Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C#C)C=CC=CC=1.[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)#[CH:10].[N:17]([C:20]1[S:21][C:22]([C:26]([NH:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])=[C:23]([CH3:25])[N:24]=1)=[N+:18]=[N-:19]>>[CH2:29]([NH:28][C:26]([C:22]1[S:21][C:20]([N:17]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)[N:19]=[N:18]2)=[N:24][C:23]=1[CH3:25])=[O:27])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: C#Cc1ccccn1
Reactant: Cc1nc(N=[N+]=[N-])sc1C(=O)NCc1ccccc1
Solvent: C#Cc1ccccc1
Product: Cc1nc(-n2cc(-c3ccccn3)nn2)sc1C(=O)NCc1ccccc1
Yield: 34 %

Procedure:
Following the procedure as described in Example 10, making variations as necessary to replace phenylacetylene with 2-ethynylpyridine to react with 2-azido-N-benzyl-4-methylthiazole-5-carboxamide, the title compound was obtained as a white solid in 34% yield: mp 184-187° C. (dichloromethane/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.96 (s, 1H), 8.65-8.63 (m, 1H), 8.21-8.19 (m, 1H), 7.84-7.79 (m, 1H), 7.39-7.27 (m, 6H), 6.13 (t, J=6.0 Hz, 1H), 4.64 (d, J=6.0 Hz, 2H), 2.71 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 160.9, 153.3, 149.8, 149.2, 149.0, 138.8, 137.4, 136.9, 128.9, 127.9, 127.8, 124.8, 123.5, 120.7, 119.4, 44.4, 17.5; MS (ES+) m/z 377.3 (M+1).
Reaction SMILES: Cl.[C:2]1([CH2:8][O:9][C:10]([NH:12][C@@H:13]([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:14](=[O:35])[CH2:15][NH:16][C@H:17]([C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].O>O1CCCC1.O>[C:2]1([CH2:8][O:9][C:10]([NH:12][C@@H:13]([CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:14]([OH:35])[CH2:15][NH:16][C@H:17]([C:25]([O:27][CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[O:26])[CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)CN[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1)OCc1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(N[C@@H](Cc1ccccc1)C(O)CN[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1)OCc1ccccc1
Reaction time: 0.08 h
Yield: 97 %

Procedure:
A solution of N-[(3S)-3-[[(phenylmethoxy)carbonyl]amino]-2-oxo-4-phenylbutyl]-L-phenylalanine, phenylmethyl ester, hydrochloride (2.12 g, 3.6 mmol) in 72 ml of 3:1 tetrahydrofuran-water was cooled to 0° C. Sodium borohydride (681 mg, 18 mmol) was added in approximately seven portions over 5-10 minutes. The reaction mixture was allowed to stir an additional 5 minutes and then poured into 150 ml of water. This mixture was extracted with 300 ml of ethyl acetate-ether (5:3). The organic extract was washed with water (2×50 ml) and brine (50 ml) and then dried (sodium sulfate) and evaporated to give 1.93 g of a colorless oil. This material was purified by flash chromatography on 150 g of Merck silica gel (230-400 mesh), eluting with hexane-ethyl acetate (1.25:1), to afford 1.14 g of the title compound as a white solid. The 13C-NMR spectrum was consistent with an approximately 2:1 mixture of alcohol diastereomers.
Reaction SMILES: O[CH2:2][C:3]1[N:7]([C:8]2[CH:9]=[C:10]([C:14]3[CH2:20][C:19](=[O:21])[NH:18][C:17]4[CH:22]=[C:23]([CH3:32])[C:24]([N:26]([CH2:28][CH:29]([CH3:31])[CH3:30])[CH3:27])=[CH:25][C:16]=4[N:15]=3)[CH:11]=[CH:12][CH:13]=2)[N:6]=[N:5][CH:4]=1.S(Cl)(Cl)=O.[Cl-].[CH:38]1([CH2:41][NH2:42])[CH2:40][CH2:39]1>ClCCl.CN(C=O)C>[CH:38]1([CH2:41][NH:42][CH2:2][C:3]2[N:7]([C:8]3[CH:9]=[C:10]([C:14]4[CH2:20][C:19](=[O:21])[NH:18][C:17]5[CH:22]=[C:23]([CH3:32])[C:24]([N:26]([CH2:28][CH:29]([CH3:31])[CH3:30])[CH3:27])=[CH:25][C:16]=5[N:15]=4)[CH:11]=[CH:12][CH:13]=3)[N:6]=[N:5][CH:4]=2)[CH2:40][CH2:39]1
Reactant: Cc1cc2c(cc1N(C)CC(C)C)N=C(c1cccc(-n3nncc3CO)c1)CC(=O)N2
Reactant: NCC1CC1
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1cc2c(cc1N(C)CC(C)C)N=C(c1cccc(-n3nncc3CNCC3CC3)c1)CC(=O)N2

Procedure:
The title compound was prepared from 4-[3-(5-hydroxymethyl-[1,2,3]triazol-1-yl)-phenyl]-7-(isobutyl-methyl-amino)-8-methyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 132) (250 mg, 0.58 mmol) by reaction with thionylchloride in dichloromethane and subsequent treatment of the corresponding chloride with cyclopropylmethylamine in DMF according to the method described in Example 45. Obtained as a light yellow solid (50 mg, 18%).
Reaction SMILES: [Br:1][CH2:2][CH:3]([O:6]C)[O:4]C.C1(C)C(S(O)(=O)=O)=[CH:10][CH:11]=[CH:12][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>>[Br:1][CH2:2][CH:3]1[O:6][CH:12]([CH3:13])[CH:11]([CH3:10])[O:4]1
Reactant: COC(CBr)OC
Reactant: Cc1ccccc1S(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC1OC(CBr)OC1C
Temperature: 25 °C

Procedure:
2-Bromo-1,1-dimethoxyethane (188 grams) 2,3-butanediol (100 grams) and toluene sulfonic acid (0.1 grams) were charged into a glass reaction vessel fitted with a mechanical stirrer, thermometer, and reflux condenser. The reaction mixture was heated to reflux for a period of about 2 hours. It was then cooled to room temperature, neutralized with potassium carbonate, and filtered. The filtrate was distilled, the desired product 2-bromomethyl-4,5-dimethyl-1,3-dioxolane being obtained as a fraction boiling at 82° C.-85° C. at a pressure of about 12 mm Hg.
Reaction SMILES: C(OC([N:8]1[CH2:39][CH2:38][C:11]2([CH2:15][N:14]([C:16](=[O:37])[C:17]3[CH:22]=[CH:21][C:20]([C:23]4[O:24][C:25]5[C:31]([CH:32]([CH3:34])[CH3:33])=[CH:30][C:29]([C:35]#[N:36])=[CH:28][C:26]=5[N:27]=4)=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:15]1[C:11]2([CH2:38][CH2:39][NH:8][CH2:9][CH2:10]2)[CH2:12][CH2:13][N:14]1[C:16]([C:17]1[CH:18]=[CH:19][C:20]([C:23]2[O:24][C:25]3[C:31]([CH:32]([CH3:34])[CH3:33])=[CH:30][C:29]([C:35]#[N:36])=[CH:28][C:26]=3[N:27]=2)=[CH:21][CH:22]=1)=[O:37]
Reactant: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)N4CCC5(CCN(C(=O)OC(C)(C)C)CC5)C4)cc3)oc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)N4CCC5(CCNCC5)C4)cc3)oc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
To a solution of tert-butyl-2-[4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)benzoyl]-2,8-diazaspiro[4.5]decane-8-carboxylate (92 mg, 0.174 mmol) in dichloromethane (4 ml) was added trifluoroacetic acid (2 ml, 26.0 mmol). The mixture was stirred for 1 h at 25° C., at which point LC/MS analysis showed the desired amine. The mixture was concentrated and then co-concentrated with toluene to provide the title compound (94 mg, 0.173 mmol, 100% yield). Mass spectrum (ESI) 429.2 (M+).
Reaction SMILES: [CH3:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([CH2:6][CH2:7][C@:8]([CH2:14][CH2:15][CH2:16][C@@H:17]([CH2:19][CH2:20][CH2:21][C@@H:22]([CH2:24][CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])[CH3:23])[CH3:18])([CH3:13])[O:9]2)=[CH:4][C:3]=1[OH:30].C([O-])([O-])=O.[K+].[K+].[CH2:37](Br)[CH:38]=[CH2:39].CC(C)=O>O.CCOC(C)=O>[CH2:39]([O:30][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([CH3:12])[C:2]=1[CH3:1])[O:9][C@:8]([CH3:13])([CH2:14][CH2:15][CH2:16][C@H:17]([CH3:18])[CH2:19][CH2:20][CH2:21][C@H:22]([CH3:23])[CH2:24][CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:7][CH2:6]2)[CH:38]=[CH2:37]
Reactant: C=CCBr
Reactant: Cc1c(O)cc2c(c1C)O[C@](C)(CCC[C@H](C)CCC[C@H](C)CCCC(C)C)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(C)=O
Product: C=CCOc1cc2c(c(C)c1C)O[C@](C)(CCC[C@H](C)CCC[C@H](C)CCCC(C)C)CC2

Procedure:
(+)-γ-tocopherol (Ex-1D-1) (300 mg, 0.72 mmol), K2CO3 (199 mg, 1.44 mmol), allyl bromide (182 μL, 1.44 mmol) and acetone (8 mL) were charged to a 50 mL RBF. The reaction was heated to reflux for 20 h after which time it was deemed complete by TLC (1:5 EtOAc:Hept). The reaction was diluted with water (10 mL). The aqueous layer was separated and washed with DCM (3×10 mL). The combined DCM layers were dried over Na2SO4, filtered and concentrated by rotary evaporation to yield a pale yellow oil. The oil was flashed through a silica plug (1:1: DCM:Heptane). After concentration of the eluent, (R,R,R)-6-allyloxy-2,7,8-trimethyl-2-(4,8,12-trimethyl-tridecyl)-chroman (Ex-1D-2) was obtained as a clear, colorless oil (334 mg, >100%), which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:23][O:24]COC)[CH2:9][O:10][C:11]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:12]=2[C:13]([NH2:22])=[N:14][C:15]([NH2:21])=[N:16]3)=[CH:4][CH:3]=1>CO.Cl.O1CCOCC1>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:9][O:10][C:11]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:12]=2[C:13]([NH2:22])=[N:14][C:15]([NH2:21])=[N:16]3)[CH2:23][OH:24])=[CH:4][CH:3]=1
Reactant: COCOCC(COc1cccc2nc(N)nc(N)c12)c1ccc(Cl)cc1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Nc1nc(N)c2c(OCC(CO)c3ccc(Cl)cc3)cccc2n1
Temperature: 60 °C
Yield: 123.4 %

Procedure:
5-[2-(4-Chlorophenyl)-3-methoxymethoxy-propoxy]-quinazoline-2,4-diamine (Step 6, Example 68) (68 mg; 0.17 mmol) is dissolved in methanol (2 mL), and diluted with 4M HCl in dioxane (1 mL). The reaction is heated in a sealed tube to 60° C. overnight. The solvent is removed under N2 flow. The resulting solid is triturated with 20% MeOH/Ether, and the resulting title compound is filtered and dried under vacuum at 35° C. for 3 hours providing a total of 40 milligrams of 2-(4-chlorophenyl)-3-(2,4-diaminoquinazolin-5-yloxy)-propan-1-ol hydrochloride.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([NH:17][C:18]3[CH:27]=[C:26]4[C:21]([CH:22]=[C:23]([C:28]([OH:30])=O)[CH:24]=[N:25]4)=[CH:20][CH:19]=3)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[CH3:33][O:34][C:35]1[CH:36]=[C:37]([CH:40]=[CH:41][CH:42]=1)[CH2:38][NH2:39].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl.C(OCC)(=O)C>[CH3:33][O:34][C:35]1[CH:36]=[C:37]([CH:40]=[CH:41][CH:42]=1)[CH2:38][NH:39][C:28]([C:23]1[CH:24]=[N:25][C:26]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[C:18]([NH:17][C:15]([C:10]1[C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:31])([F:32])[F:1])=[CH:8][CH:7]=3)=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:16])[CH:27]=2)=[O:30]
Reactant: O=C(O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Reactant: COc1cccc(CN)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc(CNC(=O)c2cnc3cc(NC(=O)c4ccccc4-c4ccc(C(F)(F)F)cc4)ccc3c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.7 %

Procedure:
7-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (50 mg, 0.11 mmol) was combined with 3-methoxybenzylamine (16 mg, 0.11 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (26 mg, 0.14 mmol), 1-hydroxybenzotriazole (17 mg, 0.13 mmol), and triethylamine (0.064 ml, 0.46 mmol) in 1 ml of dichloromethane. After stirring overnight at ambient temperature, the reaction mixture was diluted with 30 ml of ethyl acetate, and the organic phase washed sequentially with water, and brine, and then dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to afford 53 mg of the title compound as a colorless solid.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:19]#[CH:20])[CH2:10][O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[Na+].[CH3:23]COC(C)=O>C1COCC1>[C:1]([N:8]([C@H:9]([C:19]#[CH:20])[CH2:10][O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH3:23])([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: C#C[C@H](CO[Si](C)(C)C(C)(C)C)NC(=O)OC(C)(C)C
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C#C[C@H](CO[Si](C)(C)C(C)(C)C)N(C)C(=O)OC(C)(C)C

Procedure:
(R)-2-(N-Boc-N-methylamino)-1-(tert-butyldimethylsilyloxy)-but-3-yne was synthesized according to Method Y above by the treatment of (R)-N-Boc-2-amino-1-(-tert-butyldimethylsilyloxy)-but-3-yne (200 mg, 0.67 mmol) (Example 104B) with NaH (21 mg, 0.87 mmol) and Mel (189 mg, 1.34 mmol) in THF (12 mL). The product was obtained after silica gel column chromatography with a 0-10% EtOAc in hexanes gradient. (Yield 200 mg, 95%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:13]=[C:12]([NH:14][C:15](=[O:32])[C@@H:16]([NH:24]C(=O)OC(C)(C)C)[CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:11]([CH3:33])[N:10]=2)[CH:6]=[CH:5][N:4]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:24][C@@H:16]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:15]([NH:14][C:12]1[N:11]([CH3:33])[N:10]=[C:9]([C:7]2[CH:6]=[CH:5][N:4]=[C:3]([O:2][CH3:1])[CH:8]=2)[CH:13]=1)=[O:32]
Reactant: COc1cc(-c2cc(NC(=O)[C@H](Cc3ccccc3)NC(=O)OC(C)(C)C)n(C)n2)ccn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(-c2cc(NC(=O)[C@@H](N)Cc3ccccc3)n(C)n2)ccn1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 91.7 %

Procedure:
To a 50 ml flask was added tert-butyl (S)-1-(3-(2-methoxypyridin-4-yl)-1-methyl-1H-pyrazol-5-ylamino)-1-oxo-3-phenylpropan-2-ylcarbamate 105.1.D (0.99 g, 2.19 mmole) and 20 ml of dichloromethane. To the solution, 5 ml of trifluoroacetic acid was added. The reaction was stirred at room temperature for 2.5 hours at which time the solvent was removed by rotary evaporation. The residue was suspended in ethyl acetate, and washed successively with saturated sodium bicarbonate, water and brine. The organic layer was dried over anhydrous sodium sulfate, and concentrated in vacuo to give 105.1.E (706 mg, 92% yield) as yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([CH3:13])([CH3:12])[CH2:6][C:5]2([CH3:15])[CH3:14].[CH2:16]([O:18]CC)C>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH:16]=[O:18])[CH:11]=1)[O:8][C:7]([CH3:13])([CH3:12])[CH2:6][C:5]2([CH3:15])[CH3:14]
Reactant: CC1(C)CC(C)(C)c2cc(Br)ccc2O1
Reactant: CCOCC
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CC1(C)CC(C)(C)c2cc(Br)cc(C=O)c2O1
Temperature: 25 °C
Yield: 94 %

Procedure:
A stirred, cooled (ice bath) solution of 6-bromo-2,2,4,4-tetramethyl chroman, (0.5 g, 1.865 mmol) in anhydrous dichloromethane (5 mL) was treated with a 1M solution (1.86 mL, 1.86 mmol) of titanium tetrachloride in dichloromethane followed by (α,α-dichloro methyl ether (0.214 g, 1.865 mmol). The reaction mixture was allowed to warm to ambient temperature for 4 h. The reaction mixture was diluted with diethyl ether, washed with brine (×1) and dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to a residue which was subjected to flash column chromatography over silica gel (230-400 mesh) using 5% ethyl acetate in hexane to afford the title compound as a yellow solid (0.52 g, 94%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][NH:8][C:9]2[CH:28]=[CH:27][CH:26]=[CH:25][C:10]=2[C:11]([NH:13][O:14][CH2:15][C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=2)=[O:12])=[CH:3][CH:2]=1.Cl.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.O>CN(C=O)C>[N:30]1([C:20]([C:19]2[CH:18]=[CH:17][C:16]([CH2:15][O:14][NH:13][C:11](=[O:12])[C:10]3[CH:25]=[CH:26][CH:27]=[CH:28][C:9]=3[NH:8][CH2:7][C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)=[CH:24][CH:23]=2)=[O:21])[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1
Reactant: O=C(O)c1ccc(CONC(=O)c2ccccc2NCc2ccncc2)cc1
Reactant: C1COCCN1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NOCc1ccc(C(=O)N2CCOCC2)cc1)c1ccccc1NCc1ccncc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a stirred mixture of 4-{2-[(pyridin-4-ylmethyl)-amino]-benzoylaminooxymethyl}-benzoic acid (see example 404, 220 mg) in DMF (3 ml) was added N,N′-carbonyldiimidazole (99 mg). The mixture was stirred at room temperature for 45 minutes and morpholine hydrochloride (79 mg) was added. The reaction mixture was stirred at room temperature for 18 hours and poured into water. The product was extracted several times with EtOAc and the combined organic layers were washed with water and brine, dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (EtOAc as eluent) and gave the title compound. 13C-NMR (DMSO-d6) δ 168.7, 167.2, 149.5, 149.0, 148.3, 137.4, 135.3, 132.5, 128.8, 128.1, 127.0, 122.0, 114.8, 113.3, 111.5, 76.4, 66.0, 44.7
Reaction SMILES: CC(OC(=O)[N:7]([CH2:44][C:45]1[CH:50]=[CH:49][C:48]([Br:51])=[CH:47][C:46]=1[F:52])[C:8]1[CH:9]=[N:10][CH:11]=[C:12]([C:14]([N:16]2[CH2:21][CH2:20][CH:19]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][N:29](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)[CH:23]=3)[CH2:18][CH2:17]2)=[O:15])[CH:13]=1)(C)C.[ClH:54].O1CCOCC1.CCOCC>C(O)(C)C>[ClH:54].[ClH:54].[ClH:54].[NH2:29][CH2:28][C:24]1[CH:23]=[C:22]([CH:19]2[CH2:18][CH2:17][N:16]([C:14]([C:12]3[CH:11]=[N:10][CH:9]=[C:8]([NH:7][CH2:44][C:45]4[CH:50]=[CH:49][C:48]([Br:51])=[CH:47][C:46]=4[F:52])[CH:13]=3)=[O:15])[CH2:21][CH2:20]2)[CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)N(Cc1cccc(C2CCN(C(=O)c3cncc(N(Cc4ccc(Br)cc4F)C(=O)OC(C)(C)C)c3)CC2)c1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Solvent: CC(C)O
Product: NCc1cccc(C2CCN(C(=O)c3cncc(NCc4ccc(Br)cc4F)c3)CC2)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
(4-Bromo-2-fluoro-benzyl)-{5-[1-(4-{3-[N,N-bis-(tert-butoxycarbonyl)aminomethyl]-phenyl}-piperidin-1-yl)-methanoyl]-pyridin-3-yl}-carbamic acid dimethyl-ethyl ester (0.0806 g, 0.1010 mmol) was treated with 4 M HCl in 1,4-dioxane (2.0 mL, 8.0 mmol) and stirred at ambient temperature. After 25 minutes the reaction mixture was diluted with isopropyl alcohol (0.5 mL) and stirring was continued for an additional 2.5 hours. Dripping the reaction solution into ether (40 mL) with vigorous stirring afforded a white precipitate which was collected by filtration, washed with fresh ether (3.0 mL), and dried to afford 1-[4-(3-aminomethyl-phenyl)-piperidin-1-yl]-1-[5-(4-bromo-2-fluoro-benzylamino)-pyridin-3-yl]-methanone trihydrochloride (0.0563 g): 1H NMR (300 MHz, DMSO-d6) δ 8.39 (br s, 2H), 8.16 (d, J=2.7 Hz, 1H), 8.08 (s, 1H), 7.16-7.70 (m, 8H), 4.49-4.64 (br m, 1H), 4.46 (s, 2H), 4.05-4.30 (m, 1H), 4.00 (AB q, J=5.7 Hz, 2H), 3.01-3.25 (m, 1H), 2.77-2.95 (m, 2H), 1.75-1.92 (m, 1H), 1.45-1.75 (br m, 3H); 19F NMR (282 MHz, DMSO-d6) δ-114.1; MS (ESI) m/z 497 (M+H).
Reaction SMILES: [CH2:1]([CH:3]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:17])[CH:15]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]1[S:18]([C:21]1[CH:26]=[CH:25][C:24]([O:27]C)=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH3:2].B(Cl)(Cl)Cl.ClCCl>[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:1]([CH:3]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:17])[CH:15]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]1[S:18]([C:21]1[CH:22]=[CH:23][C:24]([OH:27])=[CH:25][CH:26]=1)(=[O:20])=[O:19])[CH3:2]
Reactant: CCC1c2cc(F)ccc2-c2ccccc2N1S(=O)(=O)c1ccc(OC)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: ClB(Cl)Cl
Agent: [I-]
Solvent: ClCCl
Product: CCC1c2cc(F)ccc2-c2ccccc2N1S(=O)(=O)c1ccc(O)cc1
Yield: 72.2 %

Procedure:
The title compound was prepared from 6-ethyl-8-fluoro-5-[(4-methoxyphenyl)sulfonyl]-5,6-dihydrophenanthridine (0.51 g, 1.3 mmol), tetrabutylammonium iodide (1.2 g, 3.2 mmol), and 1 M boron trichloride in dichloromethane (9.0 mL, 9.0 mmol) according to the procedure and in the same manner as described in Example 35, Step b. The crude product was purified by flash column chromatography on silica gel, eluting with a mixture of ethyl acetate-hexane (1:9 to 2:3 gradient), followed by re-crystallization from a mixture of dichloromethane-hexane, to yield 4-[(6-ethyl-8-fluorophenanthridin-5(6H)-yl)sulfonyl]phenol as a solid (0.36 g, 94%), m.p. 151° C.;
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][N:6]=[C:5]2[Cl:13].[N:14]1([CH2:19][C:20]2[CH:21]=[C:22]([CH2:26][NH2:27])[CH:23]=[CH:24][CH:25]=2)[CH2:18][CH2:17][CH2:16][CH2:15]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>CC(N(C)C)=O.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:13][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([NH:27][CH2:26][C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([CH2:19][N:14]4[CH2:18][CH2:17][CH2:16][CH2:15]4)[CH:21]=3)[CH:3]=2)[C:8](=[O:12])[NH:7][N:6]=1
Reactant: NCc1cccc(CN2CCCC2)c1
Reactant: O=c1[nH]nc(Cl)c2cc(Br)ccc12
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: O=c1[nH]nc(Cl)c2cc(NCc3cccc(CN4CCCC4)c3)ccc12
Yield: 5.3 %

Procedure:
A mixture 6-bromo-4-chloro-2H-phthalazin-1-one (200 mg, 0.770 mmol), [3-(1-pyrrolidinylmethyl)phenyl]methanamine (161 mg, 0.848 mmol), Pd2(dba)3 (71 mg, 0.077 mmol), rac-BINAP (144 mg, 0.231 mmol) and NaOtBu (230 mg, 2.393 mmol) in DMA (6 mL) was heated at 85° C. for 1.5 h. The mixture was allowed to cool, diluted with EtOAc and washed with water. The organic layer was washed with sat.aq. NaHCO3, brine and dried (Na2SO4). Chromatography (Hexanes/EtOAc) afforded 4-chloro-6-(3-pyrrolidin-1-ylmethyl-benzylamino)-2H-phthalazin-1-one (15 mg) as a yellow solid. 1H (400 MHz, d6-DMSO) δ: 1.62 (m, 4H), 2.38 (m, 4H), 3.55 (m, 2H), 4.44 (d, 2H), 6.80 (s, 1H), 7.17 (m, 2H), 7.3 (m, 3H), 7.68 (m, 1H), 7.92 (d, 1H), 12.34 (s, 1H) ppm; m/z (M+1) 369.26.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[CH:5]([O:30][CH2:31][CH3:32])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22]CC3C=CC=CC=3)=[CH:18][CH:17]=2)=[CH:9][CH:8]=1)[CH3:2]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:33])[CH:5]([O:30][CH2:31][CH3:32])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=2)=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(OCCc2ccc(OCc3ccccc3)cc2)cc1)OCC
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(Cc1ccc(OCCc2ccc(O)cc2)cc1)OCC
Yield: 87.8 %

Procedure:
3-{4-[2-(4-Benzyloxyphenyl)ethoxy]phenyl}-2-ethoxypropanoic acid ethyl ester (16 g; 35.6 mmole) was hydrogenated at atmospheric pressure in ethyl acetate (300 ml) using Pd/C (dry, 10%) as catalyst. The mixture was filtered through celite and the solvent was evaporated in vacuo to give 11.2 g (yield 88%) of 2-ethoxy-3-{4-[2-(4-hydroxyphenyl)ethoxy]phenyl}propanoic acid ethyl ester.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:8])=[N:4][O:5][C:6]=1[NH2:7].[H-].[Na+].[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:30]=[CH:31][C:32]=1[O:33][CH3:34])[CH2:16][C:17]1[S:21][C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[C:18]=1[S:26](Cl)(=[O:28])=[O:27]>C1COCC1>[Br:1][C:2]1[C:3]([CH3:8])=[N:4][O:5][C:6]=1[NH:7][S:26]([C:18]1[C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[S:21][C:17]=1[CH2:16][C:15]1[CH:30]=[CH:31][C:32]([O:33][CH3:34])=[C:13]([O:12][CH3:11])[CH:14]=1)(=[O:27])=[O:28]
Reactant: Cc1noc(N)c1Br
Reactant: COc1ccc(Cc2sc3ccccc3c2S(=O)(=O)Cl)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(Cc2sc3ccccc3c2S(=O)(=O)Nc2onc(C)c2Br)cc1OC

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-2-(3,4-dimethoxy-benzyl)-benzo[b]thiophene-3-sulfonamide was prepared in the same manner as described in Example 41. Reaction of 4-bromo-3-methyl-5-aminoisoxazole (1.0 mmoles, 0.18 g), NaH (2.5 mmoles, 60 mg), and 2-(3,4-dimethoxybenzyl)benzo[b]thiophene-3-sulfonylchloride (1.2 mmoles, 0.449) in THF (6 ml), after recrystallization from chloroform and hexanes, yielded 0.42 g (80%) of a brown solid, m.p. 151-153° C.