Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([SH:13])[CH2:10][C@H:9]1[CH2:14][N:15]([C:25](=[O:27])[CH3:26])[CH2:16][C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[F:24])=[O:7])[CH2:2][CH2:3][CH3:4].[C:28](Cl)(=[O:30])[CH3:29]>N1C=CC=CC=1.C(Cl)Cl>[CH2:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([S:13][C:28](=[O:30])[CH3:29])[CH2:10][C@H:9]1[CH2:14][N:15]([C:25](=[O:27])[CH3:26])[CH2:16][C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[F:24])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CC(=O)Cl
Reactant: CCCCOC(=O)N1C[C@H](S)C[C@H]1CN(Cc1cc(F)ccc1F)C(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCOC(=O)N1C[C@H](SC(C)=O)C[C@H]1CN(Cc1cc(F)ccc1F)C(C)=O
Temperature: 25 °C
Yield: 82.2 %

Procedure:
130 mg (0.325 mmol) [2S,4R]-2-{[acetyl-(2,5-difluoro-benzyl)-amino]-methyl}-4-mercapto-pyrrolidine-1-carboxylic acid butyl ester in 3 ml pyridine were treated with 120 μl (1.68 mmol, 5.1 eq) acetyl chloride at 0° C. The resulting suspension was diluted with 8 ml CH2Cl2, and the mixture was stirred at RT over night, concentrated in vacuo and the oil was redissolved in EtOAc/1M HCl. The inorganic phase was extracted with CH2Cl2 and the organic phases were washed with 1M HCl and brine, dried over Na2SO4. The crude product was purified by flash column chromatography with EtOAc/hexane 1:1 as eluent yielding 118.2 mg (82%) [2S,4R]-2-{[acetyl-(2,5-difluoro-benzyl)-amino]-methyl}-4-acetylsulfanyl-pyrrolidine-1-carboxylic acid butyl ester as light yellow oil, MS: 443 (MHf).
Reaction SMILES: C(OC(=O)C)(=O)C.[C:8]1([P:14]([OH:16])[OH:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O[CH2:18][NH:19][C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(O)(=O)C>[C:20]([NH:19][CH2:18][P:14]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:16])[OH:15])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: OP(O)c1ccccc1
Reactant: O=C(NCO)c1ccccc1
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: O=C(NCP(=O)(O)c1ccccc1)c1ccccc1
Yield: 72.7 %

Procedure:
43.2 g (0.424 mol) of acetic anhydride were cooled to 10° C. A solution of 28.2 g (0.2 mol) of benzenephosphonous acid in 40 ml acetic acid were then added dropwise at 15° C., with stirring and cooling. After this, 30.2 g (0.2 mol) of N-hydroxymethylbenzamide were added in portions in the course of 10 minutes at 15° C., with cooling. After this, the cooling was removed, during which process the internal temperature rose to 35° C. After this, the mixture was refluxed for 3 hours and subsequently cooled. 175 ml of water were then added; during this process, the temperature rose to 35° C. The mixture was refluxed again, and finally cooled again, with stirring. After crystallisation, a total of 40 g (73% of theory) of benzoylaminomethylphenylphosphinic acid of a melting point of 158°-160° C. were obtained. CHNP analysis revealed:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]2[CH2:16][CH2:15][CH2:14][C@H:13]2[C:17]([NH2:19])=[O:18])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Br[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:26][CH:27]=2)[C@H:12]2[CH2:16][CH2:15][CH2:14][C@H:13]2[C:17]([NH2:19])=[O:18])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: NC(=O)[C@@H]1CCC[C@@H]1NS(=O)(=O)c1ccc(Cl)cc1
Product: NC(=O)[C@@H]1CCC[C@@H]1N(Cc1ccc(C(F)(F)F)cc1)S(=O)(=O)c1ccc(Cl)cc1
Yield: 50 %

Procedure:
The titled compound (191 mg) was prepared in 50% yield from cis-2-(4-chlorobenzenesulfonylamino)-cyclopentanecarboxylic acid amide (250 mg, 0.83 mmol) and 1-bromomethyl-4-trifluoromethyl-benzene according to the N-alkylation procedure described in Example 11: 1 H NMR (DMSO-d6) δ 7.73 (d, 2 H, J=8.0 Hz), 7.56 (m, 4 H), 7.41 (d, 2 H, J=8.0 Hz), 7.08 (s br, 1 H), 6.77 (s br, 1 H), 4.66 (AB2,2 H,Δv=20,Jab=24 Hz), 4.37 (m, 1 H), 2.85 (m, 1 H), 1.76 (m, 4 H), 1.51 (m, 2 H); MS m/e 460.98 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]=1.C([Li])CCC.[S:18](Cl)(Cl)(=[O:20])=[O:19].[NH3:23]>CCOCC.CCCCCC>[C:7]1([C:3]2[S:4][CH:5]=[CH:6][C:2]=2[S:18]([NH2:23])(=[O:20])=[O:19])[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]=1
Reactant: N
Reactant: O=S(=O)(Cl)Cl
Reactant: Brc1ccsc1C1=CCCCC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: NS(=O)(=O)c1ccsc1C1=CCCCC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of 3-bromo-2-(1-cyclohexenyl)-thiophene (prepared by the method of N. Gjos and S. Gronowitz, Acta. Chem. Scan., 26, 1851-59, (1972)) (8.0 g, 32.9 mmol) in ether (30 ml) was added dropwise to a stirring solution of n-butyllithium (1.37M, 25.2 ml, 34.6 mmol) in ether (60 ml) precooled to -78° C. The solution was stirred another 30 minutes at -78° C. and was then treated with sulfuryl chloride (3.2 ml, 40 mmol) in hexane (10 ml). After an additional 30 minutes at -78° C., anhydrous ammonia (9 ml, 300 mmol) was added, the suspension warmed to 25° C. and poured into ether, washed with water and brine, dried over magnesium sulfate and reduced in volume. The product was crystallized by trituration with butyl chloride and hexane affording 2.51 g white solid (31%) m.p. 115°-121° C.
Reaction SMILES: [CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C@@H:12]4[C:17]([CH2:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C@@H:4]2[OH:21])=[CH:16][C:15](=[O:20])[CH2:14][CH2:13]4)[CH3:2].[C:22]1([CH2:28][CH2:29][C:30](Cl)=[O:31])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>N1C=CC=CC=1.C1C=CC=CC=1>[CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C@@H:12]4[C:17]([CH2:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C@@H:4]2[O:21][C:30](=[O:31])[CH2:29][CH2:28][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[CH:16][C:15](=[O:20])[CH2:14][CH2:13]4)[CH3:2]
Reactant: O=C(Cl)CCc1ccccc1
Reactant: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2O
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2OC(=O)CCc1ccccc1
Yield: 62.3 %

Procedure:
Add 13β-ethyl-17β-hydroxy-gon-4-en-3-one (0.11 g.) in dry pyridine (0.35 cc.) at -20° to 3-phenylpropionyl chloride (0.11 g.) in benzene (0.3 cc.). Keep this at -10° for 16 hours, add ice-cold water and extract with a mixture of equal volumes of ether and benzene. Wash the extracts in turn with 2N potassium hydroxide solution, water, 2N hydrochloric acid solution, and brine, and dry. Evaporate solvent to give a residue and recrystallize from a mixture of ether and ethyl acetate to obtain the title compound (0.10 g.), m.p. 135°-40°; infrared absorption peaks at 5.81, 5.99, 8.51, 13.3, 14.3 μ, showing no absorption due to hydroxyl.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][NH2:15])[C@H:10]([F:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC1C([O:24][C:25]([C:27]2[N:28]=[N:29][C:30]([CH2:46][CH2:47][CH2:48][CH3:49])=[C:31]([C:33]3[CH:38]=[CH:37][C:36]([O:39][CH:40]4[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]4)=[CH:35][CH:34]=3)[CH:32]=2)=O)=C(F)C(F)=C(F)C=1F>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][NH:15][C:25]([C:27]2[N:28]=[N:29][C:30]([CH2:46][CH2:47][CH2:48][CH3:49])=[C:31]([C:33]3[CH:38]=[CH:37][C:36]([O:39][CH:40]4[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45]4)=[CH:35][CH:34]=3)[CH:32]=2)=[O:24])[C@H:10]([F:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCCc1nnc(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)cc1-c1ccc(OC2CCCCC2)cc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](CN)[C@H](F)C1
Solvent: ClCCl
Product: CCCCc1nnc(C(=O)NC[C@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2F)cc1-c1ccc(OC2CCCCC2)cc1

Procedure:
To a stirred solution of (±)-cis-4-aminomethyl-3-fluoro-piperidine-1-carboxylic acid tert-butyl ester (0.65 mmol, 150 mg) in dichloromethane (3 mL) was added 6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazine-3-carboxylic acid pentafluorophenyl ester (Example 93, 0.75 mmol, 400 mg) and TEA (1.3 mmol, 0.2 mL). After stirring the reaction at room temperature for 8 h, dichloromethane (5 mL) was added. The reaction was washed with saturated sodium bicarbonate solution (5 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. Crude product was purified using hexane:ethyl acetate on 12 g normal phase ISCO flash column to provide (±)-cis-4-({[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazine-3-carbonyl]-amino}-methyl)-3-fluoro-piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[C:29]5[O:28][CH2:27][O:26][C:25]=5[CH:24]=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.C([O:39][CH2:40][C:41](Cl)=[O:42])(=O)C>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[CH:24][C:25]3[O:26][CH2:27][O:28][C:29]=3[C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:35])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:40](=[O:39])[CH2:41][OH:42])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:34][CH2:33]1
Reactant: Cc1[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc2c1C(=O)N[C@H]1CC[C@@H](N)CC1
Reactant: CC(=O)OCC(=O)Cl
Agent: Cl
Product: Cc1[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc2c1C(=O)N[C@H]1CC[C@@H](NC(=O)CO)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-4-[5-(cyclopropylmethoxy)-1,3-benzodioxol-4-yl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f3) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:32]([NH:34][CH:35]2[CH2:39][CH2:38][NH:37][CH2:36]2)=[O:33])=[CH:4][N:3]=1.[C:40](O)(=[O:42])[CH3:41].C(=O)([O-])[O-]>>[C:40]([N:37]1[CH2:38][CH2:39][CH:35]([NH:34][C:32]([C:5]2[C:6]3[S:10][CH:9]=[C:8]([C:11]4[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]5[N:21]([CH3:29])[C:22]6[C:27]([CH:28]=5)=[CH:26][CH:25]=[CH:24][CH:23]=6)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=4)[C:7]=3[C:2]([NH2:1])=[N:3][CH:4]=2)=[O:33])[CH2:36]1)(=[O:42])[CH3:41]
Reactant: CC(=O)O
Reactant: COc1cc(-c2csc3c(C(=O)NC4CCNC4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Agent: O=C([O-])[O-]
Product: COc1cc(-c2csc3c(C(=O)NC4CCN(C(C)=O)C4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Reaction time: 20 h

Procedure:
4-Amino-3-(3-methoxy-4-{[(1-methyl-1H-indol-2-yl)carbonyl]amino}phenyl)-N-pyrrolidin-3-ylthieno[3,2-c]pyridine-7-carboxamide (100 mg, 0.185 mmol) and acetic acid (9.6 μL, 0.168 mmol) were treated according to General Procedure D. MP-carbonate (184 mg, 0.504 mmol) was added and mixture placed on shaker for 20 hours. The mixture was then filtered and solvent removed in vacuo. The product was purified via flash chromatography to furnish the title compound as a off-white powder. (3.2 mg, 0.0051 mmol): LCMS (Conditions b): MH+=583, Rt=2.85 minutes; 1H NMR (DMSO-d6, 400 MHz) δ 9.50 (1H), 8.62 (1H), 8.54 (1H), 8.00 (1H), 7.71 (1H), 7.59 (2H), 7.35 (2H), 7.19 (1H), 7.15 (1H), 7.06 (1H), 6.04 (2H), 4.46–4.56 (1H), 4.04 (3H), 3.91 (3H), 3.91 (3H), 3.80 (1H), 3.61 (1H), 3.50 (1H), 3.39 (1H), 2.00–2.22 (2H), 1.96 (3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([N:34]1[CH2:39][CH2:38][CH2:37][CH:36]([OH:40])[CH2:35]1)(=[O:33])=[O:32]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[S:31]([N:34]3[CH2:39][CH2:38][CH2:37][CH:36]([OH:40])[CH2:35]3)(=[O:33])=[O:32])=[CH:7][C:2]=2[F:1])=[N:18][CH:19]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Reactant: O=S(=O)(c1ccccc1Br)N1CCCC(O)C1
Product: Nc1cnc(-c2ccc(-c3ccccc3S(=O)(=O)N3CCCC(O)C3)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 448 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amine and racemic-1-((2-bromophenyl)sulfonyl)piperidin-3-ol. MS (ESI): mass calcd. for C21H21FN4O3S, 428.13; m/z found, 429.1 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.34 (s, 1H), 8.31 (d, J=1.4, 1H), 8.11-8.06 (m, 1H), 8.01-7.96 (m, 1H), 7.73-7.68 (m, 1H), 7.64-7.59 (m, 1H), 7.44-7.40 (m, 1H), 7.34-7.32 (m, 1H), 7.31-7.29 (m, 1H), 3.44-3.35 (m, 1H), 3.27-3.21 (m, 1H), 3.15-3.06 (m, 1H), 2.48-2.38 (m, 1H), 2.27-2.21 (m, 1H), 1.88-1.79 (m, 1H), 1.68-1.59 (m, 1H), 1.41-1.28 (m, 1H), 1.26-1.15 (m, 1H).
Reaction SMILES: [CH3:1][N:2]([CH2:6][CH2:7][OH:8])[CH2:3][CH2:4][OH:5].C(N(CC)CC)C.Cl[C:17](Cl)([O:19]C(=O)OC(Cl)(Cl)Cl)Cl.C(OCC)C>O1CCCC1>[CH3:1][N:2]1[CH2:6][CH2:7][O:8][C:17](=[O:19])[O:5][CH2:4][CH2:3]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CN(CCO)CCO
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN1CCOC(=O)OCC1
Temperature: -20 °C
Reaction time: 2 h
Yield: 248.8 %

Procedure:
A round bottom flask was charged with N-methyl diethanolamine (10.0 g, 83.9 mmol), triethylamine (24.0 mL, 167.8 mmol), dry tetrahydrofuran (THF) (600 mL) and stirbar. The reaction flask was cooled to −20° C. under a nitrogen atmosphere. Separately, triphosgene (8.3 g, 28.8 mmol) was dissolved in dry THF (100 mL) and added slowly to the reaction mixture. A white precipitate formed instantly and stirring was continued for another 2 hours maintaining a reaction temperature less than 10° C. Diethyl ether (800 mL) was added to further precipitate any remaining HCl salts followed by filtration of the heterogeneous solution. The filtrate was concentrated yielding a yellow/brown oil product (10.4 g, 85%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:16])=[C:8]2[N:13]([CH:14]=1)[N:12]=[CH:11][NH:10][C:9]2=O)=[O:5])[CH3:2].O=P(Cl)(Cl)[Cl:19].CCN(C(C)C)C(C)C.OP([O-])([O-])=O.[K+].[K+]>O.C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:16])=[C:8]2[N:13]([CH:14]=1)[N:12]=[CH:11][N:10]=[C:9]2[Cl:19])=[O:5])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cn2nc[nH]c(=O)c2c1C
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cn2ncnc(Cl)c2c1C
Temperature: 111 °C
Reaction time: 0.33 h

Procedure:
A 2L 3-neck flask was charged with 5-methyl-4-oxo-3,4-dihydro-pyrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid ethyl ester (50 g, 226 mmol) and dry toluene (750 ml). POCl3 (41.6 g, 271.5 mmol) was added in one portion, followed by slow addition of DIEA (32.2 g, 248.9 mmol) at a rate, which maintained the temperature below 30° C. The resulting suspension was heated to 111° C. for 24 h becoming homogeneous at 80° C. The reaction was monitored by HPLC after quenching with 2 M MeNH2/THF (10 μl reaction mixture, 20 μl MeNH2/THF in 200 μl acetonitrile). Upon completion, reaction was cooled to −8° C. and a solution of K2HPO4 in H2O (170 g/775 ml) was added maintaining temperature below 1° C. The mixture was stirred for 20 min at −8° C. then warmed to ambient temperature for 1 h. The resulting light suspension was filtered through a pad of celite and the layers were separated. The organic layer was washed with K2HPO4 in H2O (27 g/130 ml), followed by water (250 ml) and dried (Na2SO4). The solution was filtered and concentrated to a yellow foam 4A (54.0 g, 100%). MS: 235 (MeNH2 adduct) (M+H)+; HPLC Ret Time (MeNH2 adduct): 2.240 min (YMC S5 ODS 4.6×50 mm column, 4 min gradient, 3 mL/min).
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+:15]>CO.O.[Pd]>[C:1]([N:5]1[CH2:10][CH2:9][CH:8]([NH2:15])[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N1CCC(=O)CC1
Reactant: [NH4+]
Agent: [Pd]
Agent: O=C[O-]
Solvent: O
Solvent: CO
Product: CC(C)(C)N1CCC(N)CC1
Reaction time: 8 h

Procedure:
To a solution of 1-tert-butylpiperidin-4-one (5.0 g) in methanol (100 mL) and water (10 mL) was added ammonium formate (20.3 g) and 0.5 g of Pd/C (10%). The mixture was stirred overnight. The mixture was filtered and the filtrate was concentrated under vacuum and the residue was diluted with ethyl acetate (500 mL) and washed with water and brine. After drying over Na2SO4 and filtration, the solvent was evaporated under vacuum to provide the title compound.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:11]=[C:12]([C:17](=[O:21])[CH:18]([CH3:20])[CH3:19])[CH:13]=[C:14]([OH:16])[CH:15]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:28]([O:30][C:31](=[O:56])[CH2:32][CH2:33][CH2:34][O:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47]Br)[C:37]=1[CH2:49][CH2:50][C:51]([O:53][CH2:54][CH3:55])=[O:52])[CH3:29]>CC(C)=O.CN(C=O)C>[CH2:28]([O:30][C:31](=[O:56])[CH2:32][CH2:33][CH2:34][O:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][O:16][C:14]2[CH:13]=[C:12]([C:17](=[O:21])[CH:18]([CH3:19])[CH3:20])[CH:11]=[C:10]([C:8]3[CH:7]=[CH:6][C:5]4[O:1][CH2:2][O:3][C:4]=4[CH:9]=3)[CH:15]=2)[C:37]=1[CH2:49][CH2:50][C:51]([O:53][CH2:54][CH3:55])=[O:52])[CH3:29]
Reactant: CC(C)C(=O)c1cc(O)cc(-c2ccc3c(c2)OCO3)c1
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCBr)c1CCC(=O)OCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(=O)C(C)C)cc(-c3ccc4c(c3)OCO4)c2)c1CCC(=O)OCC
Temperature: 75 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
To a solution of 1-(3-benzo[1,3]dioxol-5-yl-5-hydroxy-phenyl)-2-methyl-propan-1-one (109 mg) in a mixture of acetone and DMF (2:1, 3 mL) were added cesium carbonate (624 mg) and 4-[3-(6-bromo-hexyl)-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (190 mg). The resulting mixture was stirred at 75° C. overnight. Then the insoluble material was filtered out and the filtrate was diluted with ethyl acetate and washed with water and brine. The organic extract was dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column using ethyl acetate and hexanes to yield 194 mg of the title compound (75% yield). HRMS calcd for C40H50O9 [M+Na]+ 697.3347, observed 697.3344.
Reaction SMILES: C(O[C:4](=[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][C:12]1=[O:20])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)C.[CH3:21][N:22]([CH3:33])[CH2:23][CH2:24][O:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1>>[CH3:21][N:22]([CH3:33])[CH2:23][CH2:24][O:25][C:26]1[CH:32]=[CH:31][C:29]([NH:30]/[C:4](=[C:11]2\[C:12](=[O:20])[NH:13][C:14]3[C:19]\2=[CH:18][CH:17]=[CH:16][CH:15]=3)/[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)=[CH:28][CH:27]=1
Reactant: CCOC(=C1C(=O)Nc2ccccc21)c1ccccc1
Reactant: CN(C)CCOc1ccc(N)cc1
Product: CN(C)CCOc1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 11 by reacting 3-(1-ethoxy-1-phenyl-methylidene)-2-indolinone with 4-(2-dimethylaminoethyloxy)-aniline.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[O:6][C@@H:5]2[C@@H:7]([CH2:20][NH:21][CH3:22])[O:8][C@@H:9]([N:10]3[CH:18]=[N:17][C:16]4[C:11]3=[N:12][CH:13]=[N:14][C:15]=4[NH2:19])[C@@H:4]2[O:3]1.O=[C:25]1[CH2:28][CH:27]([NH:29][C:30](=[O:39])[O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:26]1.[BH3-]C#N.[Na+]>CO>[CH2:32]([O:31][C:30](=[O:39])[NH:29][CH:27]1[CH2:28][CH:25]([N:21]([CH2:20][C@@H:7]2[C@@H:5]3[C@@H:4]([O:3][C:2]([CH3:23])([CH3:1])[O:6]3)[C@H:9]([N:10]3[CH:18]=[N:17][C:16]4[C:11]3=[N:12][CH:13]=[N:14][C:15]=4[NH2:19])[O:8]2)[CH3:22])[CH2:26]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CNC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21
Reactant: O=C1CC(NC(=O)OCc2ccccc2)C1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CN(C[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21)C1CC(NC(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.1 %

Procedure:
To a solution of 9-((3aR,4R,6R,6aR)-2,2-dimethyl-6-((methylamino)methyl)tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-9H-purin-6-amine (190 mg, 0.59 mmol) and benzyl (3-oxocyclobutyl)carbamate (240 mg, 1.37 mmol) in MeOH (5 mL) was added Ti[OCH(CH3)2]4 (216 mg, 0.59 mmol). The mixture was stirred at rt for 1 h. Then NaCNBH3 (95 mg, 1.52 mmol) was added, the reaction was stirred at rt overnight. The reaction was filtered and evaporated, the residue was purified by prep-TLC (DCM:MeOH=20:1) to obtain the desired compound (90 mg, yield 29%).
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].C([O:15][CH2:16][C@H:17]1[CH2:22][N:21]([C:23]2[C:32]3[C:27](=[CH:28][C:29]([CH3:33])=[CH:30][CH:31]=3)[N:26]=[C:25]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[OH:40])[N:24]=2)[CH2:20][CH2:19][N:18]1[C:41]([O:43][C@@H:44]1[CH2:48][CH2:47][O:46][CH2:45]1)=[O:42])C1C=CC=CC=1>C(O)C.[OH-].[OH-].[Pd+2]>[F:5][C:4]([F:7])([F:6])[C:2]([OH:3])=[O:1].[OH:15][CH2:16][C@H:17]1[CH2:22][N:21]([C:23]2[C:32]3[C:27](=[CH:28][C:29]([CH3:33])=[CH:30][CH:31]=3)[N:26]=[C:25]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[OH:40])[N:24]=2)[CH2:20][CH2:19][N:18]1[C:41]([O:43][C@@H:44]1[CH2:48][CH2:47][O:46][CH2:45]1)=[O:42]
Reactant: Cc1ccc2c(N3CCN(C(=O)O[C@@H]4CCOC4)[C@@H](COCc4ccccc4)C3)nc(-c3ccccc3O)nc2c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: Cc1ccc2c(N3CCN(C(=O)O[C@@H]4CCOC4)[C@@H](CO)C3)nc(-c3ccccc3O)nc2c1
Temperature: 50 °C

Procedure:
To a solution of (2R)-(R)-tetrahydrofuran-3-yl 2-((benzyloxy)methyl)-4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazine-1-carboxylate TFA salt (94 mg, 0.17 mmol) in ethanol was added Pd(OH)2 (78 mg), and the reaction was heated at 50° C. under an H2 atmosphere at ambient pressure. The reaction was filtered, and purification using reverse phase HPLC (10-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)) gave (2R)-(R)-tetrahydrofuran-3-yl 2-(hydroxymethyl)-4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazine-1-carboxylate trifluoroacetate. LC/MS: m/z 465.5 (M+H)+ at 2.23 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6]1[N:7](S(C2C=CC=CC=2)(=O)=O)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:10][CH:9]=2.[OH-].[K+].O>O1CCCC1.CO>[O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:10][CH:9]=2
Reactant: CS(=O)(=O)c1ccc2c(c1)cc(C1CCCO1)n2S(=O)(=O)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CS(=O)(=O)c1ccc2[nH]c(C3CCCO3)cc2c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 82.2 %

Procedure:
To a solution of the compound obtained in Example 13 (1) (210 mg) in a mixture of tetrahydrofuran/methanol (2:1, 15 ml), a 1N aqueous potassium hydroxide solution (1.6 ml) was added and the mixture was stirred at 100° C. for 2 hours. The reaction solution was then poured into water, extracted with dichloromethane, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was separated using silica gel preparative thin-layer chromatography (hexane:ethyl acetate=1:1) to obtain 113 mg of the desired product as a white powder.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C([Li])CCC.[CH:13]([C:15]1[CH:16]=[C:17]([C:26]([CH3:30])([CH3:29])[C:27]#[N:28])[CH:18]=[C:19]([C:21]([CH3:25])([CH3:24])[C:22]#[N:23])[CH:20]=1)=[O:14]>C(OCC)C.CCCCCC>[OH:14][CH:13]([C:15]1[CH:20]=[C:19]([C:21]([CH3:25])([CH3:24])[C:22]#[N:23])[CH:18]=[C:17]([C:26]([CH3:30])([CH3:29])[C:27]#[N:28])[CH:16]=1)[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C#N)c1cc(C=O)cc(C(C)(C)C#N)c1
Reactant: Brc1cccnc1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CC(C)(C#N)c1cc(C(O)c2cccnc2)cc(C(C)(C)C#N)c1
Temperature: 25 °C

Procedure:
A solution of 3-bromopyridine (0.31 g) in diethyl ether was stirred and cooled to -70° while a solution of n-butyl-lithium in hexane (1.6M, 1.33 ml) was added, followed by 2,2'-(5 formyl-1,3-phenylene)di(2-methylpropiononitrile), (0.48 g). The mixture was allowed to warm to room temperature and was then extracted with 2N aqueous hydrochloric acid (10 ml). The acid extract was separated, basified with 10N aqueous sodium hydroxide solution and extracted twice with ethyl acetate. The extracts were combined, dried and evaporated to dryness under reduced pressure, and the residue was purified by flash column chromatography, eluting with ethyl acetate, to give 2,2'-[5-(1-hydroxy-1-(3-pyridyl]methyl)-1,3-phenylene]di(2-methyl propiononitrile), mp. 117°-120°.