Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][C:13]([OH:19])=[CH:14][CH:15]=3)[O:10][C:9]=2[CH:20]([CH3:22])[CH3:21])=[CH:4][CH:3]=1.C1N2CN3CN(C2)CN1C3.Cl.[C:34](O)(=[O:36])C>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:17](=[O:18])[C:16]3[C:11](=[C:12]([CH:34]=[O:36])[C:13]([OH:19])=[CH:14][CH:15]=3)[O:10][C:9]=2[CH:20]([CH3:22])[CH3:21])=[CH:6][CH:7]=1
Reactant: CC(=O)O
Reactant: CC(C)c1oc2cc(O)ccc2c(=O)c1-c1ccc(Cl)cc1
Agent: C1N2CN3CN1CN(C2)C3
Agent: Cl
Solvent: ClCCl
Product: CC(C)c1oc2c(C=O)c(O)ccc2c(=O)c1-c1ccc(Cl)cc1
Temperature: 100 °C
Reaction time: 20 h

Procedure:
A mixture of 3-(4-chlorophenyl)-7-hydroxy-2-isopropyl-chromen-4-one (12.48 g, 39.6 mmol) and hexamethylenetetramine (39.46 g, 0.28 mol) in acetic acid (250 ml) is stirred at 100° C. for 20 h. After the mixture has cooled to room temperature, the solvent is removed in vacuo to afford a black oily residue. 5M HCl solution (150 ml) is added, and the mixture is heated under reflux for 30 min. The reaction mixture is poured onto ice/water, and the resulting brown solid is isolated by filtration. The solid is taken up in dichloromethane, the mixture is passed through a bed of Celite, and the solvent is evaporated in vacuo. The solid residue is stirred at room temperature with ethyl acetate, filtered and washed with hexane to afford the desired product as a pale brown solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[CH3:32][O:33][C:34]1[CH:44]=[CH:43][C:42](/[CH:45]=[CH:46]\[C:47]2[CH:52]=[C:51]([O:53][CH3:54])[C:50]([O:55][CH3:56])=[C:49]([O:57][CH3:58])[CH:48]=2)=[CH:41][C:35]=1[O:36][CH2:37][C:38](O)=[O:39]>ClCCl.O>[S:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[NH:1][C:38](=[O:39])[CH2:37][O:36][C:35]1[CH:41]=[C:42](/[CH:45]=[CH:46]\[C:47]2[CH:52]=[C:51]([O:53][CH3:54])[C:50]([O:55][CH3:56])=[C:49]([O:57][CH3:58])[CH:48]=2)[CH:43]=[CH:44][C:34]=1[O:33][CH3:32]
Reactant: COc1ccc(/C=C\c2cc(OC)c(OC)c(OC)c2)cc1OCC(=O)O
Reactant: Nc1nc2ccccc2s1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: COc1ccc(/C=C\c2cc(OC)c(OC)c(OC)c2)cc1OCC(=O)Nc1nc2ccccc2s1
Yield: 78 %

Procedure:
To a solution of 2-aminobenzothiazole (150 mg, 1.0 mmol) in dichloromethane (20 mL) was added 1-Ethyl-3-(3-Dimethylaminopropyl)carbodiimide (EDC) (191 mg, 1.0 mmol) and 1-hydroxy-1,2,3-benzotriazole (HOBt) (13.5 mg, 0.1 mmol). Then added 2-{2-methoxy-5-[(Z)-2-(3,4,5-trimethoxyphenyl)-1-ethenyl]phenoxy}acetic acid (1) (374 mg, 1.0 mmol) and the reaction mixture was stirred at a temperature of 25° C. for 24 h and the reaction was monitored by TLC. Then to this water is added and extracted with dichloromethane. The solvent was evaporated under vacuum to afford the crude product. This was further purified by column chromatography using ethyl acetate and hexane as solvent system to obtain the pure product (8a) (395 mg, 80% yield).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[S:12][CH:13]=[CH:14][N:15]=3)[S:10][C:3]=12.[OH:16][C:17]1[CH:25]=[C:24]2[C:20]([C:21]([C:28]([NH:30][CH:31]([CH3:33])[CH3:32])=[O:29])=[C:22]([CH3:27])[N:23]2[CH3:26])=[CH:19][CH:18]=1.C([O-])([O-])=O.[Cs+].[Cs+]>>[CH:31]([NH:30][C:28]([C:21]1[C:20]2[C:24](=[CH:25][C:17]([O:16][C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[CH:8]=[C:9]([C:11]5[S:12][CH:13]=[CH:14][N:15]=5)[S:10][C:3]=34)=[CH:18][CH:19]=2)[N:23]([CH3:26])[C:22]=1[CH3:27])=[O:29])([CH3:33])[CH3:32]
Reactant: Clc1ccnc2cc(-c3nccs3)sc12
Reactant: Cc1c(C(=O)NC(C)C)c2ccc(O)cc2n1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cc1c(C(=O)NC(C)C)c2ccc(Oc3ccnc4cc(-c5nccs5)sc34)cc2n1C
Yield: 38 %

Procedure:
This material was prepared by the reaction 7-chloro-2-(1,3-thiazol-2-yl)thieno[3,2-b]pyridine 41a (0.084 g, 0.33 mmole) with 6-hydroxy-N-isopropyl-1,2-dimethyl-1H-indole-3-carboxamide 66b (0.082 g, 0.33 mmole) and Cs2CO3 (0.116 g, 0.33 mmole) to give a off-white solid (0.058 g, 38%). 1H NMR (300 MHz, CDCl3) δ 8.46 (1H, d, J=5.4 Hz), 7.93 (1H, s), 7.88 (1H, d, J=3.2Hz), 7.73 (1H, d, J=8.6 Hz), 7.42 (1H, d, J=3.2 Hz), 7.17 (1H, d, J=2.1 Hz), 7.07 (1H, dd, J=2.1, 8.6 Hz), 6.54 (1H, d, J=5.4 Hz), 5.71 (1H, d, J=7.7 Hz), 4.36 (1H, m), 3.66 (3H, s), 2.72 (3H, s), 1.31 (6H, d, J=6.6 Hz); ESIMS (MH+): 463.10.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].Br[CH2:24][CH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.BrCC1CCCCO1>>[O:28]1[CH2:29][CH2:30][CH:25]([CH2:24][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]3([C:21]4[C:12](=[CH:13][C:14]5[O:19][CH2:18][CH2:17][O:16][C:15]=5[CH:20]=4)[O:11][CH2:10]3)[C:2]2=[O:22])[CH2:26][CH2:27]1
Reactant: BrCC1CCOCC1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Agent: BrCC1CCCCO1
Product: O=C1N(CC2CCOCC2)c2ccccc2C12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, and 4-(bromomethyl)tetrahydro-2H-pyran to replace 2-(bromomethyl)tetrahydro-2H-pyran, 1′-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (95%) as a colorless solid: mp 129-131° C. (hexanes); 1H NMR (300 MHz, CDCl3) δ7.29 (ddd, J=7.9, 7.9, 1.3 Hz, 1H), 7.16 (d, J=7.5 Hz, 1H), 7.04 (ddd, J=7.4, 7.4, 1.0 Hz, 1H), 6.89 (d, J=8.1 Hz, 1H), 6.50 (s, 1H), 6.18 (s, 1H), 4.87 (d, J=8.9 Hz, 1H), 4.62 (d, J=8.9 Hz, 1H), 4.22-4.16 (m, 2H), 4.15-4.09 (m, 2H), 4.03-3.94 (m, 2H), 3.74 (dd, J=13.8, 7.7 Hz, 1H), 3.55 (dd, J=13.8, 7.1 Hz, 1H), 3.42-3.30 (m, 2H), 2.20-2.03 (m, 1H), 1.66-1.56 (m, 2H), 1.53-1.40 (m, 2H); 13C NMR (75 MHz, CDCl3) δ177.8, 155.4, 144.7, 142.8, 138.4, 132.5, 128.9, 124.2, 123.4, 121.1, 111.5, 108.7, 99.5, 80.4, 67.6, 67.5, 64.6, 64.0, 58.1, 46.2, 34.0, 30.93, 30.86; MS (ES+) m/z 394.2 (M+1); Anal. Calcd for C23H23NO5: C, 70.21; H, 5.89; N, 3.56. Found: C, 70.15; H, 5.92; N, 3.20.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][NH:9][C:10]2[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][N:13]=[C:12]([NH:19][CH2:20][C:21]3[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=3[O:28][C:29]([F:32])([F:31])[F:30])[N:11]=2)[CH2:4][CH2:3]1.Br[CH2:34][CH2:35][CH2:36][CH2:37]Br.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:27][C:25]1[CH:24]=[CH:23][C:22]([O:28][C:29]([F:31])([F:30])[F:32])=[C:21]([CH:26]=1)[CH2:20][NH:19][C:12]1[N:11]=[C:10]([NH:9][CH2:8][C@H:5]2[CH2:4][CH2:3][C@H:2]([N:1]3[CH2:37][CH2:36][CH2:35][CH2:34]3)[CH2:7][CH2:6]2)[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][N:13]=1
Reactant: N[C@H]1CC[C@H](CNc2nc(NCc3cc(Cl)ccc3OC(F)(F)F)ncc2[N+](=O)[O-])CC1
Reactant: BrCCCCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cnc(NCc2cc(Cl)ccc2OC(F)(F)F)nc1NC[C@H]1CC[C@H](N2CCCC2)CC1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
To a solution of N4-[(trans-4-aminocyclohexyl)methyl]-N2-[5-chloro-2-(trifluoromethoxy)benzyl]-5-nitropyrimidine-2,4-diamine (51 mg, 0.1 mmol) in DMF (0.5 mL) was added 1,4-dibromobutane (36 μL, 0.3 mmol) and DIPEA (104 μL, 0.6 mmol). The reaction mixture was stirred at 50° C. for 24 h and then 72 h at room temperature. The reaction mixture was then partitioned between EtOAc (20 mL) and saturated NaHCO3 (less than 1 mL). The organic phase was washed with water (2×2 mL) and dried over Na2SO4. The resulting residue was purified by preparative HPLC to afford 13 mg (25%) of the title compound as a yellow oily solid, m/z 529.3 [M+1]+
Reaction SMILES: C([O:5][C:6](=[O:40])[CH2:7][N:8]1[C:16](=[O:17])[C:15]2[N:14]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[C:13]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([O:33][C:34]([F:37])([F:36])[F:35])[CH:28]=3)=[N:12][C:11]=2[N:10]([CH3:38])[C:9]1=[O:39])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][N:14]2[C:15]3[C:16](=[O:17])[N:8]([CH2:7][C:6]([OH:40])=[O:5])[C:9](=[O:39])[N:10]([CH3:38])[C:11]=3[N:12]=[C:13]2[O:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][C:34]([F:37])([F:35])[F:36])[CH:28]=2)=[CH:24][CH:23]=1
Reactant: Cn1c(=O)n(CC(=O)OC(C)(C)C)c(=O)c2c1nc(Oc1cccc(OC(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1c(=O)n(CC(=O)O)c(=O)c2c1nc(Oc1cccc(OC(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 100.9 %

Procedure:
Step 2 tert-Butyl-2-(7-(4-chlorobenzyl)-3-methyl-2,6-dioxo-8-(3-(trifluoromethoxy)phenoxy)-2,3,6,7-tetrahydro-1H-purin-1-yl)acetate (0.20 g, 0.34 mmol) was dissolved in DCM (4 mL) and TFA (0.26 ml, 3.4 mmol) was added. The reaction was stirred at room temperature for 15 h then evaporated under reduced pressure to give 2-(7-(4-chlorobenzyl)-3-methyl-2,6-dioxo-8-(3-(trifluoromethoxy)phenoxy)-2,3,6,7-tetrahydro-1H-purin-1-yl)acetic acid (0.18 g, 100% yield). LCMS retention time=3.915 minutes and 97% purity, LCMS MH+ 525. 1H NMR (DMSO-d6) δ 7.59 (t, 1H, J=8 Hz), 7.50-7.54 (m, 1H), 7.45 (d, 1H, J=8 Hz), 7.41 (s, 4H), 7.31 (d, 1H, J=8 Hz), 5.41 (s, 2H), 4.52 (s, 2H), 3.30 (s, 3H)
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:14])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([Br:12])=[CH:7][C:6]=2[Cl:13].[CH3:15][C:16]([Si:19](Cl)([CH3:21])[CH3:20])([CH3:18])[CH3:17]>>[C:16]([Si:19]([O:14][C:3]1[C:2]([Br:1])=[CH:11][C:10]2[C:5](=[C:6]([Cl:13])[CH:7]=[C:8]([Br:12])[CH:9]=2)[CH:4]=1)([CH3:21])[CH3:20])([CH3:18])([CH3:17])[CH3:15]
Reactant: Oc1cc2c(Cl)cc(Br)cc2cc1Br
Reactant: CC(C)(C)[Si](C)(C)Cl
Product: CC(C)(C)[Si](C)(C)Oc1cc2c(Cl)cc(Br)cc2cc1Br

Procedure:
The title compound was prepared by reacting 3,6-dibromo-8-chloro-2-naphthol (3.00 g, 8.92 mmol) with TBDMS-Cl (1.75 g, 150.7 mmol) according to method F to yield 3.36 g (84%) of a white solid: mp 58-64° C.; 1H NMR (CDCl3): δ 0.34 (6H, s), 1.08 (9H, s), 7.57 (1H, s), 7.62 (1H, d, J=1.72 Hz), 7.75 (1H, d, J=1.24 Hz), 7.97 (1H, s); MS (ESI) m/z333/335/337 (M−H)−.
Reaction SMILES: [Si]([O:8][CH:9]1[CH2:13][CH:12]=[C:11]([CH2:14][C:15]#[C:16][Si](C)(C)C)[CH2:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH2:14]([C:11]1[CH2:10][CH:9]([OH:8])[CH2:13][CH:12]=1)[C:15]#[CH:16]
Reactant: CC(C)(C)[Si](C)(C)OC1CC=C(CC#C[Si](C)(C)C)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#CCC1=CCC(O)C1
Yield: 38 %

Procedure:
By using 0.85 g of (RS)-3-(3-trimethylsilyl-2-propynyl)-3-cyclopenten-1-yl (t-butyldimethylsilyl) ether and 8.5 ml of 1 M tetrahydrofuran solution of tetrabutylammonium fluoride and by the same procedures as in (5) of the intermediate preparation example 1, there was obtained 128 mg of (RS)-3-propargyl-3-cyclopenten-1-ol. Yield 37%
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][C:10]=2[F:22])=[N:6][CH:7]=1.C(N(CC)CC)C.Cl[C:38]([O:40][CH2:41][CH3:42])=[O:39]>CN(C=O)C>[Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[C:10]([F:22])=[CH:11][C:12]([CH:16]3[CH2:17][CH2:18][N:19]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:20][CH2:21]3)=[C:13]([CH3:15])[CH:14]=2)=[N:6][CH:7]=1
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNCC4)cc3F)ncc2Cl)n[nH]1
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCC(c2cc(F)c(Nc3ncc(Cl)c(Nc4cc(C)[nH]n4)n3)cc2C)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 5-chloro-N2-(2-fluoro-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (0.12 mmol) and triethylamine (50 uL, 0.36 mmol) in DMF (1.5 mL) was added ethyl chloroformate (26 mg, 0.24 mmol). The mixture was stirred at room temperature for 2 hours. The reaction was filtered and the filtrate was purified by preparative RP-HPLC to give Ethyl 4-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-5-fluoro-2-methylphenyl)piperidine-1-carboxylate as a white solid: 1H NMR (400 MHz, MeOD-d4) δ 8.13 (s, 1H), 7.54 (d, 1H), 7.10 (d, 1H), 6.28 (s, 1H), 4.30-4.26 (m, 2H), 4.14 (q, 2H), 2.99-2.96 (m, 3H), 2.33 (s, 3H), 2.29 (s, 3H), 1.8-1.77 (m, 2H), 1.64-1.55 (m, 2H), 1.28 (t, 3H); ESMS m/z 488.2 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.C(=O)([O-])O.[K+].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O>CN(C)C=O>[CH2:25]([O:10][C:9](=[O:11])[CH:8]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)[NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)c1ccc(Br)cc1
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC(C(=O)OCc1ccccc1)c1ccc(Br)cc1
Reaction time: 6 h
Yield: 49.6 %

Procedure:
(4-Bromo-phenyl)-tert-butoxycarbonylamino-acetic acid (780 mg, 2.4 mmol) was dissolved in N,N-dimethylformamide (15 mL) and to this was added potassium hydrogen carbonate (260 mg, 2.6 mmol) followed by benzyl bromide (281 μL, 2.4 mmol) and stirring continued at ambient temperature for 6 hours. The reaction was poured into water (50 mL) and extracted with ethyl acetate (2×60 mL). The organic extracts were washed with water (2×20 mL), brine, dried over sodium sulfate and filtered through a layer of silica gel. The filtrate was concentrated in vacuo and the residue crystallized from 100% hexane to give (4-bromo-phenyl)-tert-butoxycarbonylamino-acetic acid benzyl ester (500 mg, 50%).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[N:15]=[C:14]3[C:10]([N:11]=[CH:12][N:13]3[C@@H:16]3[CH2:20][C@H:19]([NH:21][C:22](=[O:33])[C@H](OCC4C=CC=CC=4)C)[C@@H:18]([OH:34])[C@H:17]3[OH:35])=[C:9]([NH:36][CH2:37][CH:38]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[N:8]=2)[CH2:3]1.[C:51]([O:55]C(=O)N[C@@H]1CCN(C2N=C3C(N=CN3[C@@H]3C[C@H](NC(=O)[C@H](OCC4C=CC=CC=4)C)[C@@H](O)[C@H]3O)=C(NCC(C3C=CC=CC=3)C3C=CC=CC=3)N=2)C1)(C)(C)[CH3:52]>>[NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[N:15]=[C:14]3[C:10]([N:11]=[CH:12][N:13]3[C@@H:16]3[CH2:20][C@H:19]([NH:21][C:22](=[O:33])[CH2:52][CH2:51][OH:55])[C@@H:18]([OH:34])[C@H:17]3[OH:35])=[C:9]([NH:36][CH2:37][CH:38]([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[N:8]=2)[CH2:3]1
Reactant: C[C@@H](OCc1ccccc1)C(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)OC(C)(C)C)C4)nc32)[C@H](O)[C@@H]1O
Reactant: C[C@@H](OCc1ccccc1)C(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](N)C4)nc32)[C@H](O)[C@@H]1O
Product: N[C@@H]1CCN(c2nc(NCC(c3ccccc3)c3ccccc3)c3ncn([C@@H]4C[C@H](NC(=O)CCO)[C@@H](O)[C@H]4O)c3n2)C1

Procedure:
The title compound is prepared analogously to (R)—N-{(1S,2R,3S,4R)-4-[2-((R)-3-amino-pyrrolidin-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-2-benzyloxy-propionamide (Example 181, step 4), by substituting {(R)-1-[9-[(1R,2S,3R,4S)-4-(3-tert-butoxy-propionylamino)-2,3-dihydroxy-cyclopentyl]-6-(2,2-diphenyl-ethylamino)-9H-purin-2-yl]-pyrrolidin-3-yl}-carbamic acid tert-butyl ester (Intermediate ZG3) for {(R)-1-[9-[(1R,2S,3R,4S)-4-((R)-2-Benzyloxy-propionylamino)-2,3-dihydroxy-cyclopentyl]-6-(2,2-diphenyl-ethylamino)-9H-purin-2-yl]-pyrrolidin-3-yl}-carbamic acid tert-butyl ester (Example 181, step 3).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH2:5][S:6]([CH3:9])(=[O:8])=[O:7])[CH3:2].[H-].[Na+].I[CH2:14][CH3:15].[Cl-].[NH4+]>CN(C=O)C.O>[CH3:9][S:6]([CH:5]([CH2:14][CH3:15])[C:4]([O:3][CH2:1][CH3:2])=[O:10])(=[O:8])=[O:7]
Reactant: CCOC(=O)CS(C)(=O)=O
Reactant: CCI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(CC)S(C)(=O)=O
Reaction time: 0.5 h
Yield: 25.7 %

Procedure:
Ethyl(methylsulfonyl)acetate (0.79 mL, 5.8 mmol, 1.0 equiv) was added dropwise via syringe to a mixture of sodium hydride (0.25 g 60% in mineral oil, 6.1 mmol, 1.1 equiv) in DMF (20 mL) at room temperature. The mixture was allowed to stir for 30 min, after which time 1-iodoethane (0.48 mL, 5.8 mmol, 1.0 equiv) was added. The reaction was allowed to stir overnight. A solution of saturated ammonium chloride (10 mL) and water (10 mL) were added, and the resulting mixture was extracted with diethyl ether (1×25 mL). The organic phase was separated, washed with water (1×10 mL), brine (1×5 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The crude material was purified by flash chromatography (2:1-0:1 heptane/ethyl acetate) to provide a white solid (0.29 g, 26%). MS (LCMS) m/z 195.4 (M+1). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.05 (t, J=7.41 Hz, 3H) 1.33 (t, J=7.12 Hz, 3H) 1.99-2.25 (m, 2H) 2.99 (s, 3H) 3.66 (dd, J=10.54, 3.90 Hz, 1H) 4.30 (q, J=7.22 Hz, 2H).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=1)O)C1C=CC=CC=1.Cl>CO.[OH-].[Pd+2].[OH-]>[CH3:24][O:23][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[CH2:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[OH:8]
Reactant: COc1cccc(C(O)c2ccccc2OCc2ccccc2)c1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: COc1cccc(Cc2ccccc2O)c1
Reaction time: 24 h
Yield: 114.9 %

Procedure:
To a solution of (2-benzyloxyphenyl)-(3-methoxyphenyl)methanol (1.68 g, 5.24 mmol) in methanol (50 ml), a 20% palladium hydroxide catalyst (168 mg) was added and furthermore 36% HCl (0.2 mL) was added thereto. The mixture was stirred under a hydrogen atmosphere for 24 hours, and then the catalyst was filtered off. The solvent was distilled under reduced pressure, and the obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:4)] to obtain the title compound (1.29 g, 100%).
Reaction SMILES: [Br:1][C:2]1[C:3]([N:20]2[CH2:25][CH2:24][N:23](C(NC3C=CC=CC=3)=O)[CH2:22][CH2:21]2)=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([N:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.BrC1C(N2CCN([CH:52]([C:54]3[CH:55]=[N:56][CH:57]=[CH:58][CH:59]=3)[CH3:53])CC2)=C([N+]([O-])=O)C(N)=NC=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].CN(C1C=CC(C=O)=CC=1)C>C(O)C.CN(C=O)C>[Br:1][C:2]1[C:3]([N:20]2[CH2:25][CH2:24][N:23]([CH:52]([C:54]3[CH:55]=[N:56][CH:57]=[CH:58][CH:59]=3)[CH3:53])[CH2:22][CH2:21]2)=[C:4]2[N:10]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([N:17]([CH3:19])[CH3:18])=[CH:15][CH:16]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)Nc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Reactant: CC(c1cccnc1)N1CCN(c2c(Br)cnc(N)c2[N+](=O)[O-])CC1
Agent: CN(C)c1ccc(C=O)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: CC(c1cccnc1)N1CCN(c2c(Br)cnc3[nH]c(-c4ccc(N(C)C)cc4)nc23)CC1
Reaction time: 16 h
Yield: 13 %

Procedure:
This was prepared using the same procedure as for 4-(6-bromo-2-(4-(dimethylamino)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)-N-phenylpiperazine-1-carboxamide, but here using 5-bromo-3-nitro-4-(4-(1-(pyridin-3-yl)ethyl)piperazin-1-yl)pyridin-2-amine (300 mg, 0.73 mmol), DMF (4.4 mL), ethanol (0.6 mL), 1M Na2S2O4 (3 eq, 2.19 mmol, 2.19 mL) and 4-(N,N-dimethylamino)benzaldehyde (1.1 eq, 0.81 mmol, 121 mg). After 16 h, concentration in vacuo and column chromatography (EtOAc-DCM-MeOH, 50:50:2) gave the product (49 mg, 13%) as a pale yellow solid; 1H-NMR (500 MHz, DMSO-d6) 1.39 (d, J=6.6 Hz, 3H, CHCH3), 2.51-2.67 (2 m, 4H, piperazine N(CH2)2), 3.00 (s, 6H, N(CH3)2), 3.58-3.66 (m, 5H, piperazine N(CH2)2 & CHCH3), 6.81 (d, J=8.9 Hz, 2H, N,N-dimethylaminophenyl), 7.39 (dd, J=7.6, 4.8 Hz, 1H, pyridine H-5), 7.78 (d, br, J=7.7 Hz, 1H, pyridine H-4), 8.00 (d, J=8.9 Hz, 2H, N,N-dimethylaminophenyl), 8.13 (s, 1H, imidazo[4,5-b]pyridine H-5), 8.48 (d, br, J=4.4 Hz, 1H, pyridine H-6), 8.58 (br s, 1H, pyridine H-2), 13.11 (br s, 1H, imidazo[4,5-b]pyridine NH);
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(O)[CH2:9][CH3:10].C(O)(C)C.S(=O)(=O)(O)O>O>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:9][CH3:10]
Reactant: CCC(O)(c1ccccc1)c1ccccc1C
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)O
Product: CC=C(c1ccccc1)c1ccccc1C
Temperature: 25 °C
Yield: 91 %

Procedure:
1-(2-Methylphenyl)-1-phenyl-1-propanol (10.4 g, 46 mmol) was dissolved into isopropanol (100 ml) and a 4 N sulphuric acid solution (50 ml) was added. The reaction mixture was heated at reflux temperature for 18 h and cooled to room temperature. Water (300 ml) was added and the mixture was extracted with dichloromethane (2×200 ml). The combined organic extracts was washed with a diluted sodium bicarbonate solution, dried over sodium sulphate and the solvent evaporated in vacuo to give 9.0 g (91% of 1-(2-methylphenyl)-1-phenyl-1-propene.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:18][C:19](=[O:27])[C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[CH:5]=[CH:6][C:7]=1[C:8]1[N:12]([CH3:13])[N:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=1.CCN(C(C)C)C(C)C.[C:37](Cl)(=[O:39])[CH3:38].C(Cl)Cl.C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[C:37]([NH:1][C:2]1[CH:3]=[C:4]([NH:18][C:19](=[O:27])[C:20]2[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=2)[CH:5]=[CH:6][C:7]=1[C:8]1[N:12]([CH3:13])[N:11]=[C:10]([C:14]([F:17])([F:15])[F:16])[CH:9]=1)(=[O:39])[CH3:38]
Reactant: Cn1nc(C(F)(F)F)cc1-c1ccc(NC(=O)c2ccc(Cl)cc2)cc1N
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: CC(=O)Nc1cc(NC(=O)c2ccc(Cl)cc2)ccc1-c1cc(C(F)(F)F)nn1C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 17 (20 mg) in 2 ml DCM was added 3 eq DIEA and acetyl chloride (20 μl). The reaction mixture was stirred at r.t. for 5 h before worked up with DCM/NaHCO3, water. The org. phase was concentrated and subjected to prep HPLC purification to furnish compound 18.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]([Cl:20])=[CH:10][C:9]=1[NH:21][C:22](=[O:45])[CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N:31]2[C:35]([CH2:36][O:37]C3CCCCO3)=[CH:34][N:33]=[N:32]2)[CH:26]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:20][C:11]1[C:12]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:13][C:8]2[N:7]=[C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([N:31]4[C:35]([CH2:36][OH:37])=[CH:34][N:33]=[N:32]4)[CH:26]=3)[CH2:23][C:22](=[O:45])[NH:21][C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCCCC2)c(Cl)cc1NC(=O)CC(=O)c1cccc(-n2nncc2COC2CCCCO2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cccc(-n3nncc3CO)c2)=Nc2cc(N3CCCCC3)c(Cl)cc2N1

Procedure:
The title compound was prepared from (RS)-[4-chloro-2-(3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionylamino)-5-piperidin-1-yl-phenyl]-carbamic acid tert.-butyl ester (Example M44) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (99 mg).
Reaction SMILES: CC1(C)COC2(CCC(CCN[C@H](C3C4C(=CC=CC=4)C=CC=3)C)(O)CC2)OC1.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.CC1(C)CO[C:46]2([CH2:69][CH2:68][C:49]3([O:54][C:53](=[O:55])[N:52]([C@H:56]([C:58]4[C:67]5[C:62](=[CH:63][CH:64]=[CH:65][CH:66]=5)[CH:61]=[CH:60][CH:59]=4)[CH3:57])[CH2:51][CH2:50]3)[CH2:48][CH2:47]2)[O:45]C1>>[C:58]1([C@@H:56]([N:52]2[CH2:51][CH2:50][C:49]3([CH2:68][CH2:69][C:46](=[O:45])[CH2:47][CH2:48]3)[O:54][C:53]2=[O:55])[CH3:57])[C:67]2[C:62](=[CH:63][CH:64]=[CH:65][CH:66]=2)[CH:61]=[CH:60][CH:59]=1
Reactant: C[C@@H](c1cccc2ccccc12)N1CCC2(CCC3(CC2)OCC(C)(C)CO3)OC1=O
Agent: C[C@H](NCCC1(O)CCC2(CC1)OCC(C)(C)CO2)c1cccc2ccccc12
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Product: C[C@@H](c1cccc2ccccc12)N1CCC2(CCC(=O)CC2)OC1=O

Procedure:
The title compound is prepared from 3,3-dimethyl-9-{2-[(S)-1-naphthalen-1-yl-ethylamino]-ethyl}-1,5-dioxa-spiro[5.5]undecan-9-ol and triphosgene following a procedure analogous to that described in Step 4 of Intermediate 2; the crude product, a mixture of the title compound and 12,12-dimethyl-3-[(S)-1-naphthalen-1-yl-ethyl]-1,10,14-trioxa-3-aza-dispiro[5.2.5.2]hexadecan-2-one, obtained thereafter is treated as described in Step 10 of Intermediate 2 to convert the intermediate to the title compound as well. Yield: 62% of theory; LC (method 6): tR=1.33 min; Mass spectrum (ESI+): m/z=338 [M+H]+.