Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:28]=[CH:27][C:21]4[CH2:22][CH2:23][NH:24][CH2:25][CH2:26][C:20]=4[CH:19]=3)[N:14]=2)[CH:6]=[N:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:36][CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40]>CN(C)C=O>[Cl:2][C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:28]=[CH:27][C:21]4[CH2:22][CH2:23][N:24]([CH2:36][CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH2:25][CH2:26][C:20]=4[CH:19]=3)[N:14]=2)[CH:6]=[N:7][C:8]=1[O:9][CH:10]([CH3:11])[CH3:12]
Reactant: CC(C)Oc1ncc(-c2nc(-c3ccc4c(c3)CCNCC4)no2)cc1Cl
Reactant: CCOC(=O)CCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCN1CCc2ccc(-c3noc(-c4cnc(OC(C)C)c(Cl)c4)n3)cc2CC1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
7-(5-{5-Chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (Example 50) (192 mg, 0.499 mmol) in N,N-dimethylformamide (2 ml) at room temperature was treated with potassium carbonate (103 mg, 0.748 mmol) and ethyl 4-bromobutanoate (0.09 ml, 0.60 mmol). The mixture was heated to 100° C. After ca. 2 hrs, the mixture was cooled and concentrated. The residue was partitioned between ethyl acetate and water. The ethyl acetate layer was washed with brine, dried and concentrated to a colourless gum. The crude material was loaded onto a silica gel column and chromatographed, eluting with a gradient of 80-100% ethyl acetate in cyclohexane gave the title compound as a colourless gum, which slowly crystallized on standing (185 mgs).
Reaction SMILES: C([O:4][CH2:5][C:6]([C@:8]1([OH:29])[C@:24]2([CH3:25])[CH:11]([CH:12]3[C:21](=[CH:22][CH2:23]2)[C@:20]2([CH3:26])[C:15](=[CH:16][C:17](=[O:27])[CH:18]=[CH:19]2)[CH2:14][CH2:13]3)[CH2:10][C@H:9]1[CH3:28])=[O:7])(=O)C.C(OCC(=O)[C@@H]1[C@]2(C)C(C3C(=CC2)[C@]2(C)C(=CC(=O)CC2)CC3)C[C@H]1C)(=O)C>>[OH:29][C@@:8]1([C:6](=[O:7])[CH2:5][OH:4])[C@:24]2([CH3:25])[CH:11]([CH:12]3[C:21](=[CH:22][CH2:23]2)[C@:20]2([CH3:26])[C:15](=[CH:16][C:17](=[O:27])[CH:18]=[CH:19]2)[CH2:14][CH2:13]3)[CH2:10][C@H:9]1[CH3:28]
Reactant: CC(=O)OCC(=O)[C@@]1(O)[C@H](C)CC2C3CCC4=CC(=O)C=C[C@]4(C)C3=CC[C@@]21C
Agent: CC(=O)OCC(=O)[C@H]1[C@H](C)CC2C3CCC4=CC(=O)CC[C@]4(C)C3=CC[C@@]21C
Product: C[C@@H]1CC2C3CCC4=CC(=O)C=C[C@]4(C)C3=CC[C@]2(C)[C@@]1(O)C(=O)CO

Procedure:
Prepared according to Example 8, Step 2 substituting 2-((10S,13S,16R,17R)-17-hydroxy-10,13,16-trimethyl-3-oxo-6,7,8,10,12,13,14,15,16,17-decahydro-3H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl acetate for 2-oxo-2-((10S,13S,16R,17S)-10,13,16-trimethyl-3-oxo-2,3,6,7,8,10,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethyl acetate.
Reaction SMILES: [C:1]([N:9]1[CH2:22][CH2:21][C:20]2[C:19]3[CH:18]=[C:17](Br)[CH:16]=[CH:15][C:14]=3[NH:13][C:12]=2[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]1([OH:30])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC1C=CC=CC=1C.[Cu-]=O>[C:1]([N:9]1[CH2:22][CH2:21][C:20]2[C:19]3[CH:18]=[C:17]([O:30][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:16]=[CH:15][C:14]=3[NH:13][C:12]=2[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)N1CCc2[nH]c3ccc(Br)cc3c2CC1
Reactant: Oc1ccccc1
Agent: O=[Cu-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1C
Product: O=C(c1ccccc1)N1CCc2[nH]c3ccc(Oc4ccccc4)cc3c2CC1
Temperature: 25 °C
Yield: 10.6 %

Procedure:
A mixture of 3-benzoyl-9-bromo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (1.00 g, 2.71 mmol), phenol (0.51 g, 5.42 mmol), copper (I) oxide (0.019 g, 0.14 mmol), and cesium carbonate (2.65 g, 8.12 mmol) in o-xylene was refluxed for 24 h. After cooling to room temperature, the mixture was filtered and washed with ethyl acetate. The filtrate was concentrated in vacuo to dryness, and the residue was subjected to column chromatography (silica gel, 60% EtOAc/hexane) to afford 0.11 g (10%) of a colorless solid as the title compound: 1H NMR (300 MHz, CDCl3) δ 7.42, 7.29-7.19, 7.03-6.86, 4.12-3.91, 3.72-3.61, 3.20-3.04, 2.90-2.76; MS (ESI+) m/z 383 (M++1).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][N:10]3[CH:15]=[C:14]([C:16]4[CH:21]=[CH:20][C:19]([C:22]#[C:23][CH2:24][OH:25])=[CH:18][CH:17]=4)[CH:13]=[N:12][C:11]=23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CC(O)C.[OH-].[OH-].[Pd+2]>[C:1]1([C:7]2[CH:8]=[N:9][N:10]3[CH:15]=[C:14]([C:16]4[CH:17]=[CH:18][C:19]([CH2:22][CH2:23][CH2:24][OH:25])=[CH:20][CH:21]=4)[CH:13]=[N:12][C:11]=23)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCC#Cc1ccc(-c2cnc3c(-c4ccccc4)cnn3c2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(C)O
Product: OCCCc1ccc(-c2cnc3c(-c4ccccc4)cnn3c2)cc1
Reaction time: 4.5 h

Procedure:
A mixture of 3-[4-(3-phenylpyrazolo[1,5-a]pyrimidin-6-yl)phenyl]prop-2-yn-1-ol (2-3, 1.48 g, 0.455 mmol) and 10% palladium hydroxide on carbon (2.0 g) in 2-propanol (500 mL) was stirred under a hydrogen balloon for 4.5 hours. The reaction mixture was filtered through celite, and the filtrate was concentrated. The residue was purified by flash column chromatography (chloroform saturated with ammonia gas) to provide 3-[4-(3-phenylpyrazolo[1,5-a]pyrimidin-6-yl)phenyl]propan-1-ol (2-4) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ8.83 (s, 2H), 8.46 (s, 1H), 8.07 (br d, 2H, J=7.8 Hz), 7.54 (d, 2H, J=8.2 Hz), 7.47 (t, 2H, J=7.8 Hz), 7.38 (d, 2H, J=8.2 Hz), 7.29 (t, 1H, J=7.8 Hz), 3.73 (q, 2H, J=6.4 Hz), 2.81 (t, 2H, J=7.3 Hz), 1.95 (m, 2H), 1.30 (t, 1H, J=5.3 Hz).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH:7]([O:10][C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=1B(O)O)([CH3:9])[CH3:8].Br[C:22]1[CH:23]=[CH:24][C:25]([N:28]2[CH2:32][CH2:31][C@H:30]([CH2:33][NH:34][C:35](=[O:56])[C:36]3[CH:41]=[CH:40][C:39]([C:42]4[O:43][C:44]5[C:50]([CH:51]([CH3:53])[CH3:52])=[CH:49][C:48]([C:54]#[N:55])=[CH:47][C:45]=5[N:46]=4)=[CH:38][CH:37]=3)[CH2:29]2)=[N:26][CH:27]=1.O>C1(C)C=CC=CC=1.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.C(O)C>[C:54]([C:48]1[CH:49]=[C:50]([CH:51]([CH3:53])[CH3:52])[C:44]2[O:43][C:42]([C:39]3[CH:40]=[CH:41][C:36]([C:35]([NH:34][CH2:33][C@H:30]4[CH2:31][CH2:32][N:28]([C:25]5[CH:24]=[CH:23][C:22]([C:12]6[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:11]=6[O:10][CH:7]([CH3:9])[CH3:8])=[CH:27][N:26]=5)[CH2:29]4)=[O:56])=[CH:37][CH:38]=3)=[N:46][C:45]=2[CH:47]=1)#[N:55]
Reactant: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NC[C@H]4CCN(c5ccc(Br)cn5)C4)cc3)oc12
Reactant: Cc1ccc(OC(C)C)c(B(O)O)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: O
Solvent: Cc1ccccc1
Product: Cc1ccc(OC(C)C)c(-c2ccc(N3CC[C@H](CNC(=O)c4ccc(-c5nc6cc(C#N)cc(C(C)C)c6o5)cc4)C3)nc2)c1
Temperature: 150 °C
Yield: 85.4 %

Procedure:
Sodium carbonate (100 μl, 2M aqueous), (2-isopropoxy-5-methylphenyl)boronic acid (39 mg), and N-{[(3R)-1-(5-bromopyridin-2-yl)pyrrolidin-3-yl]methyl}-4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)benzamide (EXAMPLE 84, 27 mg) were dissolved in toluene (2.1 ml), water (0.6 ml) and ethanol (0.3 ml). To this solution was added tetrakis(triphenylphosphine)palladium(0) (9 mg). The mixture was heated to 150° C. for 25 min via microwave, and then cooled and concentrated. The residue was dissolved in dichloromethane and purified via flash chromatography on a Biotage Horizon, 40 M column, eluting with 1 column volume of 100% ethyl acetate in hexanes, followed by a gradient of 0 to 100% ethyl acetate in hexanes over 10 column volumes, followed by 4 column volumes of 100% ethyl acetate to provide the title compound (26 mg, 84%). Mass spectrum (ESI) 614.6 (M+2). 1H NMR (500 MHz, CDCl3): δ 8.37 (d, J=2.3 Hz, 1H), 8.34 (d, J=8.2 Hz, 2H), 7.95 (d, J=8.2 Hz, 2H), 7.94 (s, 1H), 7.72 (dd, J=8.6 Hz, 2.3 Hz, 1H), 7.52 (s, 1H), 7.09 (s, 1H), 7.04 (dd, J=8.4 Hz, 2.1 Hz, 1H), 6.87 (d, J=8.2 Hz, 1H), 6.43 (d, J=8.7 Hz, 2H), 4.40 (sept, J=6.1 Hz, 1H), 3.79 (m, 2H), 3.73 (m, 1H), 3.51 (m, 3H), 3.41 (m, 1H), 2.76 (sept, J=6.9 Hz, 1H), 2.32 (s, 3H), 2.27 (m, 1H), 1.91, (m, 1H), 1.46 (d, J=6.8 Hz, 6H), 1.24 (d, J=5.9 Hz, 6H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][N:5]=[C:4]([N:12]2[CH2:17][CH2:16][N:15]3[C:18]4[CH:24]=[C:23]([S:25]([CH3:28])(=[O:27])=[O:26])[C:22]([C:29]([O:31][CH3:32])=[O:30])=[CH:21][C:19]=4[N:20]=[C:14]3[C@H:13]2[CH:33]([CH3:35])[CH3:34])[N:3]=1.[CH3:36]B1OB(C)OB(C)O1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.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>[CH:33]([C@H:13]1[N:12]([C:4]2[N:3]=[C:2]([CH3:36])[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][N:5]=2)[CH2:17][CH2:16][N:15]2[C:18]3[CH:24]=[C:23]([S:25]([CH3:28])(=[O:27])=[O:26])[C:22]([C:29]([O:31][CH3:32])=[O:30])=[CH:21][C:19]=3[N:20]=[C:14]12)([CH3:35])[CH3:34]
Reactant: CB1OB(C)OB(C)O1
Reactant: COC(=O)c1cc2nc3n(c2cc1S(C)(=O)=O)CCN(c1ncc(C(=O)OC)c(Cl)n1)[C@@H]3C(C)C
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: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1cc2nc3n(c2cc1S(C)(=O)=O)CCN(c1ncc(C(=O)OC)c(C)n1)[C@@H]3C(C)C
Temperature: 25 °C
Yield: 74.8 %

Procedure:
To a solution of (R)-methyl 2-(4-chloro-5-(methoxycarbonyl)pyrimidin-2-yl)-1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylate (20 mg, 0.04 mmol) and 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (50 mg, 0.4 mmol) in 5 mL of dioxane was added K2CO3 (54 mg, 0.4 mmol) followed by Pd(PPh3)4 (5 mg, 0.004 mmol) under N2 with stirring. The mixture was refluxed for 2 h until the material was disappeared. The reaction mixture was cooled to rt. The dioxane was removed under vacuum. Water (10 mL) was added and the mixture was extracted with EtOAc (10 mL×3). The organic layers were dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by preparative TLC to afford (R)-methyl 1-isopropyl-2-(5-(methoxycarbonyl)-4-methylpyrimidin-2-yl)-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylate (15 mg, 75% yield) as a colorless oil. LC-MS MS (ESI) m/z 502.1 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:19]=[CH:18][C:5]([O:6][CH2:7][C@H:8]([OH:17])[CH2:9][CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[CH:4][CH:3]=1.[CH2:20]([O:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C(O)C>[CH2:20]([O:27][C:28]1[CH:33]=[C:32]([C:2]2[CH:19]=[CH:18][C:5]([O:6][CH2:7][C@H:8]([OH:17])[CH2:9][CH2:10][C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)=[CH:4][CH:3]=2)[CH:31]=[CH:30][CH:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O[C@H](CCc1cccnc1)COc1ccc(Br)cc1
Reactant: OB(O)c1cccc(OCc2ccccc2)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: Cc1ccccc1
Solvent: CCO
Product: O[C@H](CCc1cccnc1)COc1ccc(-c2cccc(OCc3ccccc3)c2)cc1
Temperature: 120 °C
Yield: 83.5 %

Procedure:
Prepared according to the method described in Example 33a) from (2R)-1-(4-bromophenoxy)-4-(3-pyridyl)-2-butanol (0.97 g, Example 40a), 3-(benzyloxy)benzeneboronic acid (1.0 g, Example 93b), tetrakis(triphenylphosphine)palladium(0) (0.09 g), toluene (7.5 ml), ethanol (2 ml) and aqueous sodium carbonate (2 M, 3.5 ml) with heating at 120° C. for 2 hours 30 minutes. After work up the residue was purified by column chromatography over silica eluting with methanol:dichloromethane (5:95) to give the title compound as a white solid (1.07 g).
Reaction SMILES: [H-].[Na+].CS(O[CH2:8][C:9]([CH3:37])([CH3:36])[CH:10]([C:30]1[S:31][CH:32]=[C:33]([Cl:35])[N:34]=1)[C:11]1[NH:12][C:13]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:14]2[C:19](=[O:20])[N:18]([CH3:21])[C:17](=[O:22])[N:16]([CH3:23])[C:15]=12)(=O)=O>C1COCC1>[Cl:35][C:33]1[N:34]=[C:30]([CH:10]2[C:11]3[N:12]([C:13]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)=[C:14]4[C:19](=[O:20])[N:18]([CH3:21])[C:17](=[O:22])[N:16]([CH3:23])[C:15]4=3)[CH2:36][C:9]2([CH3:8])[CH3:37])[S:31][CH:32]=1
Reactant: Cn1c(=O)c2c(-c3ccccc3)[nH]c(C(c3nc(Cl)cs3)C(C)(C)COS(C)(=O)=O)c2n(C)c1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1c(=O)c2c(-c3ccccc3)n3c(c2n(C)c1=O)C(c1nc(Cl)cs1)C(C)(C)C3
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Sodium hydride (60% wt., 38.0 mg, 0.950 mmol) was added to a solution of 3-(4-chlorothiazol-2-yl)-3-(1,3-dimethyl-2,4-dioxo-5-phenyl-2,3,4,6-tetrahydro-1H-pyrrolo[3,4-d]pyrimidin-7-yl)-2,2-dimethylpropyl methanesulfonate (170 mg, 0.317 mmol) in THF (10 mL). The mixture was stirred at room temperature for 5 mins. The reaction was quenched with water and extracted with DCM (2×). The combined organic extracts were passed through a hydrophobic frit and evaporated under vacuum. Purification by chromatography on silica, eluting with 20-100% EtOAc/hexane afforded the title compound.
Reaction SMILES: [C:1]([NH2:4])(=O)[CH3:2].O1P2[O:11][P:12]3[O:14]P(O2)OP1[O:13]3.OO>C(O)C.O.C(#N)C.C(O)(=O)C>[NH2:4][C:1]([P:12]([OH:11])(=[O:13])[OH:14])([P:12]([OH:14])(=[O:11])[OH:13])[CH3:2]
Reactant: O1P2OP3OP1OP(O2)O3
Reactant: CC(N)=O
Agent: OO
Solvent: O
Solvent: CC(=O)O
Solvent: CC#N
Product: CC(N)(P(=O)(O)O)P(=O)(O)O
Temperature: 163 °C
Yield: 248.4 %

Procedure:
83.6 g (1.416 mols) acetamide was dissolved at about 40° C. in 45.4 g (1.1 mols) acetonitrile in a flask which was provided with a stirrer and had a fractionating column mounted thereon. Next, 52 g (0.236 mol) P4O6 was added dropwise at 40°-55° C. After this had been done, the temperature of the reaction mixture was gradually increased to 163° C. while 85.4 g distillate containing 96.4% acetonitrile and 3.5% acetic acid, corresponding to 82.3 g (2.008 mols) acetonitrile and 3.0 g (0.05 mol) acetic acid, was removed at a head temperature of 81°-85° C. After deduction of the acetonitrile feed material, 36.9 g (0.908 mol) acetonitrile was found to have been formed as a by-product. The yellow residue retained in the flask was oxidized with H2O2 and boiled in an ethanol/water-mixture (4:1). 60.1 g colorless crystalline 1-aminoethane-1,1-diphosphonic acid, corresponding to a yield of 60%, was obtained.
Reaction SMILES: Br[C:2]1[CH:15]=[N:14][C:5]2[NH:6][C:7](=[O:13])[C:8]([CH3:12])([CH3:11])[NH:9][CH2:10][C:4]=2[CH:3]=1.[CH3:16][N:17]([CH2:22][C:23]1[N:24]([CH3:32])[C:25]2[C:30]([CH:31]=1)=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:18](=[O:21])[CH:19]=[CH2:20].C(N(C(C)C)C(C)C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)CC.CN(C=O)C.CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:11][C:8]1([CH3:12])[C:7](=[O:13])[NH:6][C:5]2[N:14]=[CH:15][C:2](/[CH:20]=[CH:19]/[C:18]([N:17]([CH3:16])[CH2:22][C:23]3[N:24]([CH3:32])[C:25]4[C:30]([CH:31]=3)=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:21])=[CH:3][C:4]=2[CH2:10][NH:9]1
Reactant: C=CC(=O)N(C)Cc1cc2ccccc2n1C
Reactant: CC1(C)NCc2cc(Br)cnc2NC1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(Cc1cc2ccccc2n1C)C(=O)/C=C/c1cnc2c(c1)CNC(C)(C)C(=O)N2
Reaction time: 0.17 h
Yield: 52.3 %

Procedure:
A suspension of 7-bromo-3,3-dimethyl-1,3,4,5-tetrahydro-pyrido[2,3-e][1,4]diazepin-2-one (0.30 g, 1.1 mmol) and N-methyl-N-(1-methyl-1H-indol-2-ylmethyl)acrylamide (0.35 g, 1.3 mmol) in propionitrile (5 mL) and DMF (1.3 mL) was de-oxygenated with Ar for 10 min. The mixture was treated with (i-Pr)2EtN (0.41 mL, 2.4 mmol) and was de-oxygenated with Ar for 5 min. Pd(OAc)2 (25 mg, 0.11 mmol) and P(o-tol)3 (70 mg, 0.23 mmol) were added simultaneously, and the mixture was de-oxygenated a third time for 5 min. The mixture was heated to reflux overnight, then allowed to cool. The mixture was diluted with EtOAc (100 mL), washed with H2O (50 mL), dried over Na2SO4, filtered and concentrated to an orange residue. Purification by flash column chromatography (silica gel, CH2Cl2/MeOH, 98:2 to 97:3) gave the title compound (0.24 g, 51%) as a light pink solid: MS (ESI) m/e 418 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:19][C:20]2[C:21]3[N:28]([CH2:29][CH2:30][O:31][CH2:32][CH2:33][OH:34])[CH:27]=[CH:26][C:22]=3[N:23]=[CH:24][N:25]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1.ClC(Cl)(Cl)[C:37]([N:39]=C=O)=[O:38].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])O.[Na+]>CO.C(OCC)(=O)C.O1CCCC1>[C:37](=[O:38])([O:34][CH2:33][CH2:32][O:31][CH2:30][CH2:29][N:28]1[C:21]2[C:20]([NH:19][C:4]3[CH:5]=[CH:6][C:7]([O:8][C:9]4[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:17])([F:16])[F:18])[CH:10]=4)=[C:2]([Cl:1])[CH:3]=3)=[N:25][CH:24]=[N:23][C:22]=2[CH:26]=[CH:27]1)[NH2:39]
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: OCCOCCn1ccc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: NC(=O)OCCOCCn1ccc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Reaction time: 3 h

Procedure:
To a solution of 2-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethoxy}ethanol (84 mg) in a mixed solvent (1.0 mL) of toluene/dichloromethane (1/1) was added trichloroacetyl isocyanate (22 μL) under ice-cooling, and the mixture was stirred for 3 hrs. To the reaction mixture were added methanol (0.2 mL) and potassium carbonate (71 mg), and the mixture was stirred at room temperature for 12 hrs. The reaction mixture was poured into 5% aqueous sodium hydrogen carbonate solution (25 mL), and extracted with ethyl acetate (30 mL×3). The organic layer washed successively with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to basic silica gel chromatography (eluent:ethyl acetate/methanol=100/0→95/5). The object fraction was concentrated under reduced pressure and dried to give 2-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethoxy}ethyl carbamate (83 mg) as a colorless transparent oil. 4N Hydrochloric acid/ethyl acetate solution was added to the obtained colorless transparent oil. After stirring at room temperature for 3 hrs, the resultant precipitate was collected by filtration, washed with diisopropyl ether, ethyl acetate and ice water, and dried under reduced pressure at 60° C. to give the title compound (57 mg) as a pale-yellow powder.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[CH:4][N:3]=1.[OH:12]O>ClCCl.C[Re](=O)(=O)=O.[O-2].[O-2].[Mn+4]>[C:8]([C:6]1[CH:5]=[CH:4][N+:3]([O-:12])=[C:2]([CH3:1])[CH:7]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: OO
Reactant: Cc1cc(C(C)(C)C)ccn1
Agent: C[Re](=O)(=O)=O
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: Cc1cc(C(C)(C)C)cc[n+]1[O-]
Reaction time: 18 h

Procedure:
Dissolve 2-methyl-4-tert-butyl-pyridine (16.60 g, 111.23 mmol) in dichloromethane (80 mL) and add methyltrioxorhenium (VII) (0.139 g, 0.56 mmol) with vigorous stirring. At ambient temperature, add 30% hydrogen peroxide (40 mL) and stir vigorously for 18 hours. Quench the reaction by adding drop wise aqueous manganese dioxide (100 mg in 20 mL). After the off-gassing ceases, the aqueous turns a cloudy gray, the layers are separated and the aqueous is re-extracted with dichloromethane (3×100 mL). The organics are pooled, desiccated, filtered and concentrated to yield the title compound analytically pure (16.60 g, 100.61 mmol). MS (ESI), m/z 166 (M+1).
Reaction SMILES: [N:1]1([C:7]([O:9][CH2:10][C:11]([CH3:39])([CH3:38])[C:12]([N:14]([C@H:24]2[CH2:29][CH2:28][C@H:27]([NH:30]C(OC(C)(C)C)=O)[CH2:26][CH2:25]2)CC2C=CC(OC)=CC=2)=[O:13])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>ClCCl>[N:1]1([C:7]([O:9][CH2:10][C:11]([CH3:39])([CH3:38])[C:12]([NH:14][C@H:24]2[CH2:25][CH2:26][C@H:27]([NH2:30])[CH2:28][CH2:29]2)=[O:13])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: COc1ccc(CN(C(=O)C(C)(C)COC(=O)N2CCOCC2)[C@H]2CC[C@H](NC(=O)OC(C)(C)C)CC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(COC(=O)N1CCOCC1)C(=O)N[C@H]1CC[C@H](N)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 15C (30 mg, 0.055 mmol) in dichloromethane (0.5 mL) was treated with TFA (0.5 mL), and stirred at room temperature for 1.5 h. The reaction mixture was concentrated, and the residue was triturated with Et2O. The resulting off white solid was collected by filtration and air dried to provide 15D. This material was used without purification in the next step.
Reaction SMILES: [C:1]1([C:7]2([OH:19])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]3=[N:16][CH2:17][CH2:18][N:8]23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BrH:20]>C(O)C>[BrH:20].[NH:16]1[CH2:17][CH2:18][N:8]=[C:9]1[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=1[C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:19]
Reactant: OC1(c2ccccc2)c2ccccc2C2=NCCN21
Agent: Br
Solvent: CCO
Product: O=C(c1ccccc1)c1ccccc1C1=NCCN1

Procedure:
2-(2-Imidazolin-2-yl)benzophenone hydrobromide is prepared by admixing an ethanolic solution of 2,3-dihydro-5-phenyl-5H-imidazo[2,1-a]isoindol-5-ol with an ethanol solution containing an equivalent amount of hydrobromic acid and, thereafter, evaporating the solvent under vacuum.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=2)[O:6][CH2:5][CH2:4][O:3]1>C1C=CC=CC=1.O.[Fe]>[CH3:1][C:2]1([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)[O:3][CH2:4][CH2:5][O:6]1
Reactant: CC1(c2ccc([N+](=O)[O-])cc2)OCCO1
Agent: [Fe]
Solvent: c1ccccc1
Solvent: O
Product: CC1(c2ccc(N)cc2)OCCO1
Yield: 69.7 %

Procedure:
To a solution of 2-methyl-2-(4-nitro-phenyl)-[1,3]dioxolane (100 mg, 0.48 mmol) in benzene (6 ml) was added iron powder (700 mg, 12.5 mmol) and 3 drops of water and then heated to reflux for 30 min. The reaction mixture was cooled, filtered and the filtrate was evaporated to give 4-(2-methyl-[1,3]-dioxolan-2-yl)-phenylamine (60 mg, 70%).
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Cl:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15].N1C=CN=C1>CN(C=O)C>[Cl:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: OCCCCCCl
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCCCCCl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of t-butyldimethylsilyl chloride (29.5 g, 0.196 mole) and 5-chloro-1-pentanol (20 g, 0.163 mole) under an inert atmosphere was treated with a solution of imidazole (27.7 g, 0.407 mole) in dry DMF (40 mL). The reaction was stirred overnight at room temperature then partitioned between water (200 mL) and OEt2 l (300 mL). The aqueous layer was extracted with more OEt2 (2×100 mL), and the combined extract was dried (Na2SO4). The OEt2 was removed and the residue fractionally distilled. A small fore-run was collected (bp 57° C. (16 mm)) and then [(5-chloro-1-pentyl)oxy](1,1-dimethylethyl)dimethylsilane as a colorless oil (44.8 g, 97%): bp 120°-5° C. (17 mm), IR (film) cm-1 2960, 2940, 2900, 2865, 1475, 1465, 1390, 1365, 1290, 1260, 1110, 1055, 1030, 1010, 982, 940, 910, 840, 815, 780, 725, 660; 1H NMR (200 MHz, CDCl3) δ 3.62 (t, 6.1 Hz, 2H), 3.54 (t, 6.7 Hz, 2H), 1.79 (pentet, 7 Hz, 2H), 1.52 (m, 4H), 0.89 (s, 9H), 0.05 (s, 6H); 13C NMR (22.5 MHz, CDCl3) δ 62.8, 44.9, 32.5, 32.1, 26.0 (3C), 23.3, 18.3 (tertiary), -5.3 (2C); mass spectrum (70 eV) m/e (% base) 238, 236 (M+, not observed), 181, 179 (M+ - t-Bu., 1.0, 2.7), 125 (10.4), 123 (28.3), 95 (9.0), 93 (20.3), 75 (10.6), 73 (10.3) 70 (7.6), 69 (100.0); high resolution mass spectrum (70 eV) m/e 181.0636, 179.0656 (calculated 181.0630, 179.0660 for C7H16OClSi).