Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH2:19][CH2:20][CH2:21][O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:11]=2)[CH2:8][NH:7][CH2:6]1)=[O:4].Cl[C:30]([O:32][CH3:33])=[O:31]>C(Cl)Cl.CN(C1C=CN=CC=1)C.CCOCC>[CH3:33][O:32][C:30]([N:7]1[CH2:8][C@@H:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH2:19][CH2:20][CH2:21][O:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:11]=2)[C@H:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:6]1)=[O:31]
Reactant: COC(=O)C1CNCC1c1ccc(OC)c(OCCCOc2ccccc2)c1
Reactant: COC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)[C@@H]1CN(C(=O)OC)C[C@H]1c1ccc(OC)c(OCCCOc2ccccc2)c1
Reaction time: 2 h
Yield: 76.4 %

Procedure:
To a solution of 3-methoxycarbonyl-4-[3-(3-phenoxypropoxy)-4-methoxyphenyl]pyrrolidine (720 mg, 1.87 mmol) in 5 mL of CH2Cl2 at 0° C. was added DMAP (275 mg, 2.25 mmol), followed by methyl chloroformate (213 mg, 2.25 mmol). The solution was stirred for 2 hr, diluted with ether, and washed with 1M H3PO4. The aqueous layer was extracted with ether (2×) and ethyl acetate (1×). The combined organic layers were dried over MgSO4, filtered and concentrated to a colorless oil. Silica gel chromatography (4:2:1, hexanes:ethyl acetate:CH2Cl2) provided trans-1-methoxycarbonyl-3-methoxycarbonyl-4-[3-(3-phenoxypropoxy)-4-methoxyphenyl]pyrrolidine as a colorless oil (634 mg, 77%). Anal. Calcd for C24H29NO7 : C, 64.99; H, 6.59; N, 3.16. Found: C, 64.85; H, 6.57; N, 3.15.
Reaction SMILES: [C:1]12([O:11][CH2:12][C:13](O)=[O:14])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:28][C:29]1([CH3:37])[O:34][C:33](=[O:35])[CH2:32][C:31](=[O:36])[O:30]1.N1C=CC=CC=1>C(Cl)Cl>[C:1]12([O:11][CH2:12][C:13](=[C:32]3[C:33](=[O:35])[O:34][C:29]([CH3:37])([CH3:28])[O:30][C:31]3=[O:36])[OH:14])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=C(O)COC12CC3CC(CC(C3)C1)C2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(C)OC(=O)C(=C(O)COC23CC4CC(CC(C4)C2)C3)C(=O)O1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A mixture of (adamantan-1-yloxy)-acetic acid (Example 216, step a) (32.3 g, 0.153 mol) and 1,1′-carbonyl-diimidazole (27.6 g, 0.17 mol) in anhydrous DCM (600 ml) was stirred at 0° C. for 15 min, then at room temperature for 75 min. The mixture was concentrated in vacuo (˜300 ml) and the solution was added dropwise over 20 min to a solution of 2,2-dimethyl-1,3-dioxan-4,6-dione (22.1 g, 0.153 mol) and pyridine (30 ml, 0.371 mol) in anhydrous DCM (450 ml) at 0° C. under argon. The mixture was allowed to warm to room temperature and stirred for 16 h. The solution was washed with 2M HCl (2×500 ml), brine (500 ml) and dried (MgSO4). Filtration and evaporation gave the product as a white solid, which was washed with hexane, isolated by filtration and dried (50.1 g, 97%). 1H NMR (300MHz, CDCl3) 4.92 (2H, s), 2.19 (3H, br s), 1.82 (6H, s), 1.74 (6H, s), 1.64 (6H, m).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[NH2:11])[NH:7][C:6](=[O:12])[CH2:5]2.N1C=CC=CC=1.[CH3:19][O:20][CH2:21][C:22](Cl)=[O:23]>O1CCCC1>[F:1][C:2]1[C:10]([NH:11][C:22](=[O:23])[CH2:21][O:20][CH3:19])=[CH:9][C:8]2[C:4](=[CH:5][C:6](=[O:12])[N:7]=2)[CH:3]=1
Reactant: Nc1cc2c(cc1F)CC(=O)N2
Reactant: COCC(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COCC(=O)Nc1cc2c(cc1F)=CC(=O)N=2
Temperature: 25 °C
Yield: 40.9 %

Procedure:
5-Fluoro-6-Amino-indol-2-one 9d (2.028 g, 12.2 mmol) was dissolved in 30 mL of tetrahydrofuran under stirring at room temperature, and 1.3 mL of pyridine was then added to the solution. The reaction system was cooled down to −50° C. in a dry ice-ethanol bath. Methoxy-acetyl chloride (1.35 g, 12.5 mmol) was dissolved in 20 mL of tetrahydrofuran under stirring, and the solution was then added dropwise to the above reaction system. Upon completion of the addition, the dry ice-ethanol bath was removed. The reaction system was allowed to warm up to room temperature and stirred overnight until TLC showed the disappearance of starting materials. The resulting solid was filtered, washed with water (10 mL ×3) and recrystallized from methanol to give the title compound 5-fluoro-6-methoxyacetamido-2-oxoindole 13a (1.18 g, yield 40.6%) as a gray solid.
Reaction SMILES: [NH2:1][C@H:2]([C:22]([OH:24])=[O:23])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][S:8]([C:11]1[C:20]([CH3:21])=[C:18]([CH3:19])[C:15]([O:16][CH3:17])=[CH:14][C:12]=1[CH3:13])(=[O:10])=[O:9].C([O-])(O)=O.[Na+].[NH:30]([C:49]([O:51][CH2:52][CH:53]1[C:65]2[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=2)[C:59]2[C:54]1=[CH:55][CH:56]=[CH:57][CH:58]=2)=[O:50])[C@H:31]([C:39](ON1C(=O)CCC1=O)=[O:40])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C1COCC1>O.COCCOC>[NH:30]([C:49]([O:51][CH2:52][CH:53]1[C:65]2[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=2)[C:59]2[C:54]1=[CH:55][CH:56]=[CH:57][CH:58]=2)=[O:50])[C@H:31]([C:39]([NH:1][C@H:2]([C:22]([OH:24])=[O:23])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][S:8]([C:11]1[C:20]([CH3:21])=[C:18]([CH3:19])[C:15]([O:16][CH3:17])=[CH:14][C:12]=1[CH3:13])(=[O:10])=[O:9])=[O:40])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: COc1cc(C)c(S(=O)(=O)NCCCC[C@H](N)C(=O)O)c(C)c1C
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)ON1C(=O)CCC1=O)OCC1c2ccccc2-c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: COCCOC
Product: COc1cc(C)c(S(=O)(=O)NCCCC[C@H](NC(=O)[C@H](Cc2ccccc2)NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)c(C)c1C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A suspension of Lys(Mtr) 2 (4.686 g, 11.20 mmol) and NaHCO3 (941.0 mg, 1 equiv) in water (100 mL) and DME (50 mL) was treated with a solution of Fmoc-Phe-OSu 7a (11.20 mmol) in DME (50 mL). THF (25 mL) was then added to aid solubility. The mixture was stirred at rt for 2 days and then as much DME as possible was removed on the rotovap (bath at 30° C.). The resulting gummy suspension was partitioned between ethyl acetate and pH 5 buffer. The organic phase was washed with water and brine, dried and evaporated to give a pale yellow foam. This was flushed with methylene chloride (100 mL). TLC showed the product to be satisfactorily pure and it was carried on without further purification (8.559 g, 97%). 1H-NMR (CDCl3/CD3OD) δ 1.10-1.93 (m, 6H), 2.31 (t, 2H), 3.00 (m, 2H), 3.71 (s, 3H), 4.02-4.48 (m, 5H), 6.79 (d, 2H), 7.00-7.75 (m, 25H). MS (FAB) 788.2 (MH)+, 810.4 (M+Na)+, 826 (M+K)+. Anal. Calcd for C50H49N3O6—H2O: C-74.51, H-6.38, N-5.21. Found: C-74.17, H-6.57, N-5.41.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]2[C:14]([O:21][C@@H:22]3[O:48][C@H:47]([CH2:49][O:50][C:51](=[O:56])[C:52]([CH3:55])([CH3:54])[CH3:53])[C@@H:39]([O:40][C:41](=[O:46])[C:42]([CH3:45])([CH3:44])[CH3:43])[C@H:31]([O:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])[C@H:23]3[O:24][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])=[N:15][NH:16][C:17]=2[CH:18]([CH3:20])[CH3:19])=[C:8]([O:57][CH:58]2[CH2:63][CH2:62][O:61][CH2:60][CH2:59]2)[CH:7]=1.[N-:64]=[N+:65]=[N-:66].[Na+].O>CN(C)C=O>[N:64]([CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]2[C:14]([O:21][C@@H:22]3[O:48][C@H:47]([CH2:49][O:50][C:51](=[O:56])[C:52]([CH3:55])([CH3:54])[CH3:53])[C@@H:39]([O:40][C:41](=[O:46])[C:42]([CH3:45])([CH3:44])[CH3:43])[C@H:31]([O:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])[C@H:23]3[O:24][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])=[N:15][NH:16][C:17]=2[CH:18]([CH3:20])[CH3:19])=[C:8]([O:57][CH:58]2[CH2:63][CH2:62][O:61][CH2:60][CH2:59]2)[CH:7]=1)=[N+:65]=[N-:66]
Reactant: CC(C)c1[nH]nc(O[C@@H]2O[C@H](COC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@H]2OC(=O)C(C)(C)C)c1Cc1ccc(OCCCCl)cc1OC1CCOCC1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1[nH]nc(O[C@@H]2O[C@H](COC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@H]2OC(=O)C(C)(C)C)c1Cc1ccc(OCCCN=[N+]=[N-])cc1OC1CCOCC1
Temperature: 80 °C
Reaction time: 3 h
Yield: 99.3 %

Procedure:
To a solution of 4-{[4-(3-chloropropoxy)-2-(tetrahydro-4H-pyran-4-yloxy)phenyl]methyl}-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole (0.3 g) in N,N-dimethylformamide (5 mL) was added sodium azide (43 mg), and the mixture was stirred at 80° C. for 3 hours. To the reaction mixture was added water, and the precipitated crystals were collected by filtration. The crystals were washed with water and n-hexane, and dried under reduced pressure to give the title compound (0.3 g).
Reaction SMILES: P(Cl)(Cl)Cl.[CH2:5]([NH:11][C@H:12]([C:17]([OH:19])=[O:18])[CH2:13][C:14]([OH:16])=O)[CH2:6][C:7]([CH3:10])([CH3:9])[CH3:8]>C(O)(=O)C>[CH2:5]([NH:11][C@@H:12]1[C:17](=[O:18])[O:19][C:14](=[O:16])[CH2:13]1)[CH2:6][C:7]([CH3:8])([CH3:9])[CH3:10]
Reactant: CC(C)(C)CCN[C@@H](CC(=O)O)C(=O)O
Solvent: CC(=O)O
Solvent: ClP(Cl)Cl
Product: CC(C)(C)CCN[C@H]1CC(=O)OC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 34 %

Procedure:
Phosphorous trichloride (3.7 ml, 43 mmol) was added, dropwise, to a 10° C. slurry of N-neohexyl-L-aspartic acid (11.6 g, 53.4 mmol) in glacial acetic acid (50 ml). After addition was complete (0.5 hr), the resulting clear solution was stirred at room temperature overnight. The resulting solid precipitate was collected by vacuum filtration, washed with acetic acid and methylene chloride, then dried at 35-40° C. for 3 hours to give 3.62 g (69.8%) of pure N-neohexyl-L-aspartic anhydride.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:23]=[C:22]([CH3:24])[O:21][N:20]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.CCO.[N:28]1([CH2:34][C:35]2[CH:42]=[CH:41][C:38]([CH:39]=O)=[CH:37][CH:36]=2)[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(OCC)C>[Cl:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:23]=[C:22]([CH3:24])[O:21][N:20]=3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:39]([C:38]3[CH:37]=[CH:36][C:35]([CH2:34][N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[CH:42][CH:41]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Cc1cc(CN2CCN(c3c(Cl)cnc(N)c3[N+](=O)[O-])CC2)no1
Reactant: O=Cc1ccc(CN2CCOCC2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Product: Cc1cc(CN2CCN(c3c(Cl)cnc4[nH]c(-c5ccc(CN6CCOCC6)cc5)nc34)CC2)no1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
To a mixture of 5-chloro-4-[4-(5-methyl-isoxazol-3-ylmethyl)-piperazin-1-yl]-3-nitro-pyridin-2-ylamine (0.031 g, 0.09 mmol) and EtOH (3.0 ml) was added 4-morpholin-4-ylmethyl-benzaldehyde (0.025 g, 0.12 mmol) followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.36 ml, 0.36 mmol). The reaction mixture was stirred at 80° C. for 20 h, then allowed to cool to room temperature and concentrated in vacuo. The resulting residue was absorbed on silica, and the free-running powder was placed on a 10 g isolute silica column. Elution with a gradient of methanol (0 to 7%) in ethyl acetate/dichloromethane (v:v; 1:1) afforded a yellow solid. The title compound was obtained as a yellow solid after trituration with diethyl ether (0.018 g, 39%); 1H-NMR (500 MHz, DMSO-d6) 2.38 (br s, 4H) and 3.58 (t, J=4.8 Hz, 4H) (morpholine N(CH2)2 and morpholine O(CH2)2), 2.40 (s, 3H, isoxazole 5-CH3), 2.63 (br s, 4H, piperazine N(CH2)2), 3.53 (s, 2H) and 3.60 (s, 2H) (C6H4CH2N and NCH2 isoxazole), 3.70 (br s, 4H, piperazine N(CH2)2), 6.25 (s, 1H, isoxazole 4-H), 7.47 (d, J=8.2 Hz, 2H) and 8.13 (d, J=8.2 Hz, 2H) (3,5-C6H4— and 2,6-C6H4—), 8.11 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.48 (br s, 1H, imidazo[4,5-b]pyridine N—H);
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[CH:9]=1)[CH:5]=[O:6].[BH4-].[Na+].O>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:7]=[C:8]([O:10][Si:11]([C:14]([CH3:15])([CH3:16])[CH3:17])([CH3:13])[CH3:12])[CH:9]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(Br)cc(C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1cc(Br)cc(CO)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-Bromo-5-(tert-butyl-dimethyl-silanyloxy)-benzaldehyde (7 g, 22.2 mmol) was dissolved in THF and sodium borohydride (0.92 g; 24.4 mmol) was added. The reaction mixture was stirred at room temperature for 2 h and water was added, and the reaction mixture was partly evaporated to strip off THF. Ethyl acetate was added and the phases separated. The organic phase was washed with water, dried, and evaporated to dryness. Yield: 6.4 g; HPLC-MS: m/z: 317.0 (M+); Rt: 2.37 min.
Reaction SMILES: [NH2:1][C:2]1[O:3][CH:4]=[C:5]([C:7]([OH:9])=O)[N:6]=1.[NH2:10][C@@H:11]([CH2:27][CH3:28])[CH2:12][N:13]1[CH:17]=[CH:16][C:15]([C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[C:20]([Cl:26])[CH:19]=2)=[N:14]1>>[NH2:1][C:2]1[O:3][CH:4]=[C:5]([C:7]([NH:10][C@@H:11]([CH2:27][CH3:28])[CH2:12][N:13]2[CH:17]=[CH:16][C:15]([C:18]3[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[C:20]([Cl:26])[CH:19]=3)=[N:14]2)=[O:9])[N:6]=1
Reactant: CC[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: Nc1nc(C(=O)O)co1
Product: CC[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1coc(N)n1
Yield: 4.32 %

Procedure:
(S)-2-amino-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)butan-2-yl)-oxazole-4-carboxamide was prepared using the method of Example 34(d) starting from 2-amino-1,3-oxazole-4-carboxylic acid (343 mg, 2.68 mmol) and (S)-4-(1-(2-aminobutyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (613 mg, 2.231 mmol). The product was triturated using diethyl ether. Yield 4.32%. 1H-NMR (400 MHz; DMSO-d6): δ 0.86 (t, 3H), 1.41-1.51 (m, 2H), 4.18-4.39 (m, 3H), 6.78 (s, 2H), 6.93 (d, 1H), 7.74 (d, 1H), 7.76 (s, 1H), 7.79 (d, 1H), 7.94-8.00 (m, 2H), 8.08 (s, 1H).
Reaction SMILES: C=C[CH2:3][N:4]1[C@@H:21]2[CH2:22][C:9]3[CH:10]=[CH:11][C:12]([OH:24])=[C:13]4[O:14][C@H:15]5[C:16]([CH2:18][CH2:19][C@:20]2([OH:23])[C@:7]5([C:8]=34)[CH2:6][CH2:5]1)=[O:17]>ClCCl>[CH3:3][N:4]1[C@@H:21]2[CH2:22][C:9]3[CH:10]=[CH:11][C:12]([OH:24])=[C:13]4[O:14][C@H:15]5[C:16]([CH:18]=[CH:19][C@:20]2([OH:23])[C@:7]5([C:8]=34)[CH2:6][CH2:5]1)=[O:17]
Reactant: C=CCN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)CC[C@@]3(O)[C@H]1C5
Solvent: ClCCl
Product: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)C=C[C@@]3(O)[C@H]1C5
Reaction time: 8 h

Procedure:
Naloxone (compound (104)) is contacted with an allyl scavenger, e.g., N,N-dimethyl barbituric acid (compound (146)), and a transition metal catalyst, e.g., tetrakis(triphenylphosphine)palladium[0], in dichloromethane at a temperature of about 20° C. Naloxone as a suspension in dichloromethane is added, and the resulting mixture stirred overnight at a temperature within the range of from about 10° C. to about 70° C., or from about 20° C. to about 60° C., or from about 30° C. to about 60° C. The mixture is cooled and the solids collected by filtration, washed with dichloromethane, and then washed with water. The washed solids are dissolved in aqueous acid (e.g., 10:1 water:concentrated sulfuric acid) at a temperature within the range of from about 10° C. to about 70° C., or from about 20° C. to about 60° C., or from about 30° C. to about 60° C., and the solution washed with dichloromethane before being basified to a pH within the range of from about pH 8 to about pH 10, e.g., using 28% ammonium hydroxide. The solids are collected by filtration and dried to provide the desired product, noroxymorphone (see, e.g., Example 7).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][C@H:7]([CH3:9])[N:6]2[C:10]3[C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][NH:16][C:15](=[O:23])[C:11]=3[C:12]([O:13][CH3:14])=[C:5]2[C:4]1=[O:24])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1.[Cl:40][C:41]1[CH:42]=[C:43]([CH:46]=[CH:47][C:48]=1[F:49])[CH2:44]Br>CN(C=O)C>[Cl:40][C:41]1[CH:42]=[C:43]([CH:46]=[CH:47][C:48]=1[F:49])[CH2:44][N:16]1[CH:17]=[C:18]([C:19]([O:21][CH3:22])=[O:20])[C:10]2[N:6]3[C@@H:7]([CH3:9])[CH2:8][N:3]([CH2:1][CH3:2])[C:4](=[O:24])[C:5]3=[C:12]([O:13][CH3:14])[C:11]=2[C:15]1=[O:23]
Reactant: Fc1ccc(CBr)cc1Cl
Reactant: CCN1C[C@H](C)n2c(c(OC)c3c(=O)[nH]cc(C(=O)OC)c32)C1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCN1C[C@H](C)n2c(c(OC)c3c(=O)n(Cc4ccc(F)c(Cl)c4)cc(C(=O)OC)c32)C1=O
Temperature: -25 °C
Reaction time: 0.42 h

Procedure:
To a cold (−25° C.) solution of methyl (6S)-8-ethyl-10-(methoxy)-6-methyl-1,9-dioxo-1,2,6,7,8,9-hexahydropyrido-[3′,4′:4,5]pyrrolo[1,2-a]-pyrazine-4-carboxylate (0.29 g, 0.87 mmol) in anhydrous DMF (15 mL) under an atmosphere of nitrogen, a solution of lithium bis(trimethylsilyl)amide in THF (1 M, 0.96 mmol) was added. The reaction mixture was stirred at −25° C. for 25 minutes and treated with 3-chloro-4-fluorobenzyl bromide (0.27 g, 1.2 mmol; passed through activated basic alumina). The reaction mixture was stirred at 0° C. for 40 minutes and concentrated under vacuum. The residue was partitioned between ethyl acetate and dilute aqueous HCl. The organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluted with ethyl acetate-hexane gradient. Collection and concentration of appropriate fractions provided the titled product.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[NH:12][C:13](=[O:25])[N:14]([C:15]4[C:16]([CH3:24])=[N:17][N:18]([CH2:20][C:21]([OH:23])=O)[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[B-](F)(F)(F)F.CN(C(ON1C(=O)C=CC=C1)=[N+](C)C)C.[CH3:46][N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1>CC(N(C)C)=O>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[NH:12][C:13](=[O:25])[N:14]([C:15]4[C:16]([CH3:24])=[N:17][N:18]([CH2:20][C:21]([N:50]5[CH2:51][CH2:52][N:47]([CH3:46])[CH2:48][CH2:49]5)=[O:23])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1
Reactant: Cc1nn(CC(=O)O)cc1-n1c(=O)[nH]c2cnc3ccc(Br)cc3c21
Reactant: CN1CCNCC1
Agent: CN(C)C(On1ccccc1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC(=O)N(C)C
Product: Cc1nn(CC(=O)N2CCN(C)CC2)cc1-n1c(=O)[nH]c2cnc3ccc(Br)cc3c21
Temperature: 25 °C
Reaction time: 19 h

Procedure:
A solution of [4-(8-bromo-2-oxo-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)-3-methyl-pyrazol-1-yl]-acetic acid (Stage 101.1.2, 178 mg, 0.443 mmol), DIPE (0.232 ml, 1.33 mmol), TPTU (223 mg, 0.752 mmol) in DMA (5 ml) was stirred at rt for 5 min, then was added N-methylpiperazine (0.1 ml, 0.90 mmol). The reaction mixture was stirred 19 h at rt and then was added N-methylpiperazine (0.1 ml, 0.90 mmol) and the reaction mixture was stirred 25 h at rt. The reaction mixture was purified by prep. HPLC to give the title compound as an off-white solid. (HPLC: tR 1.98 min (Method A); M+H=484, 486 MS-ES)
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1.C([O-])(=O)C.[Na+].[S:26]1[CH2:32][C:30](=[O:31])[NH:29][C:27]1=[S:28]>C(O)(=O)C>[F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[C:32]2[S:26][C:27](=[S:28])[NH:29][C:30]2=[O:31])=[CH:13][CH:12]=1
Reactant: O=Cc1ccc(OCc2ccccc2C(F)(F)F)cc1
Reactant: O=C1CSC(=S)N1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1NC(=S)SC1=Cc1ccc(OCc2ccccc2C(F)(F)F)cc1

Procedure:
Under a nitrogen atmosphere in a round bottom flask 4-[(2-trifluoromethylphenyl)methoxy]benzaldehyde (2.98 g, 10.63 mmol), sodium acetate (3.05 g, 37.2 mmol), and rhodanine (1.42 g, 10.7 mmol) were dissolved in 53 ml of acetic acid. The reaction solution was then heated to reflux and maintained at this temperature for about three days.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]2[NH:8][N:9]=[CH:10][C:3]=12.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:20]=[C:21]([CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[NH:22][CH:23]=2)=[CH:15][CH:14]=1.C(O)(C)C.C(N(C(C)C)CC)(C)C>CO.C(Cl)Cl>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:20]=[C:21]([CH:24]3[CH2:29][CH2:28][N:27]([C:2]4[N:7]=[CH:6][N:5]=[C:4]5[NH:8][N:9]=[CH:10][C:3]=45)[CH2:26][CH2:25]3)[NH:22][CH:23]=2)=[CH:15][CH:14]=1
Reactant: Clc1ncnc2[nH]ncc12
Reactant: COc1ccc(-c2c[nH]c(C3CCNCC3)n2)cc1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: COc1ccc(-c2c[nH]c(C3CCN(c4ncnc5[nH]ncc45)CC3)n2)cc1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
Place 4-chloro-1H-pyrazolo[3,4-d]pyrimidine (135 mg; 1.10 equiv; 873.45 μmoles) and 4-[4-(4-Methoxy-phenyl)-1H-imidazol-2-yl]-piperidine (205 mg, 1.00 equiv; 796.63 μmoles; 205.00 mg) in a microwave vial and dissolve in isopropyl alcohol (3 mL; 39.24 mmoles; 3.00 mL). Add diisopropylethylamine (0.5 mL; 2.87 mmoles; 500.00 μL). Heat the mixture to 70° C. in a microwave with stirring on and hold for 1 hr. Dissolve in 5% MeOH/DCM and wash with saturated aqueous sodium bicarbonate. Dry over sodium sulfate, filter and concentrated. Purify using ISCO chromatography over a biotage 40S column eluting with a gradient of 2.5% MeOH/DCM to 10% MeOH/DCM at a flow rate of 40 mL/min. over 35 min collection. Combine the fractions to give 4-{4-[4-(4-Methoxy-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-1H-pyrazolo[3,4-d]pyrimidine.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[N:5]([C:14]1[CH:19]=[C:18]([CH:20]=C)[N:17]=[C:16]([NH2:22])[C:15]=1[N+:23]([O-:25])=[O:24])[CH2:6][C:7]1[CH:8]=[N:9][C:10]([CH3:13])=[CH:11][CH:12]=1)[CH3:2].I([O-])(=O)(=O)=[O:28].[Na+]>CC(C)=O.O.[Os](=O)(=O)(=O)=O>[CH2:1]([O:3][C:4](=[O:26])[N:5]([C:14]1[CH:19]=[C:18]([CH:20]=[O:28])[N:17]=[C:16]([NH2:22])[C:15]=1[N+:23]([O-:25])=[O:24])[CH2:6][C:7]1[CH:8]=[N:9][C:10]([CH3:13])=[CH:11][CH:12]=1)[CH3:2]
Reactant: C=Cc1cc(N(Cc2ccc(C)nc2)C(=O)OCC)c([N+](=O)[O-])c(N)n1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)N(Cc1ccc(C)nc1)c1cc(C=O)nc(N)c1[N+](=O)[O-]
Reaction time: 0.08 h
Yield: 81.1 %

Procedure:
(2-Amino-3-nitro-6-vinyl-pyridin-4-yl)-(6-methyl-pyridin-3-ylmethyl)-carbamic acid ethyl ester (270 mgs/0.755 mmols) was dissolved in acetone (5 mls)/water (5 mls) and osmium tetroxide (2.5% wt in tBuOH) (0.10 mls/0.008 mmols) was added. Stirred for 5 mins to give brown solution then added sodium metaperiodate (500 mgs/3.47 mmols). Orange suspension stirred for 1 hour. Partitioned between EtOAc (100 mls) and sodium thiosulfate pentahydrate (20% wt in H2O) (50 mls). Organic collected, washed with brine, dried over Na2SO4, filtered and concentrated to a brown resin. Purification by column chromatography eluting with EtOAc gave the title compound (220 mgs) as a yellow oil.
Reaction SMILES: [BH4-].[Na+].[C:3]([O:6][CH:7]([C:20]1[CH:24](O)[O:23][C:22](=[O:26])[C:21]=1[CH3:27])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])(=[O:5])[CH3:4]>C1COCC1>[C:3]([O:6][CH:7]([C:20]1[CH:21]([CH3:27])[C:22](=[O:26])[O:23][CH:24]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])(=[O:5])[CH3:4]
Reactant: CCCCCCCCCCCCC(OC(C)=O)C1=C(C)C(=O)OC1O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCC(OC(C)=O)C1=COC(=O)C1C
Reaction time: 1 h

Procedure:
NaBH4 (25 mg, 0.67 mmol) was added to a solution of 4-(1-acetoxytridecyl)-3-methyl-5-hydroxy-2(5-H)-furanone (157 mg, 0.44 mmol) in anhydrous THF (20 mL) at room temperature under argon. After 2 hours aqueous HCL (1N) was added carefully until pH2 was reached and the resulting mixture was stirred an additional 1 hour. This mixture was extracted with ethyl acetate and the combined organic fractions were washed with 5% sodium bicarbonate and brine. Evaporation of the dried (magnesium sulfate) extracts gave an oil which was purified by flash chromatography on silica using 30% ethyl acetate/hexane. Fractions with Rf of about 0.45 on evaporation afforded the title compound.