Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][C:26]([F:29])([F:28])[F:27])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:31][C:32]([N:34]1[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]1)=[O:33]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][C:26]([F:27])([F:28])[F:29])[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:31][C:32]([N:34]2[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]2)=[O:33])=[CH:4][CH:3]=1
Reactant: CN1CCN(C(=O)CCl)CC1
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCC(c2ccccc2OC(F)(F)F)CC1
Product: CN1CCN(C(=O)Cn2cc(C(=O)N3CCC(c4ccccc4OC(F)(F)F)CC3)c3ccc(Cl)cc32)CC1

Procedure:
Following general procedure II, the alkylation of (6-chloro-1H-indol-3-yl)-[4-(2-trifluoromethoxy-phenyl)-piperidin-1-yl]-methanone (preparation described herein), with (commercially available) 2-chloro-1-(4-methyl-piperazin-1-yl)-ethanone gave the title compound.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:15]=[CH:14][C:13]([CH:16]([CH3:19])[C:17]#[N:18])=[C:12]([O:20][CH3:21])[CH:11]=1.O1C2C=CC=CC=2N=[C:23]1[C:31]1C=CC(C#N)=C(OC)C=1.BrCCCBr>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:15]=[CH:14][C:13]([C:16]2([C:17]#[N:18])[CH2:31][CH2:23][CH2:19]2)=[C:12]([O:20][CH3:21])[CH:11]=1
Reactant: COc1cc(-c2nc3ccccc3o2)ccc1C#N
Reactant: COc1cc(-c2nc3ccccc3o2)ccc1C(C)C#N
Agent: BrCCCBr
Product: COc1cc(-c2nc3ccccc3o2)ccc1C1(C#N)CCC1

Procedure:
Utilizing the general procedure outlined in the synthesis of 2-[4-(1,3-benzoxazol-2-yl)-2-methoxyphenyl]propanenitrile, 4-(1,3-benzoxazol-2-yl)-2-methoxybenzonitrile (250 mg, 0.95 mmol) was reacted with 1,3-Dibromopropane (120 μL, 1.1 mmol) to afford the desired 1-[4-(1,3-benzoxazol-2-yl)-2-methoxyphenyl]cyclobutanecarbonitrile as a colorless solid: 1H NMR (CDCl3, 300 MHz) δ 7.89–7.87 (m, 3H), 7.62–7.55 (m, 1H) 7.39–7.36 (m, 2H), 7.32–7.26 (m, 1H), 4.05 (s, 3H), 2.90–2.83 (m, 2H), 2.67–2.47 (m, 4H). MS (ESI) 305 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:35])[CH:5]([C:10]1[CH:11]=[C:12]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)[CH:13]=[C:14]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]2[CH2:22][CH2:23][CH3:24])[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])C.[OH-].[Na+]>CO>[CH3:9][CH:7]([CH3:8])[CH2:6][CH:5]([C:10]1[CH:11]=[C:12]([C:25]2[CH:26]=[CH:27][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:30]=2)[CH:13]=[C:14]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]2[CH2:22][CH2:23][CH3:24])[CH:15]=1)[C:4]([OH:35])=[O:3]
Reactant: CCCC1CCCCN1c1cc(-c2ccc(C(F)(F)F)cc2)cc(C(CC(C)C)C(=O)OCC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC1CCCCN1c1cc(-c2ccc(C(F)(F)F)cc2)cc(C(CC(C)C)C(=O)O)c1
Temperature: 60 °C

Procedure:
To a solution of 4-methyl-2-[5-(2-propyl-piperidin-1-yl)-4′-trifluoromethyl-biphenyl-3-yl]-pentanoic acid ethyl ester (24 mg, 0.05 mmol) in MeOH (1 mL) was added 3N NaOH (0.200 mL) and heated to 60° C. for 2 h. The reaction was concentrated in vacuo to remove MeOH. The thick liquid was acidified to pH 2 by 2N HCl. The resulting acidic solution was extracted with EtOAc. The organic fraction was dried (MgSO4) and concentrated in vacuo. The crude mixture was purified by Gilson reverse phase column chromatography to obtain 4-methyl-2-[5-(2-propyl-piperidin-1-yl)-4′-trifluoromethyl-biphenyl-3-yl]-pentanoic acid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[N:17]=2)[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.[Cl:23][C:24]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27]>>[Cl:23][C:24]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:25]=1[C:26]([NH:1][CH2:2][C:3]1([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[N:17]=2)[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:14])([CH3:15])[CH3:13])=[O:10])[CH2:5][CH2:4]1)=[O:27]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(CN)(c2cccc(F)n2)CC1
Product: CC(C)(C)OC(=O)N1CCC(CNC(=O)c2ccc(Cl)cc2Cl)(c2cccc(F)n2)CC1

Procedure:
tert-Butyl 4-(aminomethyl)-4-(6-fluoropyridin-2-yl)piperidine-1-carboxylate (0.82 mmol) was acylated with 2,4-dichlorobenzoyl chloride (0.12 mL, 0.82 mmol) using the method described in example 8-1 to afford the desired product: tert-butyl 4-{[(2,4-dichlorobenzoyl)amino]methyl}-4-(6-fluoropyridin-2-yl)piperidine-1-carboxylate: 1H NMR δ (ppm)(CDCl3): 7.81 (1 H, q, J=8.0 Hz), 7.61 (1 H, d, J=8.3 Hz), 7.38 (1 H, d, J=1.9 Hz), 7.29 (1 H, dd, J=8.0, 2.0 Hz), 7.24 (1 H, dd, J=7.7, 2.7) 6.82 (1 H, dd, J=3.0, 8.1 Hz), 6.69 (1 H, m), 3.80 (1 H, br s) 3.68-3.62 (2 H, m), 3.40-3.34 (2 H, m), 2.22-2.16 (2 H, m), 1.87-1.81 (2 H, m), 1.45 (9 H, s).
Reaction SMILES: [Cl:1][C:2]1[C:14]2[CH2:13][CH2:12][CH:11]3[CH:7]([CH2:8][NH:9][CH2:10]3)[C:6]=2[CH:5]=[C:4]([Cl:15])[C:3]=1[NH2:16].[CH:17](=O)[CH2:18][CH3:19].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[Cl:1][C:2]1[C:14]2[CH2:13][CH2:12][CH:11]3[CH:7]([CH2:8][N:9]([CH2:17][CH2:18][CH3:19])[CH2:10]3)[C:6]=2[CH:5]=[C:4]([Cl:15])[C:3]=1[NH2:16]
Reactant: Nc1c(Cl)cc2c(c1Cl)CCC1CNCC21
Reactant: CCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCCN1CC2CCc3c(cc(Cl)c(N)c3Cl)C2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.1 %

Procedure:
6,8-Dichloro-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]isoindol-7-ylamine (275 mg, 1.07 mmol) and propionaldehyde (81 μl, 1.12 mmol) were dissolved in tetrahydrofuran (25 ml). Acetic acid (90 μl, 1.6 mmol) and sodium trisacetoxyborohydride (340 mg, 1.6 mmol) were sequentially added to the reaction mixture and stirred for 1 hour at room temperature. The reaction mixture was concentrated and the residue was dissolved in a 1 M NaOH solution (20 ml) and ethyl acetate (20 ml). The aqueous phase was extracted once more with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered, and evaporated to dryness to yield the pure product (295 mg, 92%).
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8](=[O:11])[CH:7](C)[NH:6]1)([CH3:4])([CH3:3])[CH3:2].C(N1C(=O)C(=O)C(C2C=CC=CC=2)N1)(C)(C)C.C(N1C(=O)C(=O)C(C2C=CC(Cl)=CC=2)N1)(C)(C)C.C(N1C(=O)C(=O)C(C2C=CC=C(OC)C=2)N1)(C)(C)C.C(N1C(=O)C(=O)C(C2C=CC(OC)=CC=2)N1)(C)(C)C.C(N1C(=O)C(=O)C(C2C=CC=C([N+]([O-])=O)C=2)N1)(C)(C)C.C(N1C(=O)C(=O)C(C2C=CC(C)=CC=2)N1)(C)(C)C.C(N1C(=O)C(=O)C(OC)N1)(C)(C)C.C(N1C(=O)C(=O)C(OCC)N1)(C)(C)C.C(N1C(=O)C(=O)C(N(C)C)N1)(C)(C)C.C(N1C(=O)C(=O)C(N(CC)CC)N1)(C)(C)C.C(N1C(=O)C(=O)C(NC(=O)C)N1)(C)(C)C.C(N1C(=O)C(=O)C(C(O)=O)N1)(C)(C)C.C(N1C(=O)C(=O)C(C(OC)=O)N1)(C)(C)C.C(N1C(=O)C(=O)C(C(OCC)=O)N1)(C)(C)C>>[C:1]([N:5]1[C:9](=[O:10])[C:8](=[O:11])[CH2:7][NH:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1NN(C(C)(C)C)C(=O)C1=O
Agent: CC(=O)NC1NN(C(C)(C)C)C(=O)C1=O
Agent: CC(C)(C)N1NC(C(=O)O)C(=O)C1=O
Agent: CC(C)(C)N1NC(c2ccc(Cl)cc2)C(=O)C1=O
Product: CC(C)(C)N1NCC(=O)C1=O

Procedure:
1-tert-butyl-3-methyl-4,5-pyrazolinedione; 1-tert-butyl-3-phenyl-4,5-pyrazolinedione; 1-tert-butyl-3-(4′-chlorophenyl)-4,5-pyrazolinedione; 1-tert-butyl-3-(3′-methoxyphenyl)-4,5-pyrazolinedione; 1-tert-butyl-3-(4′-methoxyphenyl)-4,5-pyrazolinedione; 1-tert-butyl-3-(3′-nitrophenyl)-4,5-pyrazolinedione; 1-tert-butyl-3-(4′-methylphenyl)-4,5-pyrazolinedione; 1-tert-butyl-3-(2′-furyl)-4,5-pyrazolinedione; 1-tert-butyl-3-(2′-thienyl)-4,5-pyrazolinedione; 1-tert-butyl-3-(5′-pyrazolyl)-4,5-pyrazolinedione; 1-tert-butyl-3-methoxy-4,5-pyrazolinedione; 1-tert-butyl-3-ethoxy-4,5-pyrazolinedione; 1-tert-butyl-3-dimethylamino-4,5-pyrazolinedione: 1-tert-butyl-3-diethylamino-4,5-pyrazolinedione; 1-tert-butyl-3-acetamido-4,5-pyrazolinedione; 1-tert-butyl-3-carboxy-4,5-pyrazolinedione; 1-tert-butyl-3-methoxycarbonyl-4,5-pyrazolinedione; 1-tert-butyl-3-ethoxycarbonyl-4,5-pyrazolinedione;
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH2:11][C@H:12]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>>[I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:11][C@H:12]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(I)cc1
Reactant: CCOC(=O)CC[C@H](N)C(=O)OCC
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(I)cc1)C(=O)OCC
Yield: 56 %

Procedure:
Diethyl N-(4-iodobenzoyl)-L-glutamate is prepared from 4-iodobenzoyl chloride and diethyl L-glutamate in 56% yield by the same method. m.p. 105°-106° C.; NMR (CDCl3, 300 MHz) delta 1.26 (t, 3H, J=7.2 Hz), 1.33 (t, 3H, J=7.2 Hz), 2.11-2.60 (m, 4H), 4.14 (q, 2H, J=7.2 Hz), 4.78 (m, 1H), 7.15 (d, 1H, J=7.2 Hz), 7.58 (d, 2H, J=8.4 Hz), 7.83 (d, 2H, J=8.4 Hz).
Reaction SMILES: [NH2:1][C@:2]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:34])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1.[Si:41]([O:48][CH2:49][CH:50]=O)([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C([O-])(O)=O.[Na+].CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[Si:41]([O:48][CH2:49][CH2:50][NH:1][C@:2]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:34])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:22])([CH3:23])[C:11]([C:24]2[CH:25]=[CH:26][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:32][CH:33]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1)([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42]
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Agent: [Ti+4]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(C)[O-]
Solvent: ClCCCl
Product: C=C(C)[C@@H]1CC[C@]2(NCCO[Si](C)(C)C(C)(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 54.5 %

Procedure:
To a solution of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (300 mg, 0.552 mmol) in DCE (4 mL) was added (tert-butyldimethylsilyloxy)acetaldehyde (131 mL, 0.690 mmol) and titanium(IV) isopropoxide (0.202 mL, 0.690 mmol). The mixture was stirred at rt for 45 minutes and sodium triacetoxyborohydride (234 mg, 1.103 mmol) was added. The mixture was stirred at rt for 23 h and an additional 0.1 mL of (tert-butyldimethylsilyloxy)acetaldehyde and an additional 150 mg of sodium triacetoxyborohydride were added. The mixture was stirred at rt for an additional 22 h, then was diluted with 15 mL of sat. NaHCO3 and was extracted with dichloromethane (3×15 mL). The combined organic layers were dried with Na2SO4, the drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was adsorbed to silica gel and was purified by flash chromatography using a 0-10% EtOAc in hexanes gradient. The fractions containing the expected product were combined and were concentrated under reduced pressure to give the title compound (0.211 g, 0.301 mmol, 54.5% yield) as a clear yellow film. The product was used in the next step with no additional purification. LCMS: m/e 702.7 (M+H)+, 2.35 min (method 2).
Reaction SMILES: C(C1C=CC=CC=1N[C@@H](CC1C=CC(C2C=CC=C(N(C)C(NCCCCCCC)=O)C=2)=CC=1)C(O)=O)(=O)C1C=CC=CC=1.[C:45]([CH2:53][NH:54][CH2:55][C:56]1[CH:57]=[C:58]([C:62]2[CH:67]=[CH:66][C:65]([CH2:68][C@H:69]([NH:75][C:76]3[CH:86]=[CH:85][CH:84]=[CH:83][C:77]=3[C:78]([O:80]CC)=[O:79])[C:70]([O:72]CC)=[O:71])=[CH:64][CH:63]=2)[CH:59]=[CH:60][CH:61]=1)(=[O:52])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.[OH-].[Li+].C(N(CC1C=C(C2C=CC(C[C@H](NC3C=CC=CC=3C(O)=O)C(O)=O)=CC=2)C=CC=1)C)(=O)C1C=CC=CC=1>>[C:45]([CH2:53][NH:54][CH2:55][C:56]1[CH:57]=[C:58]([C:62]2[CH:67]=[CH:66][C:65]([CH2:68][C@H:69]([NH:75][C:76]3[CH:86]=[CH:85][CH:84]=[CH:83][C:77]=3[C:78]([OH:80])=[O:79])[C:70]([OH:72])=[O:71])=[CH:64][CH:63]=2)[CH:59]=[CH:60][CH:61]=1)(=[O:52])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: CCOC(=O)c1ccccc1N[C@@H](Cc1ccc(-c2cccc(CNCC(=O)c3ccccc3)c2)cc1)C(=O)OCC
Agent: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(C[C@H](Nc3ccccc3C(=O)c3ccccc3)C(=O)O)cc2)c1
Agent: CN(Cc1cccc(-c2ccc(C[C@H](Nc3ccccc3C(=O)O)C(=O)O)cc2)c1)C(=O)c1ccccc1
Agent: [Li+]
Product: O=C(CNCc1cccc(-c2ccc(C[C@H](Nc3ccccc3C(=O)O)C(=O)O)cc2)c1)c1ccccc1
Yield: 74 %

Procedure:
In a manner similar to the preparation of the (S)-2-(2-benzoylphenylamino)-3-[3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propionic acid (Example 2), using 300 mg (0.53 mmol) of ethyl (S)-2-(2-{3′-[(benzoyl-methylamino)methyl]biphenyl-4-yl}-1-ethoxycarbonylethylamino)benzoate (Example 32) and 300 mg (7.14 mmol) of lithium hydroxide, 200 mg of (S)-2-(2-{3′-[(benzoyl methylamino)methyl]biphenyl-4-yl}-1-carboxyethylamino)-benzoic acid are obtained with a 74% yield.
Reaction SMILES: [Cl-].[NH4+].[CH3:3][O:4][C:5]([NH:7][C:8]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[C:9]=1[CH2:10][O:11][C:12]1[C:13]([N+:18]([O-])=O)=[N:14][CH:15]=[CH:16][CH:17]=1)=[O:6]>O.C(O)C.[Fe]>[NH2:18][C:13]1[C:12]([O:11][CH2:10][C:9]2[C:21]([CH3:25])=[CH:22][CH:23]=[CH:24][C:8]=2[NH:7][C:5]([O:4][CH3:3])=[O:6])=[CH:17][CH:16]=[CH:15][N:14]=1
Reactant: COC(=O)Nc1cccc(C)c1COc1cccnc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COC(=O)Nc1cccc(C)c1COc1cccnc1N
Reaction time: 0.5 h

Procedure:
To a mixture of iron powder (2.76 g) and ammonium chloride (0.275 g) in water (19 ml) and ethanol (63 ml) was added portionwise 3-(2-methoxycarbonylamino-6-methylbenzyloxy)-2-nitropyridine (6.27 g) under reflux and then stirred for an additional 30 minutes. The hot mixture was filtered by suction and the filtrate was made alkaline with sodium bicarbonate and evaporated in vacuo. The residue was washed with water, dried, and recrystallized from ethyl acetate to give 2-amino-3-(2-methoxycarbonylamino-6-methylbenzyloxy)pyridine.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:11]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])(=[O:13])[CH3:12].[Cl:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[N:25]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]([C:36](OCC)=[O:37])=[CH:23]2>C1COCC1>[CH2:29]([N:25]1[C:26]2[C:22](=[CH:21][C:20]([Cl:19])=[CH:28][CH:27]=2)[CH:23]=[C:24]1[C:36](=[O:37])[CH2:12][C:11]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CC(=O)OC(C)(C)C
Reactant: CCOC(=O)c1cc2cc(Cl)ccc2n1Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC(=O)c1cc2cc(Cl)ccc2n1Cc1ccccc1
Reaction time: 0.5 h

Procedure:
To a cooled (−78° C.) solution of LHMDS (38 mL, 1.0 M in THF, 38 mmol) was added tert-butyl acetate (5.2 mL, 38.3 mmol). After 30 min, a solution of the title compound of Example 12 Step A (4.00 g, 12.8 mmol) in THF (10 mL) was added, and the mixture was held at −78° C. for 50 min, whereupon it was placed in a 0° C. bath. After 2 h, the reaction mixture was quenched by addition of sat. aq. NH4Cl, and the aqueous phase was extracted with EtOAc. The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. Purification by flash chromatography on silica gel (0 to 20%, then 20-100% EtOAc in hexanes) provided the title compound: LCMS B, tr=2.70 min, m/z 328.1 [M−tBu+H]+; 1H NMR (500 MHz, CDCl3) δ 7.70 (s, 1H), 7.31 (s, 1H), 7.29-7.18 (m, 5H), 7.02 (d, J=7.0 Hz, 2H), 5.84 (s, 2H), 3.86 (s, 2H), 1.40 (s, 9H).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([C@H:7]2[O:9][C@@H:8]2[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:5][CH:6]=1.[CH3:16][O:17][CH:18]([O:21][CH3:22])[CH2:19][NH2:20]>>[CH3:16][O:17][CH:18]([O:21][CH3:22])[CH2:19][NH:20][CH:7]([C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)[CH:8]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[OH:9]
Reactant: COC(CN)OC
Reactant: c1ccc([C@H]2O[C@@H]2c2ccccc2)cc1
Product: COC(CNC(c1ccccc1)C(O)c1ccccc1)OC
Temperature: 140 °C
Reaction time: 16 h
Yield: 71.3 %

Procedure:
A mixture of trans-stilbene oxide (1.96 g, 0.010 mol) and 2,2-dimethoxyethylamine (3.15 g, 0.030 mol) was heated in an oil bath at 140° C. for 5 hours. After standing at ambient temperature for 16 hours, the solid reaction mixture was triturated with isooctane and the white solid that remained was collected by filtration to obtain 2.15 g (71%) of the product. The product was recrystallized from toluene-isooctane; mp 147°-149° C.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH:7]([CH3:14])[CH2:8][C:9]1[CH2:13][CH2:12][CH2:11][CH:10]=1)(=[O:3])[CH3:2].[H][H]>[Ni].[Pd].C(O)(C)C>[C:1]([O:4][CH2:5][CH2:6][CH:7]([CH3:14])[CH2:8][CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13]1)(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)OCCC(C)CC1=CCCC1
Agent: [Ni]
Agent: [Pd]
Solvent: CC(C)O
Product: CC(=O)OCCC(C)CC1CCCC1
Yield: 93 %

Procedure:
A solution of 4-cyclopentenyl-3-methylbutyl acetate (1.96 kg, 10.0 mols), isopropyl alcohol (1000 ml) and Raney nickel (100 g), Pd/C 100 g) or other suitable sponge-metal catalyst was hydrogenated at 400 psi, at 140° C. for 10-12 h until the theoretical amount of hydrogen was taken up. The mixture was cooled and filtrated. The isopropyl alcohol was evaporated and the residue obtained was distilled under reduced pressure to provide 4-cyclopentyl-3-methylbutyl acetate (1.84 kg, yield: 93%, purity: 98%.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])#[CH:2].C([Li])CCC.CON(C)[C:27]([C:29]1[N:33]2[CH:34]=[CH:35][C:36]([O:38][CH2:39][CH2:40][O:41][CH3:42])=[CH:37][C:32]2=[N:31][CH:30]=1)=[O:28]>C1COCC1>[CH3:10][O:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[C:2][C:27]([C:29]2[N:33]3[CH:34]=[CH:35][C:36]([O:38][CH2:39][CH2:40][O:41][CH3:42])=[CH:37][C:32]3=[N:31][CH:30]=2)=[O:28])[C:4]=1[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16]
Reactant: C#Cc1cccc(OC)c1NC(=O)OC(C)(C)C
Reactant: COCCOc1ccn2c(C(=O)N(C)OC)cnc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCCOc1ccn2c(C(=O)C#Cc3cccc(OC)c3NC(=O)OC(C)(C)C)cnc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To tert-butyl 2-ethynyl-6-methoxyphenylcarbamate (1.77 g, 7.18 mmol) in THF (40 mL) was added butyllithium (0.919 g, 14.4 mmol) at −78° C., and the reaction was stirred for 1 hour. N-methoxy-7-(2-methoxyethoxy)-N-methylimidazo[1,2-a]pyridine-3-carboxamide (1.67 g, 5.98 mmol) in THF (55 mL) was then added to the reaction mixture dropwise. After the addition, the cold bath was removed and the reaction was warmed to ambient temperature. Following a 2 hour stir at ambient temperature, the reaction mixture was poured into cold saturated NH4Cl (40 mL) and EtOAc (50 mL). The phases were separated and the aqueous phase was extracted with EtOAc, dried over Na2SO4, filtered and concentrated. The residue was triturated with DCM to give product as a solid. The DCM solution was concentrated and purified by flash column chromatography (EtOAc/MeOH 10:0 to 10:1) to provide the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9]/[C:10](/[C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:5][CH:4]=1>CCO.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH:10]([C:17]2[CH:18]=[CH:19][C:20]([C:23]([F:24])([F:26])[F:25])=[CH:21][CH:22]=2)[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][CH:8]=1
Reactant: CCOC(=O)/C=C(/Cc1ccc(OC)cc1)c1ccc(C(F)(F)F)cc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CC(Cc1ccc(OC)cc1)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 40.9 %

Procedure:
To a suspension of 10% Pd/C (600 mg) in absolute EtOH (50 mL) was added ethyl (±)-4-(4-methoxyphenyl)-3-[4(trifluoromethyl)phenyl]crotonate (2.2 g. 6 mmole), and the mixture was shaken on a Parr apparatus at RT under H2 (50 psi). After 4 hr, the mixture was filtered through a pad of celite®, and the filtrate was concentrated. This reaction sequence was repeated three times. The residue was chromatographed on silica gel (35% EtOAc/hexanes) to afford the title compound (900 mg, 56%) as an oil: TLC (5% EtOAc/hexanes) Rf0.46; 1H NMR (300 MHz, CDCl3) δ 7.51 (d, J=8.2 Hz, 2 H), 7.24 (d, J=8.2 Hz, 2 H), 6.94 (d, J=8.7 Hz, 2 H), 6.76 (d, J=8.7 Hz, 2 H), 3.99 (q, J=7.1 Hz, 2 H), 3.76 (s, 3H), 3.35-3.50 (m, 1 H), 2.75-2.93 (m, 2H), 2.69 (dd, J=15.6, 6.4 Hz, 1 H), 2.60 (dd, J=15.6, 8.9 Hz, 1H), 1.11 (t, J=7.1 Hz 3 H).
Reaction SMILES: [N+]([O-])([O-])=[O:2].[U+2:5](=[O:7])=[O:6].[N+]([O-])([O-])=O.[N+]([O-])(O)=O.[CH:16]([O-:18])=[O:17].[U+2](=O)=O.[CH:22]([O-:24])=[O:23]>C(O)=O>[OH2:2].[CH:16]([O-:18])=[O:17].[U+2:5](=[O:7])=[O:6].[CH:22]([O-:24])=[O:23]
Reactant: O=[N+]([O-])[O-]
Agent: O=C[O-]
Agent: O=[U+2]=O
Solvent: O=CO
Solvent: O=[N+]([O-])O
Product: O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To demonstrate the feasibility of preparing U3O8 having a controlled particle size distribution, an exemplary feed solution (85 ml) was prepared of uranyl nitrate having a concentration of 250 gU/l at 2 M HNO3. Feed solution was contacted in suitable denitration apparatus with 70 ml of 19.9 M formic acid at a feed rate of 0.70 moles formic acid/(min)(liter of uranyl nitrate feed) solution at a temperature of 90° C. Sufficient formic acid was added to achieve a concentration of 0.3 moles /100 grams of solution at the completion of denitration. The solution was digested for one hour after completion of the formic acid addition to assure complete denitration and formation of an unsaturated solution of uranyl formate. An additional 365 ml of 19.9 M formic acid was added to the unsaturated uranyl formate solution at a feed rate of 1.27 moles/(min)(liter of uranyl nitrate feed) at 90° C. to precipitate uranyl formate monohydrate. To maximize uranium precipitation the formic acid was added until the solution acid concentration reached 1.4 moles/100 g of solution. The solution was evaporated to reduce the solution volume by 60% and adjusted with 75 ml of 90% formic acid. The slurry was cooled to ambient temperature and the precipitate recovered by filtration at a formic acid concentration of 1.7 moles/100 g solution. The precipitate was washed with 90% formic acid and the resulting filter cake was dried at 110° C. for 2 hours to provide crystalline uranyl formate monohydrate salt. This salt was then calcined in a static bed in an air atmosphere at 800° C. for 6 hours. The resulting product was a crystalline free-flowing U3O8 powder having the particle size distribution shown in the FIGURE of the attached drawing.
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4](Cl)=[O:5].[C:7]1([CH:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:15][CH2:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>C1C=CC=CC=1>[Br:1][CH2:2][CH2:3][C:4]([N:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:13]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:14]1)=[O:5]
Reactant: O=C(Cl)CCBr
Reactant: c1ccc(C2CNc3ccccc32)cc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: O=C(CCBr)N1CC(c2ccccc2)c2ccccc21
Temperature: 10 °C

Procedure:
A solution of 9.1 ml of 3-bromopropionylchloride in 10 ml of dry benzene was added dropwise to a solution of 10.0 g of 3-phenylindoline and 10 ml of triethylamine in 100 ml of dry benzene cooled to 10° C. The precipitated triethylamine hydrochloride was separated by filtration, the benzene was removed from the filtrate in vacuo at room temperature and the residue recrystallized from ethanol to give 5.6 g of the desired N-(3-bromopropionyl)-3-phenylindoline having a melting point of 98°-9° C.