Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([OH:15])=O)[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[NH2:47][C:48]1[CH:49]=[C:50]2[C:54](=[CH:55][CH:56]=1)[NH:53][C:52]([CH:57]([CH3:63])[C:58]([O:60][CH2:61][CH3:62])=[O:59])=[CH:51]2>C(#N)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:47][C:48]4[CH:49]=[C:50]5[C:54](=[CH:55][CH:56]=4)[NH:53][C:52]([CH:57]([CH3:63])[C:58]([O:60][CH2:61][CH3:62])=[O:59])=[CH:51]5)=[O:15])[CH2:11][CH2:12]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(O)C1(c2ccc3c(c2)OCO3)CC1
Reactant: CCOC(=O)C(C)c1cc2cc(N)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)C(C)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.2 %

Procedure:
To a solution of 1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid (0.079 g, 0.384 mmol) in acetonitrile (1.5 mL) were added HBTU (0.146 g, 0.384 mmol) and Et3N (160 μL, 1.15 mmol) at room temperature. The mixture was allowed to stir at room temperature for 10 min before a solution of ethyl 2-(5-amino-1H-indol-2-yl)propanoate (0.089 g, 0.384 mmol) in acetonitrile (2.16 mL) was added. After addition, the reaction mixture was stirred at room temperature for 2 h. The solvent was evaporated under reduced pressure and the residue was dissolved in dichloromethane. The organic layer was washed with 1 N HCl (1×3 mL) and then saturated aqueous NaHCO3 (1×3 mL). The organic layer was dried over Na2SO4, filtered and evaporated under reduced pressure. The crude material was purified by column chromatography on silica gel (ethyl acetate/hexane=1/1) to give ethyl 2-(5-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-1H-indol-2-yl)propanoate (0.081 g, 50%). 1H NMR (400 MHz, CDCl3) δ 8.51 (s, 1H), 7.67 (s, 1H), 7.23-7.19 (m, 2H), 7.04-7.01 (m, 3H), 6.89 (d, J=0.0 Hz, 1H), 6.28 (s, 1H), 6.06 (s, 2H), 4.25-4.17 (m, 2H), 3.91 (q, J=7.2 Hz, 1H), 1.72-1.70 (m, 2H), 1.61 (s, 2H), 1.29 (t, J=7.1 Hz, 4H), 1.13-1.11 (m, 2H).
Reaction SMILES: CN(C)C=O.Br[CH2:7][C:8]1[C:13]([CH:14]([F:16])[F:15])=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:17].C(=O)([O-])[O-].[K+].[K+].[CH2:24]([N:30]1[CH2:35][CH2:34][CH:33]([NH:36][C:37]([C@:39]2([CH2:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[C@H:43]([CH3:44])[CH2:42][NH:41][CH2:40]2)=[O:38])[CH2:32][CH2:31]1)[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>O.C(OCC)(=O)C>[Cl:17][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([CH:14]([F:16])[F:15])[C:8]=1[CH2:7][N:41]1[CH2:42][C@@H:43]([CH3:44])[C@@:39]([CH2:45][C:46]([O:48][C:49]([CH3:51])([CH3:50])[CH3:52])=[O:47])([C:37](=[O:38])[NH:36][CH:33]2[CH2:32][CH2:31][N:30]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:35][CH2:34]2)[CH2:40]1
Reactant: CCCCCCN1CCC(NC(=O)[C@@]2(CC(=O)OC(C)(C)C)CNC[C@H]2C)CC1
Reactant: FC(F)c1cccc(Cl)c1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCCCN1CCC(NC(=O)[C@@]2(CC(=O)OC(C)(C)C)CN(Cc3c(Cl)cccc3C(F)F)C[C@H]2C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.5 %

Procedure:
N,N-Dimethylformamide (400 μl), 2-(bromomethyl)-1-chloro-3-(difluoromethyl)benzene obtained in Example 10f (24.9 mg, 0.0976 mmol) and potassium carbonate (20.2 mg, 0.146 mmol) were added to tert-butyl 2-[(3R*,4S*)-3-[(1-hexylpiperidin-4-yl)carbamoyl]-4-methylpyrrolidin-3-yl]acetate obtained in Example 10i (20 mg, 0.0488 mmol), followed by stirring at room temperature overnight. Ethyl acetate and water were added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. This was concentrated, and the resulting crude product was purified by column chromatography (NH silica gel, elution solvent: heptane/ethyl acetate=98/2->80/20) to give the title compound (14.4 mg, yield 50.2%).
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[C:15]3[CH:14]=[C:13]([C:16]4[C:21]([Cl:22])=[CH:20][N:19]=[C:18](Cl)[N:17]=4)[S:12][C:11]=3[CH:10]=[CH:9][CH:8]=2)=[O:6])[CH2:3][CH2:2]1.C(OC([N:31]1[CH2:36][CH2:35][N:34]([CH2:37][CH2:38][CH2:39][NH2:40])[C@@H:33]([CH3:41])[CH2:32]1)=O)(C)(C)C.[ClH:42]>Cl.Cl.ClC1C(C2SC3C=CC=C(C(N)=O)C=3C=2)=NC(NCCC2CCN(C)CC2)=NC=1>[ClH:22].[ClH:42].[ClH:22].[CH:1]1([NH:4][C:5]([C:7]2[C:15]3[CH:14]=[C:13]([C:16]4[C:21]([Cl:22])=[CH:20][N:19]=[C:18]([NH:40][CH2:39][CH2:38][CH2:37][N:34]5[CH2:35][CH2:36][NH:31][CH2:32][C@@H:33]5[CH3:41])[N:17]=4)[S:12][C:11]=3[CH:10]=[CH:9][CH:8]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: O=C(NC1CC1)c1cccc2sc(-c3nc(Cl)ncc3Cl)cc12
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1CCCN
Agent: CN1CCC(CCNc2ncc(Cl)c(-c3cc4c(C(N)=O)cccc4s3)n2)CC1
Agent: Cl
Product: C[C@H]1CNCCN1CCCNc1ncc(Cl)c(-c2cc3c(C(=O)NC4CC4)cccc3s2)n1

Procedure:
Using the method of (R)-2-{5-chloro-2-[3-(2-methylpiperazin-1-yl)-propylamino]-pyrimidin-4-yl}-benzo[b]thiophene-4-carboxylic acid methylamide, free base of the title compound is synthesized from 2-(2,5-dichloropyrimidin-4-yl)-benzo[b]thiophene-4-carboxylic acid cyclopropylamide and (S)-4-(3-aminopropyl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester. After treating the free base with 12 N HCl (10 equivalents) as described in 2-{5-chloro-2-[2-(1-methylpiperidin-4-yl)-ethylamino]-pyrimidin-4-yl}-benzo[b]thiophene-4-carboxylic acid amide di-hydrochloride, the title compound is isolated as a yellow solid. ES+(m/z) 485 (35Cl) and 487 (37Cl) [M(free base)+H].
Reaction SMILES: [CH3:1][C:2]1[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([N:10]1[C:19]2[C:14](=[C:15](C3C=CN=C(C(OC)=O)C=3)[CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1)=[O:9].BrC1C=CN=C(C(OC)=O)C=1.Br[C:47]1[S:51][C:50]([CH2:52][OH:53])=[N:49][CH:48]=1>>[CH3:1][C:2]1[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([N:10]1[C:19]2[C:14](=[C:15]([C:48]3[N:49]=[C:50]([CH2:52][OH:53])[S:51][CH:47]=3)[CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1)=[O:9]
Reactant: COC(=O)c1cc(-c2cccc3c2CCCN3C(=O)CCCOc2cccc(C)c2C)ccn1
Reactant: OCc1ncc(Br)s1
Agent: COC(=O)c1cc(Br)ccn1
Product: Cc1cccc(OCCCC(=O)N2CCCc3c(-c4csc(CO)n4)cccc32)c1C

Procedure:
The title compound was prepared using a procedure analogous to methyl 4-(1-(4-(2,3-dimethylphenoxy)butanoyl)-1,2,3,4-tetrahydroquinolin-5-yl)picolinate except that methyl 4-bromopicolinate was replaced with (5-bromothiazol-2-yl)methanol. LCMS, [M+H]+=437.1. 1H NMR (400 MHz, CDCl3) δ 7.33 (d, J=7.0 Hz, 1H), 7.26-7.19 (m, 2H), 7.06 (s, 1H), 7.03-6.95 (m, 1H), 6.73 (d, J=7.5 Hz, 1H), 6.63 (d, J=8.2 Hz, 1H), 5.01 (s, 2H), 3.92 (t, J=5.2 Hz, 2H), 3.79 (t, J=6.9 Hz, 2H), 2.74 (t, J=7.3 Hz, 2H), 2.62 (t, J=6.2 Hz, 2H), 2.25-2.11 (m, 5H), 1.93 (s, 3H), 1.89-1.80 (m, 2H).
Reaction SMILES: C(OC([C:6]1[C:7]([N:15]2[CH2:20][CH2:19][C:18]([NH2:29])([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[CH2:17][CH2:16]2)=[C:8]2[CH:14]=[N:13][NH:12][C:9]2=[N:10][CH:11]=1)=O)C.O>[OH-].[K+]>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][C:18]2([NH2:29])[CH2:19][CH2:20][N:15]([C:7]3[CH:6]=[CH:11][N:10]=[C:9]4[NH:12][N:13]=[CH:14][C:8]=34)[CH2:16][CH2:17]2)=[CH:23][CH:24]=1
Reactant: CCOC(=O)c1cnc2[nH]ncc2c1N1CCC(N)(Cc2ccc(Cl)cc2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: NC1(Cc2ccc(Cl)cc2)CCN(c2ccnc3[nH]ncc23)CC1
Yield: 58.5 %

Procedure:
4-[4-Amino-4-(4-chlorobenzyl)-piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester (55 mg, 0.13 mmol) was suspended in 2M potassium hydroxide (1.5 mL) and irradiated in a microwave reactor (250W) for 2 hours at 120° C. After cooling, water (2 mL) was added and the solids formed were collected by filtration. The filtrate was extracted with ethyl acetate (2×4 mL) and dried (Na2SO4). The extracts were evaporated and the resulting yellow solids were combined with the previous material and dissolved in acetone (10 mL) and n-hexanes (2 mL). The solvents were concentrated until precipitation occurred. The solids were collected by filtration and washed with n-hexanes to give 4-(4-chlorobenzyl)-1-(1H-pyrazolo[3,4-b]pyridin-4-yl)-piperidin-4-ylamine as a light yellow powder (26 mg, 57%). LC-MS (LCT2) m/z 342 [M+H+], Rt 2.07 min.
Reaction SMILES: [CH:1]([C:4]1[CH:35]=[CH:34][CH:33]=[CH:32][C:5]=1[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:21](=[O:22])[CH2:20][C:19](=[O:23])[NH:18][C:17]3[C:24]4[C:29]([CH:30]=[CH:31][C:16]2=3)=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:11][CH:10]=1)=[O:7])=[CH:2][CH3:3]>CO.O1CCCC1.[C].[Pd]>[CH2:1]([C:4]1[CH:35]=[CH:34][CH:33]=[CH:32][C:5]=1[C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[C:21](=[O:22])[CH2:20][C:19](=[O:23])[NH:18][C:17]3[C:24]4[C:29]([CH:30]=[CH:31][C:16]2=3)=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:13][CH:14]=1)=[O:7])[CH2:2][CH3:3]
Reactant: CC=Cc1ccccc1C(=O)Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CCCc1ccccc1C(=O)Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Reaction time: 16 h
Yield: 46.5 %

Procedure:
5-[4-(2-Propenylbenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (30 mg, 0.065 mmol) was dissolved in a mixture of methanol (0.3 mL) and tetrahydrofuran (0.3 mL), the atmosphere was substituted with argon, then the solution was added with 10% palladiumcarbon (3 mg), and the mixture was stirred for 16 hours under a hydrogen atmosphere. After completion of the reaction, the reaction mixture was filtered through Celite, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform/methanol=100/1) to give the title compound (14 mg, yield 46%).
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:30]=[CH:29][C:13]2[N:14]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]([O:27]C)=[O:26])=[CH:21][CH:20]=3)[C:15]([CH3:17])=[N:16][C:12]=2[CH:11]=1.[OH-].[Na+].CO>C(Cl)(Cl)Cl>[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:30]=[CH:29][C:13]2[N:14]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]([OH:27])=[O:26])=[CH:21][CH:20]=3)[C:15]([CH3:17])=[N:16][C:12]=2[CH:11]=1
Reactant: COC(=O)c1ccc(Cn2c(C)nc3cc(-c4nc5ccccc5o4)ccc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1nc2cc(-c3nc4ccccc4o3)ccc2n1Cc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 86.8 %

Procedure:
To a solution of 5-(benzoxazol-2-yl)-1-(4-methoxycarbonylphenylmethyl)-2-methylbenzimidazole (see Working Example 113-3) (55 mg, 0.138 mmol) in chloroform (3 mL) was added aqueous sodium hydroxide solution (1 M, 0.6 mL, 0.6 mmol). This two-layer solution was homogenized by the addition of methanol, and this was stirred at room temperature for 20 hours. After the reaction was complete, the solution was concentrated, aqueous acetic acid solution was added, and this was stirred at room temperature. The precipitated crystals were filtered, and after washing with water were dried to yield the title compound (45.9 mg, 87% yield) as yellow crystals.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[C:11]1([CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][C:25]#N)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[OH2:27].Cl>O1CCCC1>[C:11]1([CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][CH:25]=[O:27])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O
Reactant: N#CCCOCCOCCc1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Product: O=CCCOCCOCCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Diisobutylaluminum hydride (3.3 ml, 1.5M in toluene) was added dropwise to a cooled (0°) stirred solution of 3-[2-[2-phenylethoxy]ethoxy]propanenitrile (1.0 g) from step a) in tetrahydrofuran. After 30 min the mixture was warmed to room temperature and stirred for a further 2 hours. Water and 10% aqueous hydrochloric acid were added cautiously and the reaction stirred for a further 5 min. The reaction was extracted several times with ether and the combined ethereal extracts were washed with saturated aqueous sodium bicarbonate solution and brine, dried (MgSO4) and evaporated under reduced pressure to yield the subtitled compound as a yellow oil. The material was used in the next step without purification.
Reaction SMILES: CC1C(=[O:8])[C@@H](O)CC(C)(C)C=1/C=C/C(/C)=C/C=C/C(/C)=C/C=C/C=C(\C)/C=C/C=C(\C)/C=C/C1C(C)(C)C[C@H](O)C(=O)C=1C.CCN(C(C)C)C(C)C.Cl[C:55]([O:57]C(Cl)C(Cl)(Cl)Cl)=[O:56].[CH2:64]([OH:75])[C@H:65]([C@H:67]([C@@H:69]([C@@H:71]([CH2:73][OH:74])[OH:72])[OH:70])[OH:68])[OH:66]>C(Cl)Cl.CN(C1C=CN=CC=1)C.CN(C=O)C>[C:55](=[O:56])([OH:8])[OH:57].[CH2:73]([OH:74])[C@H:71]([C@H:69]([C@@H:67]([C@@H:65]([CH2:64][OH:75])[OH:66])[OH:68])[OH:70])[OH:72]
Reactant: O=C(Cl)OC(Cl)C(Cl)(Cl)Cl
Reactant: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C2=C(C)C(=O)[C@@H](O)CC2(C)C)C(C)(C)C[C@H](O)C1=O
Agent: CN(C)c1ccncc1
Agent: OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(O)O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of astaxanthin 2E (0.100 g, 0.168 mmol) in DCM (4 mL) at 0° C. was added DIPEA (0.585 mL, 3.36 mmol), and 1,2,2,2-tetrachloroethyl chloroformate (0.103 mL, 0.672 mmol). The reaction mixture was stirred at 0° C. for 2 hours, then at room temperature for 1.5 hours, at which time (D)-mannitol (0.3060 g, 1.68 mmol), DMF (3 mL), and DMAP (0.2052 g, 1.68 mmol) were added to the reaction. The reaction mixture was stirred at room temperature for 24 hours, at which time the reaction was diluted with DCM, quenched with brine (20 mL), and then extracted with DCM. The combined organic layers were concentrated to yield mannitol monocarbonate (LVII) (10.19%) HPLC retention time: 9.474 min., 10.19% (AUC); LRMS (ESI) m/z (relative intensity): 827 (M++Na) (50), 804 (M+) (25), 725 (58), 613 (100), and astaxanthin 2E (53.73%).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:15])[C@@H:10]([CH:12]([CH3:14])[CH3:13])[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[BH-](O[C:26](=[O:28])[CH3:27])OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:15])[C@H:10]([NH:11][CH2:14][C:12]1[CH:13]=[CH:27][C:26]2[O:28][CH2:1][O:8][C:9]=2[CH:10]=1)[CH:12]([CH3:13])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC(C)[C@@H](N)C(=O)OCc1ccccc1
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)[C@@H](NCc1ccc2c(c1)OCO2)C(=O)OCc1ccccc1
Reaction time: 15 h
Yield: 170.1 %

Procedure:
To a solution of D-valine benzyl ester free base (12.92 g, 62 mmol) in dry methylene chloride (120 mL) was added 3,4-(methylenedioxy)phenyl methanol (9.45 g, 62 mmol) and sodium triacetoxyborohydride (18.50 g, 86.8 mmol). After 15 h, the reaction mixture was quenched with saturated aqueous sodium bicarbonate (120 mL) and the aqueous layer was separated and extracted with methylene chloride. The combined methylene chloride layers were washed with brine, dried over magnesium sulfate, and concentrated. The residue was chromatographed (300 g SiO2, 5% ethyl acetate-hexanes) to afford 2(R)-(3,4-methylenedioxy-benzylamino)-3-methylbutyric acid benzyl ester (18 g) as a colorless oil.
Reaction SMILES: CN(C=O)C.[F:6][C:7]([F:20])([F:19])[C:8]1[C:16]([C:17]#[N:18])=[CH:15][CH:14]=[C:13]2[C:9]=1[CH:10]=[CH:11][NH:12]2.C([O-])([O-])=O.[Cs+].[Cs+].Cl[CH2:28][C:29]1[N:33]=[C:32]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[CH:35]=2)[O:31][N:30]=1>O>[F:20][C:7]([F:19])([F:6])[C:8]1[C:16]([C:17]#[N:18])=[CH:15][CH:14]=[C:13]2[C:9]=1[CH:10]=[CH:11][N:12]2[CH2:28][C:29]1[N:33]=[C:32]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:41])[F:42])[CH:35]=2)[O:31][N:30]=1
Reactant: FC(F)(F)c1cccc(-c2nc(CCl)no2)c1
Reactant: N#Cc1ccc2[nH]ccc2c1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc2c(ccn2Cc2noc(-c3cccc(C(F)(F)F)c3)n2)c1C(F)(F)F
Temperature: 90 °C

Procedure:
A DMF solution (25 mL) of 4-(trifluoromethyl)-1H-indole-5-carbonitrile (2.66 mmol max) was treated with Cs2CO3 (1.73 g, 5.32 mmol) followed by 3-(chloromethyl)-5-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazole (0.699 g, 2.66 mmol). The resulting suspension was heated to 90° C. for 30 min. The cooled reaction mixture was diluted with H2O (25 mL) and then extracted with EtOAc (3×25 mL). The pooled organic portions were washed with H2O and brine. Drying (Na2SO4) and filtration were followed by concentration. Column chromatography (SiO2, EtOAc/hexanes) afforded the title compound in excellent purity as a pale yellow solid (900 g, 75% over two stages): 1H NMR (DMSO-d6) δ 8.32 (d, J=6.0 Hz, 1H), 8.25 (bs, 1H), 8.11-8.06 (m, 2H), 7.98 (d, J=3.0 Hz, 1H), 8.86-8.81 (m, 2H), 6.82-6.81 (m, 1H), 5.95 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([F:11])[CH:3]=1.[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:8])=[C:4]([F:11])[CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1F
Reactant: C1CCNC1
Product: O=C(c1ccc(Br)cc1F)N1CCCC1

Procedure:
The sub-title compound was prepared by the method of example 18 step a) using 4-bromo-2-fluoro-benzoic acid and pyrrolidine.
Reaction SMILES: Cl.Cl.[CH3:3][N:4]([CH3:11])[C:5]12[CH2:10][CH:9]1[CH2:8][NH:7][CH2:6]2.[Cl:12][C:13]1[N:18]=[C:17]([N:19]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[N:20]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:16]([F:42])=[C:15](Cl)[N:14]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C.CCOCC>[CH3:27][C:24]([O:23][C:21]([N:20]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:19]([C:17]1[C:16]([F:42])=[C:15]([N:7]2[CH2:8][CH:9]3[C:5]([N:4]([CH3:11])[CH3:3])([CH2:10]3)[CH2:6]2)[N:14]=[C:13]([Cl:12])[N:18]=1)[C:35]([O:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[O:36])=[O:22])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)c1nc(Cl)nc(Cl)c1F
Reactant: CN(C)C12CNCC1C2
Agent: Cl
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C12CC1CN(c1nc(Cl)nc(N(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1F)C2
Reaction time: 8 h
Yield: 84.5 %

Procedure:
To a solution of racemic N,N-dimethyl-3-azabicyclo[3.1.0]hexan-1-amine dihydrochloride (assumed 0.5339 g, 2.681 mmol) in DMF (13 mL) was added tris(1,1-dimethylethyl) 2-(2,6-dichloro-5-fluoro-4-pyrimidinyl)-1,1,2-hydrazinetricarboxylate (1.33 g, 2.674 mmol) and N,N-diisopropylethylamine (1.87 mL, 10.74 mmol). The solution was stirred overnight and then diluted with Et2O (100 mL). The mixture was washed with water (2×50 mL), and the combined aqueous phase was extracted with a fresh portion of Et2O (50 mL). The combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by gradient silica gel chromatography (0% to 100% EtOAc in hexanes; 1% Et3N) to afford racemic tris(1,1-dimethylethyl)2-{2-chloro-6-[1-(dimethylamino)-3-azabicyclo[3.1.0]hex-3-yl]-5-fluoro-4-pyrimidinyl}-1,1,2-hydrazinetricarboxylate (1.3261 g, 84%) as a white foam. LCMS: (M+H)+: 587.3.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([CH3:23])[CH:18]=3)[NH:14][N:13]=2)=[CH:8][C:7]=1[N+:24]([O-:26])=[O:25])[CH:2]([CH3:4])[CH3:3].[C:27]([O:33][CH2:34]Cl)(=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([CH3:23])[CH:18]=3)[N:14]([CH2:34][O:33][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])[N:13]=2)=[CH:8][C:7]=1[N+:24]([O-:26])=[O:25])[CH:2]([CH3:4])[CH3:3]
Reactant: Cc1cc(-c2nc(-c3ccc(OCC(C)C)c([N+](=O)[O-])c3)n[nH]2)ccn1
Reactant: CC(C)(C)C(=O)OCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(-c2nc(-c3ccc(OCC(C)C)c([N+](=O)[O-])c3)nn2COC(=O)C(C)(C)C)ccn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.4 %

Procedure:
354 mg of the powder obtained in Example 1 was dissolved in 3 ml of DMF, 181 mg of pivaloyloxymethyl chloride and 276 mg of potassium carbonate were added thereto, and the mixture was stirred at room temperature for 18 hours. Ethyl acetate was added to the reaction mixture, which was then washed with water and dried over magnesium sulfate. After the magnesium sulfate was filtered off, the solvent was evaporated under reduced pressure and the residue was subjected to silica gel column chromatography. Chloroform-acetone (95:5) was used as an eluent and 358 mg of the object compound was obtained as a white powder.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([C:17]([OH:19])=O)[N:10]([CH2:12][C:13]([F:16])([F:15])[F:14])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:20][O:21][CH2:22][CH2:23][N:24]([CH3:32])[C:25]1[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][N:26]=1>>[CH3:20][O:21][CH2:22][CH2:23][N:24]([CH3:32])[C:25]1[N:26]=[CH:27][C:28]([NH:31][C:17]([C:9]2[N:10]([CH2:12][C:13]([F:14])([F:15])[F:16])[N:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:8]=2)=[O:19])=[CH:29][CH:30]=1
Reactant: O=C(O)c1cc(-c2ccccc2)nn1CC(F)(F)F
Reactant: COCCN(C)c1ccc(N)cn1
Product: COCCN(C)c1ccc(NC(=O)c2cc(-c3ccccc3)nn2CC(F)(F)F)cn1

Procedure:
With a procedure similar to example 16 above, 5-phenyl-2-(2,2,2-trifluoro-ethyl)-2H-pyrazole-3-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide was prepared from 5-phenyl-2-(2,2,2-trifluoro-ethyl)-2H-pyrazole-3-carboxylic acid and N2-(2-methoxy-ethyl)-N2-methyl-pyridine-2,5-diamine. LCMS calcd for C21H22F3N5O2 (m/e) 433, obsd 434 (M+H). The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: [CH2:1]([CH:10]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)[N:11]1[CH:14]([O:15][C:16](=[O:18])[CH3:17])[CH:13]([CH:19]=[CH2:20])[C:12]1=[O:21])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[BH4-].[Na+].Cl.[O:34]1CCCC1>O.[OH-].[Na+].C(OCC)C>[CH2:22]([CH:10]([CH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1)[N:11]1[CH:14]([O:15][C:16](=[O:18])[CH3:17])[CH:13]([CH:19]([OH:34])[CH3:20])[C:12]1=[O:21])[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1
Reactant: C1CCOC1
Reactant: C=CC1C(=O)N(C(Cc2ccc(OC)cc2)Cc2ccc(OC)cc2)C1OC(C)=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: COc1ccc(CC(Cc2ccc(OC)cc2)N2C(=O)C(C(C)O)C2OC(C)=O)cc1
Reaction time: 0.09 h

Procedure:
A solution of 1-(di-p-anisylmethyl)-3-ethenyl-4-acetoxy-2-azetidinone (3.80 g) and mercuric acetate (3.20 g) in tetrahydrofuran (10 ml) and water (4 ml) was stirred for 1 hour at room temperature. The reaction mixture was treated with 1N sodium hydroxide (9 ml) at 0° C. and then a solution of sodium borohydride (0.4 g) in 1N aqueous sodium hydroxide. After stirring at the same temperature for 5 to 6 minutes, the reaction mixture was neutralized with dilute hydrochloric acid, diluted with diethyl ether and filtered to remove any insoluble materials over Cerite. The filtrate was extracted with diethyl ether and the ether extract was washed successively with aqueous sodium bicarbonate and water, dried over anhydrous sodium sulfate and evaporated to give an oily residue which was then purified by silica gel chromatography to give 1-(di-p-anisylmethyl)-3-(1-hydroxyethyl)-4-acetoxy-2-azetidinone.