Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([CH3:10])[N:3]=1.[Br:11][C:12]1[C:13]([S:17]([N:20]=[C:21]=[O:22])(=[O:19])=[O:18])=[CH:14][S:15][CH:16]=1>O1CCCC1>[Br:11][C:12]1[C:13]([S:17]([NH:20][C:21]([NH:1][C:2]2[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([CH3:10])[N:3]=2)=[O:22])(=[O:18])=[O:19])=[CH:14][S:15][CH:16]=1
Reactant: COc1nc(C)nc(N)n1
Reactant: O=C=NS(=O)(=O)c1cscc1Br
Solvent: C1CCOC1
Product: COc1nc(C)nc(NC(=O)NS(=O)(=O)c2cscc2Br)n1
Temperature: 10 °C

Procedure:
To 1.1 g of 2-amino-4-methoxy-6-methyl-1,3,5-triazine in 20 ml of tetrahydrofuran was added 2 g of 4-bromo-3-thiophenesulfonyl isocyanate in 5 ml of tetrahydrofuran. The mixture was then stirred and warmed on a steam bath for 15 minutes and allowed to stir at ambient temperature for 70 hours. It was then heated to reflux for 2 hours, cooled to 10° C., filtered and the filtrate evaporated. The residual oil was triturated to yield the desired product as a solid which after recrystallization from acetonitrile melted at 180°-183°, yield 1.5 g.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][CH2:7][N:8]2[CH2:12][CH2:11][C@H:10]([O:13]C(=O)C3C=CC([N+]([O-])=O)=CC=3)[CH2:9]2)=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][CH2:7][N:8]2[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C(O[C@H]1CCN(CCc2ccc(Cl)cc2)C1)c1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O[C@H]1CCN(CCc2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(S)-1-(4-Chlorophenethyl)-3-(4-nitrobenzoyloxy)pyrrolidine (315 mg, 0.84 mmol) was dissolved in methanol (10 ml). 1 M-NaOH (1 ml) was added dropwise in the obtained mixture. After stirring at room temperature for 1 hour, the solvent was evaporated under reduced pressure. The residue was distributed in water and ethyl acetate. The organic layer was dried, and the solvent was evaporated under reduced pressure to obtain (S)-1-(4-chlorophenethyl)-3-hydroxypyrrolidine in the form of a light yellow oil (190 mg, 100%).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[CH2:12][CH2:11][C:10]3([CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[O:19])[CH2:13]3)[C:9]2=[O:28])[CH2:4][CH2:3]1.N1C=CN=C1.[Si:34](Cl)([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35].CCCCCCC>CN(C)C=O>[Si:34]([O:1][C@@H:2]1[CH2:3][CH2:4][C@H:5]([N:8]2[CH2:12][CH2:11][C:10]3([CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][CH2:21][C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)=[O:19])[CH2:13]3)[C:9]2=[O:28])[CH2:6][CH2:7]1)([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C(OCc1ccccc1)N1CCCC2(CCN([C@H]3CC[C@@H](O)CC3)C2=O)C1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCCCCCC
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@H](N2CCC3(CCCN(C(=O)OCc4ccccc4)C3)C2=O)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 71.3 %

Procedure:
To a stirred solution of benzyl 2-(cis-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]decane-7-carboxylate (60.00 g, 155.2 mmol) in anhydrous N,N-dimethylformamide (160 mL) at r.t. was added 1H-imidazole (32.0 g, 466 mmol) and tert-butyldimethylsilyl chloride (36.2 g, 233 mmol). The reaction mixture was stirred at r.t. for 4 h, quenched with water (150 mL), and extracted with EtOAc (3×150 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the crude product (84 g). The pure product (55.4 g) was obtained by re-crystallization of the crude product from heptane. The mother liquor was concentrated and subjected to purification by flash chromatography on a silical gel column eluting with AcOEt/Haxane to give additional 14.4 g of the product with a total 89.7% yield.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([NH:6][C:7]([NH:9][C:10]1[CH:15]=[C:14]([CH2:16][C:17]2[C:26]3[CH2:25][CH2:24][CH2:23][CH2:22][C:21]=3[C:20](=[O:27])[NH:19][N:18]=2)[CH:13]=[CH:12][C:11]=1[F:28])=[O:8])[CH3:5].[OH-].[Na+].Cl>CC(N(C)C)=O>[F:28][C:11]1[CH:12]=[CH:13][C:14]([CH2:16][C:17]2[C:26]3[CH2:25][CH2:24][CH2:23][CH2:22][C:21]=3[C:20](=[O:27])[NH:19][N:18]=2)=[CH:15][C:10]=1[N:9]1[C:3](=[O:2])[CH:4]([CH3:5])[NH:6][C:7]1=[O:8]
Reactant: COC(=O)C(C)NC(=O)Nc1cc(Cc2n[nH]c(=O)c3c2CCCC3)ccc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)N(C)C
Product: CC1NC(=O)N(c2cc(Cc3n[nH]c(=O)c4c3CCCC4)ccc2F)C1=O
Reaction time: 0.17 h

Procedure:
To a solution of 2-{3-[2-fluoro-5-(4-oxo-3,4,5,6,7,8-hexahydro-phthalazin-1-ylmethyl)-phenyl]-ureido}-propionic acid methyl ester (12) (0.425 g, 1.053 mmol), in dry DMA (5 ml), was added ground sodium hydroxide (0.433 mg, 1.053 mmol) in one portion. The reaction mixture was then placed in a preheated oil bath at 50° C. for 10 minutes and neutralised by addition of HCl (2N, ca 1 ml). The mixture was then concentrated to dryness and subjected to flash chromatography, eluent neat ethyl acetate (Rf=0.15). Single peak in LC-MS, (0.457 g, 99% purity); 1H NMR (300 MHz, D6 DMSδ ppm 12.61 (s, 1H), 8.51 (s, 1H), 7.40-7.15 (m, 3H), 4.32 (m, 1H), 3.93 (s, 2H), 2.46 (m, 4H), 1.63 (s, 4H), 1.35 (d, J=6.94 Hz, 3H). M/z (LC-MS, ESP), RT=3.28 mins (M+H 371.1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:10](=[O:17])[C@@H:9]([CH2:18][C:19]#[N:20])[S:8][C@H:7]([C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=[CH:23][CH:22]=3)[C:6]=2[CH:31]=1.C[Sn]([N:36]=[N+:37]=[N-:38])(C)C.C1(C)C=CC=CC=1>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][C:13]([CH3:14])([CH3:15])[CH3:16])[C:10](=[O:17])[C@@H:9]([CH2:18][C:19]3[NH:38][N:37]=[N:36][N:20]=3)[S:8][C@H:7]([C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=[CH:23][CH:22]=3)[C:6]=2[CH:31]=1
Reactant: CC(C)(C)CN1C(=O)[C@@H](CC#N)S[C@H](c2cccc3ccccc23)c2cc(Cl)ccc21
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)CN1C(=O)[C@@H](Cc2nnn[nH]2)S[C@H](c2cccc3ccccc23)c2cc(Cl)ccc21
Yield: 71.2 %

Procedure:
A heterogeneous mixture of trans-7-chloro-5-(naphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzothiazepine-3-acetonitrile (75 mg, 167 μmol), trimethyltin azide (70 mg, 334 μmol) and toluene (2 mL) was heated at reflux for 18 hours. Reaction mixture concentrated under reduced pressure and purified by flash column chromatography (80:15:1 chloroform/methanol/ammonium hydroxide) to yield a clear oil which was taken up in ethyl acetate, washed with 0.5 N hydrochloric acid, dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide 58.5 mg (71 %) of the title compound as a white powder.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[C:4]([O:14][CH2:15][C:16]([CH3:21])([CH3:20])[C:17]([OH:19])=[O:18])=[CH:3][CH:2]=1.C1C2NC3C(=CC=CC=3)C=2C(OC(C)(C)C(O)=O)=CC=1.Cl[CH2:43][C:44]1[CH:62]=[CH:61][C:47]([O:48][CH2:49][C:50]2[N:51]=[C:52]([C:56]3[O:57][CH:58]=[CH:59][CH:60]=3)[O:53][C:54]=2[CH3:55])=[C:46]([O:63][CH3:64])[CH:45]=1.ClCC1C=CC(OCC2N=C(C3C=CC=CC=3)OC=2C)=C(OC)C=1>>[O:57]1[CH:58]=[CH:59][CH:60]=[C:56]1[C:52]1[O:53][C:54]([CH3:55])=[C:50]([CH2:49][O:48][C:47]2[CH:61]=[CH:62][C:44]([CH2:43][N:12]3[C:13]4[CH:1]=[CH:2][CH:3]=[C:4]([O:14][CH2:15][C:16]([CH3:21])([CH3:20])[C:17]([OH:19])=[O:18])[C:5]=4[C:6]4[C:11]3=[CH:10][CH:9]=[CH:8][CH:7]=4)=[CH:45][C:46]=2[O:63][CH3:64])[N:51]=1
Reactant: CC(C)(COc1cccc2[nH]c3ccccc3c12)C(=O)O
Reactant: COc1cc(CCl)ccc1OCc1nc(-c2ccco2)oc1C
Agent: CC(C)(Oc1cccc2[nH]c3ccccc3c12)C(=O)O
Agent: COc1cc(CCl)ccc1OCc1nc(-c2ccccc2)oc1C
Product: COc1cc(Cn2c3ccccc3c3c(OCC(C)(C)C(=O)O)cccc32)ccc1OCc1nc(-c2ccco2)oc1C

Procedure:
The subject compound was prepared by performing the same operation as that of the example 3 by using 3-(9H-carbazole-4-yloxy)-2,2-dimethylpropionic acid prepared by the reference 30 instead of 2-(9H-carbazole-4-yloxy)-2-methylpropionic acid used in the example 3, and using 4-((4-(chloromethyl)-2-methoxyphenoxy)methyl)-2-(furan-2-yl)-5-methyloxazole prepared by the reference 2 instead of 4-((4-(chloromethyl)-2-methoxyphenoxy)methyl)-5-methyl-2-phenyloxazole.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:15]3([CH2:19][O:18][C:17]([NH2:20])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([O:21][CH3:22])[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1.CN(C=O)C.[CH3:28][C:29]([CH3:33])([CH3:32])[C:30]#[CH:31].C(NC(C)C)(C)C>O.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.[Cu]I.C(OCC)(=O)C>[CH3:28][C:29]([CH3:33])([CH3:32])[C:30]#[C:31][C:2]1[CH:3]=[C:4]2[C:15]3([CH2:19][O:18][C:17]([NH2:20])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([O:21][CH3:22])[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1
Reactant: COc1ccc2c(c1)C1(COC(N)=N1)c1cc(Br)cnc1O2
Reactant: C#CC(C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: COc1ccc2c(c1)C1(COC(N)=N1)c1cc(C#CC(C)(C)C)cnc1O2
Temperature: 90 °C

Procedure:
Combined 3-bromo-7-methoxy-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine (104186-10-peak 1) (500 mg, 1.381 mmol), tetrakis(triphenylphosphine)palladium (160 mg, 0.138 mmol), copper(i) iodide (52.6 mg, 0.276 mmol). Added DMF (6903 μL, 1.381 mmol), 3,3-dimethylbut-1-yne (340 mg, 4.14 mmol) and diisopropylamine (4837 μL, 34.5 mmol), flushed with argon, sealed and heated at 90° C. for 2 hours. The reaction was diluted with water (100 mL) and poured into a separatory funnel containing ethyl acetate (100 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with water and then brine, dried over sodium sulfate, filtered and concentrated in vacuo to provide a brown oil that was purified by silica gel chromatography (Redi-Sep pre-packed silica gel column (40 g), 0-10% methanol in methylenechloride with 0.1% ammonium hydroxide) to provide the desired product contaminated with triphenylphosphine. The yellow solid was suspended in 25 mL of ether, resulting in the formation of a fine white precipitate. Decanted ether and washed the solid with 10 mL of ether. Dried under reduced pressure to provide 3-(3,3-dimethylbut-1-ynyl)-7-methoxy-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.[CH3:9][C:10]1([CH3:17])[C:14](=[O:15])[CH:13]=[C:12]([CH3:16])[O:11]1.[OH-].[Na+].[Cl-].[Na+]>C(O)C>[CH3:9][C:10]1([CH3:17])[C:14](=[O:15])[CH:13]=[C:12]([CH:16]=[CH:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[O:11]1
Reactant: O=Cc1cccnc1
Reactant: CC1=CC(=O)C(C)(C)O1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C)OC(C=Cc2cccnc2)=CC1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 53.3 %

Procedure:
To a solution of 3-pyridinecarboxaldehyde (1.4 g, 13.2 mM) and 2,2,5-trimethyl-3(2H)-furanone (2.0 g, 15.9 mM) in ethanol (100 mL), was added 1N aqueous sodium hydroxide (1.6 mL, 1.6 mM). The reaction solution was stirred at room temperature for one day. After saturated aqueous sodium chloride (400 mL) was added, the aqueous layer was extracted with diethyl ether (3×100 mL). The combined ethereal extracts were washed with saturated aqueous sodium chloride (50 mL), dried over MgSO4, filtered and concentrated to give a yellow solid. The crude product was purified by chromatography (silica gel, hexane/ethyl acetate) to afford a white crystalline solid (1.5 g, 53% yield), m.p. 68°-70° C.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:28])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]=[C:14]([C:16]3[S:17][C:18]([CH2:22][N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])=[C:19]([CH3:21])[CH:20]=3)[O:13][N:12]=2)=[CH:7][CH:6]=1.[CH3:29][N:30]([CH3:35])[S:31](Cl)(=[O:33])=[O:32]>>[CH3:29][N:30]([CH3:35])[S:31](=[O:33])(=[O:32])[NH:1][CH2:2][CH:3]([OH:28])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]=[C:14]([C:16]3[S:17][C:18]([CH2:22][N:23]([CH2:24][CH3:25])[CH2:26][CH3:27])=[C:19]([CH3:21])[CH:20]=3)[O:13][N:12]=2)=[CH:7][CH:6]=1
Reactant: CN(C)S(=O)(=O)Cl
Reactant: CCN(CC)Cc1sc(-c2nc(-c3ccc(CC(O)CN)cc3)no2)cc1C
Product: CCN(CC)Cc1sc(-c2nc(-c3ccc(CC(O)CNS(=O)(=O)N(C)C)cc3)no2)cc1C
Yield: 33.1 %

Procedure:
The title compound (21 mg) is prepared in analogy to Example 166 starting from rac-1-amino-3-{4-[5-(5-diethylaminomethyl-4-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-phenyl}-propan-2-ol (50 mg, 125 μmol) and dimethylsulfamoyl chloride (22 mg, 150 μmol); LC-MS: tR=0.76 min; [M+1]+=508.18; 1H NMR (CDCl3): δ1.11 (t, J=7.0 Hz, 6H), 2.25 (s, 3H), 2.64 (q, J=7.0 Hz, 4H), 2.83 (s, 6H), 2.85-2.94 (m, 2H), 3.03-3.10 (m, 1H), 3.24-3.30 (m, 1H), 3.73 (s, 2H), 4.04-4.11 (m, 1H), 7.37 (d, J=8.3 Hz, 2H), 7.66 (s, 1H), 8.10 (d, J=8.3 Hz, 2H).
Reaction SMILES: [C:1]([C:4]1[CH:5]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=2)[C:6]([C:12](=[O:19])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]Br)=[C:7]([CH3:11])[NH:8][C:9]=1[CH3:10])(=[O:3])[CH3:2].[I-].[Na+].[ClH:31].[C:32]1([C:38]2([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(#N)C>[ClH:31].[C:1]([C:4]1[CH:5]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=2)[C:6]([C:12](=[O:19])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:41]2[CH2:42][CH2:43][C:38]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[CH2:39][CH2:40]2)=[C:7]([CH3:11])[NH:8][C:9]=1[CH3:10])(=[O:3])[CH3:2]
Reactant: CC(=O)C1=C(C)NC(C)=C(C(=O)CCCCCBr)C1c1cccc([N+](=O)[O-])c1
Reactant: c1ccc(C2(c3ccccc3)CCNCC2)cc1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CC(=O)C1=C(C)NC(C)=C(C(=O)CCCCCN2CCC(c3ccccc3)(c3ccccc3)CC2)C1c1cccc([N+](=O)[O-])c1

Procedure:
9 g (20 mmol) 5-acetyl-1,4-dihydro-2,6-dimethyl-3-(6-bromohexanoyl)4-(3-nitrophenyl) -pyridine are reacted first with 6 g (40 mmol) sodium iodide, as described for starting compound B, and then with 11 g (38 mmol) 4,4-diphenylpiperidine hydrochloride. Working up is carried out as described for starting compound B. The crude product is chromatographed with toluene/acetone=1/1. The product thus obtained is taken up in 20 ml acetonitrile. The title compound is precipitated by addition of ethereal hydrochloric acid. Yield: 4 g (31%). M.p. 136° C. decomp. (acetonitrile).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([OH:13])=O)=[N:9][CH:10]=1.S(Cl)(Cl)=O.Cl.[NH2:19][CH2:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:22]=1[C:23](=[O:39])[N:24]([CH:31]1[CH2:36][CH2:35][C:34](=[O:37])[NH:33][C:32]1=[O:38])[C:25]2=[O:30].C(N(CC)CC)C>C1COCC1>[O:38]=[C:32]1[CH:31]([N:24]2[C:23](=[O:39])[C:22]3[C:26](=[CH:27][CH:28]=[CH:29][C:21]=3[CH2:20][NH:19][C:11]([C:8]3[CH:7]=[CH:6][C:5]([CH2:4][CH2:3][CH2:2][CH3:1])=[CH:10][N:9]=3)=[O:13])[C:25]2=[O:30])[CH2:36][CH2:35][C:34](=[O:37])[NH:33]1
Reactant: CCCCc1ccc(C(=O)O)nc1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCc1ccc(C(=O)NCc2cccc3c2C(=O)N(C2CCC(=O)NC2=O)C3=O)nc1
Yield: 64.7 %

Procedure:
A mixture of fusaric acid (0.36 g, 2.0 mmol) and thionyl chloride (10 mL) was heated to reflux for 1 hour. Excess thionyl chloride was removed under vacuum. To the acid chloride, was then added 4-aminomethyl-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione hydrochloride (0.65 g, 2.0 mmol), THF (30 mL) and triethylamine (0.61 g, 6.0 mmol), and the resulting mixture was stirred at room temperature for 16 hours. The solvent was evaporated, and the crude residue was chromatographed using a methylene chloride-methanol gradient, eluting the product with 95:5 methylene chloride-methanol. This material was further purified by preparative HPLC, eluting with 1:1 acetonitrile-water, providing 0.58 g of the purified product in 64% yield: mp 137-139° C.; 1H NMR (DMSO-d6) δ 0.91 (t, J=7.3 Hz, 3H), 1.24-1.39 (m, 2H), 1.54-1.65 (m, 2H), 2.06-2.10 (m, 2H), 2.51-2.72 (m, 4H), 2.84-2.97 (m, 1H), 4.94 (d, J=6.4 Hz, 2H), 5.17 (dd, J=12.6 Hz, d=5.4 Hz, 1H), 7.66-7.71 (m, 1H), 7.77-7.86 (m, 3H), 7.97 (d, J=8.0 Hz, 1H), 8.54 (d, J=1.7 Hz, 1H), 9.43 (t, J=6.4 Hz, 1H), 11.16 (s, 1H); 13C NMR (DMSO-d6) δ 13.7, 21.6, 22.0, 31.0, 31.7, 32.6, 38.5, 48.9, 121.8, 121.9, 127.2, 131.6, 133.0, 134.8, 137.3, 139.2, 141.2, 147.5, 148.5, 164.5, 167.0, 167.6, 169.9, 172.8; Anal. calcd for C24H24N4O5.0.3H2O: C, 63.51; H, 5.46; N, 12.34. Found: C, 63.52; H, 5.55; N, 12.05.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([N+:17]([O-])=O)[CH:15]=3)[NH:10][CH:9]=2)=[CH:4][CH2:3]1>[Pd].CO.CN(C=O)C>[NH2:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]2[CH:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1
Reactant: CN1CC=C(c2c[nH]c3ccc([N+](=O)[O-])cc23)CC1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CO
Product: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reaction time: 18 h
Yield: 64.3 %

Procedure:
A mixture of 3-(1-methyl-1,2,5,6-tetrahydropyridin-4-yl)-5-nitro-1H-indole (D1, 2.00 g, 7.8 mmole) and 10% palladium on carbon (0.25 g) in methanol (50 ml) and DMF (50 ml) was shaken under an atmosphere of hydrogen at 50 psi/344.8 KPa for 18 hours. The mixture was filtered and evaporated to dryness. The residue was partitioned between dichloromethane (75 ml) and water (30 ml). The organic phase was separated, washed with brine, dried (Na2SO4) and evaporated to dryness. Trituration of the residue with diethyl ether afforded the title compound as pale brown solid (1.15 g).
Reaction SMILES: [C:1]([C:5]1([C:8]([F:15])([N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)[CH3:9])[CH2:7][O:6]1)([CH3:4])([CH3:3])[CH3:2].[F:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1.[K]>COCCOCCOC>[F:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:7][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([OH:6])[C:8]([F:15])([CH3:9])[N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:19][CH:18]=1
Reactant: Oc1ccc(F)cc1
Reactant: CC(C)(C)C1(C(C)(F)n2cncn2)CO1
Agent: [K]
Solvent: COCCOCCOC
Product: CC(C)(C)C(O)(COc1ccc(F)cc1)C(C)(F)n1cncn1
Temperature: 0 °C
Yield: 17.8 %

Procedure:
6.0 g of 2-tert.-butyl-2-[1-fluoro-1-(1H-1,2,4-triazol-1-yl)-ethyl]-oxirane, 3.1 g of 4-fluorophenol and 0.4 g of potassium p-fluorophenate in 20 ml of diethylene glycol dimethyl ether are heated at 140° C. for 6 hours. After cooling, the reaction mixture is taken up in ice water and extracted with ethyl acetate. The combined organic phases are washed successively with water, saturated sodium chloride solution, 2N sodium hydroxide solution, water and saturated sodium chloride solution, dried over sodium sulfate and evaporated. Chromatography over silica gel using a 4:1 hexane/ethyl acetate mixture gives 1.6 g of 1-(4-fluorophenoxy)-2-tert.-butyl-2-hydroxy-3-fluoro-3-methyl-3-(1H-1,2,4-triazol-1-yl)-propane as a mixture of diastereomers, melting point 90°-93° C.
Reaction SMILES: C(N(CC)CC)C.[OH:8][CH2:9][C:10]1[N:14]=[CH:13][NH:12][N:11]=1.[C:15](Cl)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>ClCCl.O1CCCC1>[OH:8][CH2:9][C:10]1[N:14]=[CH:13][N:12]([C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:11]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OCc1nc[nH]n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClCCl
Product: OCc1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 112.2 %

Procedure:
Triethylamine (1.13 ml, 8.08 mmol) was added to a suspension of 3-hydroxymethyl-1 H- 1, 2,4-triazole [J Am Chem Soc, 77, 1538 (1955)], (400 mg, 4.04 mmol) in dry dichloromethane (8 ml) at 0° C. A solution of trityl chloride (1.24 g, 4.44 mmol) in anhydrous tetrahydrofuran was added, and the mixture was stirred at room temperature for 3 h. The mixture was partitioned between water (75 ml) and dichloromethane (75 ml). The organic layer was dried (MgSO4) and concentrated under reduced pressure to give the title compound (1.547 g, >100%) which was used without purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](B5OC(C)(C)C(C)(C)O5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.Cl[C:36]1[C:41]([CH3:42])=[CH:40][C:39]([C:43]2[N:44]=[C:45]([CH3:49])[N:46]([CH3:48])[CH:47]=2)=[CH:38][C:37]=1[CH3:50].BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([C:36]5[C:41]([CH3:42])=[CH:40][C:39]([C:43]6[N:44]=[C:45]([CH3:49])[N:46]([CH3:48])[CH:47]=6)=[CH:38][C:37]=5[CH3:50])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: Cc1cc(-c2cn(C)c(C)n2)cc(C)c1Cl
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(-c6cn(C)c(C)n6)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 4-(4-chloro-3,5-dimethyl-phenyl)-1,2-dimethyl-imidazole following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 7): tR=1.06 min; Mass spectrum (ESI+): m/z=541 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:15](=[O:16])[CH2:14][CH2:13][C:12]=2[C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:19][CH:18]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>[Pd].CO>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]2[CH:15]([OH:16])[CH2:14][CH2:13][CH:12]2[C:17]2[CH:18]=[CH:19][C:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:21][CH:22]=2)=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C2=C(c3ccc(C(C)(C)C)cc3)C(=O)CC2)cc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1ccc(C2CCC(O)C2c2ccc(C(C)(C)C)cc2)cc1

Procedure:
A mixture of Example 7E (20 mg, 0.049 mmol) and 10% palladium on carbon (5.25 mg, 0.049 mmol) in methanol (4 mL) was stirred at 25° C. under a hydrogen atmosphere (balloon) for 16 hours. The mixture was filtered, and the filtrate was concentrated in vacuo. The residue was directly used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ ppm 6.67-7.25 (m, 8H), 6.26 (s, 1H), 4.53 (brs, 1H), 3.52 (brs, 1H), 3.29 (br, 1H), 1.82-2.24 (m, 4H), 1.45 (s, 9H), 1.20 (s, 9H); LC/MS (ESI) m/z 408 (M−H)−.