Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:9]1[CH:22]=[CH:21][C:12]([O:13][CH2:14][C@H:15]2[O:19][C:18]([NH2:20])=[N:17][CH2:16]2)=[CH:11][CH:10]=1)([CH3:8])[CH2:3][C:4]([CH3:7])([CH3:6])[CH3:5].C([O:25][C:26](=O)[C:27]#[C:28][CH3:29])C>C(Cl)(Cl)Cl>[CH3:29][C:28]1[N:17]2[CH2:16][C@@H:15]([CH2:14][O:13][C:12]3[CH:21]=[CH:22][C:9]([C:2]([CH3:1])([CH3:8])[CH2:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[CH:10][CH:11]=3)[O:19][C:18]2=[N:20][C:26](=[O:25])[CH:27]=1
Reactant: CC#CC(=O)OCC
Reactant: CC(C)(C)CC(C)(C)c1ccc(OC[C@@H]2CN=C(N)O2)cc1
Solvent: ClC(Cl)Cl
Product: Cc1cc(=O)nc2n1C[C@@H](COc1ccc(C(C)(C)CC(C)(C)C)cc1)O2

Procedure:
The title compound was prepared from (S)-5-(4-(1,1,3,3-tetramethyl-butyl) -phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine (see Example 27) and but-2-ynoic acid ethyl ester employing the procedure described in Example 95. [α]D25 −36.20 (c 0.5, CHCl3).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.[C:11](O)(=[O:15])[C:12]([CH3:14])=[CH2:13]>>[C:11]([O:10][CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=1)(=[O:15])[C:12]([CH3:14])=[CH2:13]
Reactant: OCCc1ccc(O)cc1
Reactant: C=C(C)C(=O)O
Product: C=C(C)C(=O)OCCc1ccc(O)cc1

Procedure:
2-(p-hydroxyphenyl)ethyl methacrylate was synthesized by carrying out a dehydration reaction between 2-(p-hydroxyphenyl) ethanol and methacrylic acid in the presence of an acidic catalyst. The 2-(p-hydroxyphenyl)ethyl methacrylate thus obtained was dissolved in 2 -methyoxyethanol and subjected to a radical polymerization by use of an azo-based initiator V-601 (manufactured by Wako Pure Chemical Industries, Ltd.). The reaction product was mixed with water and the resulting polymer was precipitated. In this way, a binder polymer [BP-2] was obtained. The weight average molecular weight of the polymer was 56,000 (using polyhydroxystyrene as a standard substance).
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1B1OC(C)(C)C(C)(C)O1)[CH3:2].Br[C:20]1[CH:21]=[CH:22][C:23]2[N:24]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[N:28]=2)[CH:25]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.C(OCC)(=O)C>[CH2:1]([S:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:20]1[CH:21]=[CH:22][C:23]2[N:24]([CH:26]=[C:27]([C:29]([F:31])([F:32])[F:30])[N:28]=2)[CH:25]=1)[CH3:2]
Reactant: FC(F)(F)c1cn2cc(Br)ccc2n1
Reactant: CCSc1ccccc1B1OC(C)(C)C(C)(C)O1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCSc1ccccc1-c1ccc2nc(C(F)(F)F)cn2c1
Temperature: 110 °C
Reaction time: 7 h
Yield: 44.3 %

Procedure:
A mixture of 0.53 g of 2-ethylsulfanylphenylboronic acid pinacol ester, 0.52 g of 6-bromo-2-trifluoromethylimidazo[1,2-a]pyridine, 0.02 g of tris(dibenzylideneacetone)dipalladium(0), 0.05 g of 2-dicyclohexylphosphino-2′,6′-dimethoxyphenyl, 0.84 g of tripotassium phosphate and 6 ml of 1,4-dioxane was stirred at 110° C. for 7 hours. Ethyl acetate and water were added to the cooled reaction mixture, and the mixture was filtered. The filtrate was extracted with ethyl acetate and then dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure, and the resulting residue was applied to a silica gel column chromatography to obtain 0.28 g of 6-(2-ethylsulfanylphenyl)-2-trifluoromethylimidazo[1,2-a]pyridine (Compound of Present Invention 26).
Reaction SMILES: [Cl-:1].[CH2:2]([N+:6]1[CH:10]=[CH:9][N:8]([CH3:11])[CH:7]=1)[CH2:3][CH2:4][CH3:5].[CH2:12]1[CH2:19][O:18][S:15](=[O:17])(=[O:16])[CH2:14][CH2:13]1>>[Cl:1][CH2:19][CH2:12][CH2:13][CH2:14][S:15]([O-:18])(=[O:17])=[O:16].[CH2:2]([N+:6]1[CH:10]=[CH:9][N:8]([CH3:11])[CH:7]=1)[CH2:3][CH2:4][CH3:5]
Reactant: [Cl-]
Reactant: O=S1(=O)CCCCO1
Agent: CCCC[n+]1ccn(C)c1
Product: O=S(=O)([O-])CCCCCl
Temperature: 40 °C
Reaction time: 24 h

Procedure:
The mixture of equivalent of 1-butyl-3-methylimidazolium chloride and 20 equivalents of 1,4-butane sultone is stirred at 40° C. (temperature in the oil-bath) for 24 hours). The excess of 1,4-butane sultone was distilled off in vacuum and the residue was dried overnight at 50° C. in high vacuum (1·10−3mbar). Liquid 1-butyl-3-methylimidazolium 4-chlorobutylsulfonate is obtained in close to quantitative yield. The material was characterized by NMR spectroscopy.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[N:4](S(C2C=CC=CC=2)(=O)=O)[CH:3]=1.CN.[CH3:25][N:26](C=O)[CH3:27]>O>[CH3:25][N:26]([CH3:27])[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[NH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cnc2c(c1)c(Br)cn2S(=O)(=O)c1ccccc1
Reactant: CN(C)C=O
Agent: CN
Solvent: O
Product: CN(C)c1c[nH]c2ncc([N+](=O)[O-])cc12
Temperature: 150 °C
Yield: 51 %

Procedure:
3-Bromo-5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (200 mg, 0.523 mmol) and methylamine (1.31 mL, 10.47 mmol, 40% solution in water) were combined with DMF (1 mL) in a microwave vessel and heated to 150° C. in a microwave reactor for one hour. The mixture was then diluted with water, extracted with EtOAc, extracts dried over sodium sulfate and concentrated under reduced pressure. Sep Pak purification (10 g cartridge, 1:1 ethyl acetate:hexanes to 100% ethyl acetate) afforded N,N-dimethyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-3-amine as a solid (55 mg, 51%). 1H NMR (400 MHz, d6-DMSO) δ 12.03 (br s, 1H), 8.70-8.72 (m, 1H), 8.20-8.23 (m, 1H), 5.46-5.47 (m, 1H), 2.98 (s, 6H); (APCI-pos) M+1=207.2.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:25]=[CH:24][C:14]([O:15][C:16]4[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=4[CH:18]=O)=[CH:13][CH:12]=3)=[CH:9][N:8]([CH:26]3[CH2:30][CH2:29][O:28][CH2:27]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl>[O:34]1[CH2:35][CH2:36][N:31]([CH2:18][C:17]2[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=2[O:15][C:14]2[CH:13]=[CH:12][C:11]([C:10]3[C:3]4[C:2]([NH2:1])=[N:7][CH:6]=[N:5][C:4]=4[N:8]([CH:26]4[CH2:30][CH2:29][O:28][CH2:27]4)[CH:9]=3)=[CH:25][CH:24]=2)[CH2:32][CH2:33]1
Reactant: C1COCCN1
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3C=O)cc1)cn2C1CCOC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3CN3CCOCC3)cc1)cn2C1CCOC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 2-[4-(4-amino-7-(3-tetrahydrofuryl)-7H-pyrrolo[2,3-d)pyrimidin-5-yl)phenoxy]benzaldehyde (0.15 g), morpholine (64 mg), sodium triacetoxyborohydride (117 mg) and 1,2 dichloroethane (5 ml) was stirred at ambient temperature for 18 hours. Saturated aqueous sodium bicarbonate solution was added and the mixture was filtered through an EMPORE® cartridge. The filtrate was evaporated and the residue was dissolved in dichloromethane (5 ml) and then tris(2-aminoethyl)amine-polymer bound (0.3 g) and 2 drops of glacial acetic acid were added and the mixture was stirred at ambient temperature overnight. The polymer was removed by filtration and washed with dichloromethane and then with methanol. The combined organic filtrate and washings were evaporated under reduced pressure to give an oil which was triturated with diethyl ether/ethyl acetate with warming to dissolve the solid and then the solution was cooled in ice and filtered to give 5-[4-(2-morpholinomethylphenoxy)phenyl] -7-(3-tetrahydrofuryl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine, m.p. 169-171° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[S:11](=[O:14])(=[O:13])[NH2:12].S(Cl)([Cl:17])=O>CCCCCC>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:17])=[O:7])=[CH:4][C:3]=1[S:11](=[O:14])(=[O:13])[NH2:12]
Reactant: NS(=O)(=O)c1cc(C(=O)O)ccc1Cl
Reactant: O=S(Cl)Cl
Solvent: CCCCCC
Product: NS(=O)(=O)c1cc(C(=O)Cl)ccc1Cl
Temperature: 25 °C
Yield: 97.1 %

Procedure:
A mixture of 4-chloro-3-sulfamoyl-benzoic acid (50 g, 212 mmol) and thionyl chloride (31 mL, 424 mmol) are heated to reflux for 5 h then allowed to cool to room temperature. To this mixture is added hexane and the resulting solid is filtered, washed with hexane and dried in vacuo to yield 52.3 g (97%) of the title compound as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:31][CH3:32])[CH2:22][N:23]([CH3:30])[S:24]([CH:27]3[CH2:29][CH2:28]3)(=[O:26])=[O:25])[C:11](=[O:33])[C@:10]([CH2:35][C:36]([O:38][CH3:39])=[O:37])([CH3:34])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:40]N(P(N(C)C)(N(C)C)=O)C.[Li+].CC([N-]C(C)C)C.IC>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)[N:12]([C@@H:21]([CH2:31][CH3:32])[CH2:22][N:23]([CH3:30])[S:24]([CH:27]3[CH2:28][CH2:29]3)(=[O:26])=[O:25])[C:11](=[O:33])[C@:10]([C@H:35]([CH3:40])[C:36]([O:38][CH3:39])=[O:37])([CH3:34])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Reactant: CC[C@@H](CN(C)S(=O)(=O)C1CC1)N1C(=O)[C@@](C)(CC(=O)OC)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CC[C@@H](CN(C)S(=O)(=O)C1CC1)N1C(=O)[C@@](C)([C@H](C)C(=O)OC)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetate (0.040 g, 0.067 mmol)from Step A above and HMPA (0.012 mL, 0.067 mmol) in anhydrous THF (1 mL) was added LDA, 2.0M in THF (0.037 mL, 0.074 mmol) at −78° C. Let it stir for 0.5 h at −78° C. Then iodomethane (0.057 mL, 0.913 mmol) was added. After stirring for 1 h, the reaction was quenched with sat. aq. NH4Cl solution and extracted with EtOAc. The organics were pooled, washed with sat. aq. NaCl solution, dried (MgSO4), filtered and the filtrate was concentrated under the reduced pressure to provide a yellow oil. This was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](Br)[CH:3]=1.[CH3:9][Si:10](Cl)([CH3:12])[CH3:11].Cl>C(OCC)C>[CH3:9][Si:10]([CH3:12])([CH3:11])[C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cccc(Br)c1
Reactant: C[Si](C)(C)Cl
Agent: Cl
Solvent: CCOCC
Product: C[Si](C)(C)c1cccc(Br)c1
Temperature: 0 °C
Yield: 55 %

Procedure:
A mixture of 1,3-dibromobenzene (25.0 g, 106.4 mmol) and trimethylsilylchloride (11.6 g, 106.4 mmol) in diethyl ether (50 ml) was added dropwise in 11/2 hours on magnesium (2.59 g, 106.4 mmol) in diethyl ether (25 ml). Then the mixture was refluxed for 18 hours, cooled to 0° C., treated with 4N HCl (75 ml). The organic layer was separated, washed with water, brine, dried over MgSO4 and concentrated. 3-Trimethylsilylbromobenzene was obtained by fractional distillation as a colorless oil (13.4 g, 55% yield, b.p.: 55°-62° C. (0.8 mmHg).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH2:18]([N:26]=[C:27]=[O:28])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CCCCCC.CCOC(C)=O>C1COCC1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][N:15]([C:27]([NH:26][CH2:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:28])[CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc2c(N3CCNCC3)ccnc2c1
Reactant: O=C=NCCc1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=C(NCCc1ccccc1)N1CCN(c2ccnc3cc(Cl)ccc23)CC1

Procedure:
7-Chloro-4-(piperazin-1-yl)quinoline (62 mg, 0.25 mmol) and phenethyl isocyanate (45 μL, 0.30 mmol) in THF (10 mL) are reacted according to method C yielding the title product as a colorless oil after column chromatography with hexane-EtOAc.
Reaction SMILES: [Cl:1][CH2:2][CH:3]([OH:6])[CH2:4][Cl:5].B(F)(F)F.O.O.[CH2:13]=[CH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>>[CH2:13]=[CH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].[Cl:1][CH2:2][CH:3]([O:6][CH:23]([CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH3:13])[CH3:24])[CH2:4][Cl:5]
Reactant: OC(CCl)CCl
Agent: C=CCCCCCCCCCC
Agent: FB(F)F
Solvent: O
Product: CCCCCCCCCCC(C)OC(CCl)CCl
Temperature: 95 °C

Procedure:
To a 1000 ml round bottom flask equipped with condenser, overhead stirrer, and nitrogen inlet system is added 528 g of 1,3-dichloro-2-propanol, 6.6 g of BF3 dihydrate, and 103 g of 1-dodecene at room temperature. The mixture is heated to 95° C. for 6 hours. The reaction mixture is cooled to room temperature and is then transferred to a 1000 ml separation funnel; 200 ml of heptane is added and two phases are separated. The lower phase (containing excess dichloropropanol, ether products, unreacted and isomerized olefins, and the catalyst) is extracted with 200 ml of heptane three more times. The heptane solutions are combined and the heptane is removed on a rotary evaporator. Distillation of residual heptane under reduced pressure affords 46.3 g of dodecene isomers mixture and 94.4 g of sec-dodecyl 1,3-dichloro-2-propyl ether and isomers. The dodecene mixtures is collected at 80-105° C./0.6 mmHg, and the ether product is collected as 128-141° C./0.6 mmHg)
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([OH:17])[C:11]([CH3:16])([N+:13]([O-])=O)[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.[Ni].O>[NH2:13][C:11]([CH3:16])([CH3:12])[CH:10]([OH:17])[CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C(O)COCc1ccccc1)[N+](=O)[O-]
Agent: [Ni]
Solvent: CO
Solvent: O
Product: CC(C)(N)C(O)COCc1ccccc1
Reaction time: 24 h
Yield: 87.6 %

Procedure:
To a solution of 1-(benzyloxy)-3-methyl-3-nitrobutan-2-ol (5.2 g, 21.7 mmol) in MeOH (40 ml) was added a slurry of Raney Nickel in H2O (50%, 1 ml). The vessel was pressurized with H2 (450 psi) and the suspension stirred for 24 h. The mixture was filtered through Celite and concentrated in vacuo to give the title compound as a clear liquid (4.0 g, 19 mmol, 89%). 1H NMR (CDCl3, 400 MHz) δ 1.09 (s, 3H), 1.14 (s, 2H), 1.90 (br s, 2H) 3.50-3.54 (m, 2H), 3.61-3.67 (m, 1H), 4.57 (s, 2H), 7.28-7.39 (m, 5H). LRMS (ESI/APCI) m/z 210 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:16]([O:18][CH3:19])=[O:17])[C:5]2[C:6]([CH:14]=O)=[CH:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.C1(C)C=CC(S(=O)=O)=CC=1.S1(CCCC1)(=O)=O.C([BH3-])#N.[Na+]>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([C:16]([O:18][CH3:19])=[O:17])[C:5]2[C:6]([CH3:14])=[CH:7][N:8]([CH:11]([CH3:12])[CH3:13])[C:9]=2[CH:10]=1
Reactant: COC(=O)c1cc(Br)cc2c1c(C=O)cn2C(C)C
Agent: Cc1ccc([SH](=O)=O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: O=S1(=O)CCCC1
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Br)cc2c1c(C)cn2C(C)C
Temperature: 100 °C
Reaction time: 1 h
Yield: 41.8 %

Procedure:
To a stirred solution of methyl 6-bromo-3-formyl-1-isopropyl-1H-indole-4-carboxylate (60 g, 185 mmol) in DMF (220 mL) was added p-toluenesulfonic acid mono hydride (4.57 g, 24 mmol), p-toluenesulfonyl hydrazide (44.8 g, 240 mmol) followed by sulfolane (220 mL). The mixture was stirred at 100° C. for 1 h. The contents were cooled to room temperature and then sodium cyanoborohydride (46.5 g, 740 mmol) was added portion wise over a period of 25 min. Then the mixture was stirred at 100° C. for 2 h. Then the reaction mixture was stirred for 16 h at room temperature. The reaction mixture was diluted with water and extracted with 20% EtOAc: Pet ether, finally organic layer was washed with cold water, brine solution dried over anhydrous Na2SO4 and concentrated. Crude compound was purified by column chromatography using silica gel (100-200 mesh) and 20% DCM: Pet ether as an eluent to afford desired product methyl 6-bromo-1-isopropyl-3-methyl-1H-indole-4-carboxylate (24 g, 89.2% purity), (16 g, and 62.2% purity). 1H NMR (CDCl3, 400 MHz) δ 1.486 (d, J=6.4 Hz, 6H), 2.361 (s, 3H), 3.947 (s, 3H), 4.535-4.602 (m, 1H), 7.080 (s, 1H), 7.619 (s, 1H), 7.684 (s, 1H). LCMS (ES+) m/z=310.07 (M+H)
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[CH3:5][C:6]1[CH:7]=[C:8]2[N:13]([C:14]=1[C:15]([O:17][CH3:18])=[O:16])[CH:12]=[CH:11][CH:10]=[CH:9]2>O.C(O)(=O)C>[CH3:5][C:6]1[C:7]([N:1]=[O:3])=[C:8]2[N:13]([C:14]=1[C:15]([O:17][CH3:18])=[O:16])[CH:12]=[CH:11][CH:10]=[CH:9]2
Reactant: COC(=O)c1c(C)cc2ccccn12
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1c(C)c(N=O)c2ccccn12
Reaction time: 0.5 h
Yield: 82.3 %

Procedure:
A solution of sodium nitrite (2.2 g, 31.90 mmol) in water (10 mL) was added slowly at 0-5° C. to a stirred solution of methyl 2-methylindolizine-3-carboxylate 2 (3.9 g, 20.61 mmol) in glacial acetic acid (50 mL). After 30 min, the brown reaction mixture was poured into water. Green crystals were collected by filtration, washed with water and then dried under vacuum to give 3.7 g of expected compound; m.p.: 131-132° C. 1H NMR (CDCl3): 9.63 (d, J=7.0 Hz, 1H), 8.39 (d, J=8.5 Hz, 1H), 7.74-7.69 (m, 1H), 7.23-7.18 (m, 1H), 4.03 (s, 3H), 3.26 (s, 3H), 13C NMR (CDCl3): δ 162.5, 154.5, 141.7, 135.7, 127.9, 123.2, 118.4, 118.3, 114.5, 51.7, 11.1. Analysis calculated for C11H10N2O3: C, 60.55; H, 5.54; N, 12.84, found: C, 60.65; H, 5.60; N, 12.90.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:10][C@H:11]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH3:40][C:41]1[CH:46]=[CH:45][C:44]([S:47]([O:50][CH2:51][C:52]2([CH2:64]OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:57][O:56][CH:55]([C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)[O:54][CH2:53]2)(=[O:49])=[O:48])=[CH:43][CH:42]=1>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:10][C@H:11]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:64][C:52]2([CH2:51][O:50][S:47]([C:44]3[CH:43]=[CH:42][C:41]([CH3:40])=[CH:46][CH:45]=3)(=[O:48])=[O:49])[CH2:57][O:56][CH:55]([C:58]3[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=3)[O:54][CH2:53]2)=[CH:22][CH:21]=1)[C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](C[C@H](Cc1ccc(O)cc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)OCC2(COS(=O)(=O)c3ccc(C)cc3)COC(c3ccccc3)OC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)OCC2(COc3ccc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc3)COC(c3ccccc3)OC2)cc1
Temperature: 100 °C

Procedure:
To 466 mg (1.0 mmol) of di-tert-butyl (4S)—N-(tert-butoxycarbonyl)-4-(4-hydroxybenzyl)-L-glutamate in 12 mL N,N-dimethylformamide were added 138 mg (1.0 mmol) of potassium carbonate and 533 mg (1.0 mmol) of (2-phenyl-1,3-dioxane-5,5-diyl)bis(methylene) bis(4-methylbenzenesulfonate) (Heterocycles 34. (1992), 739), and the resulting suspension was heated for 2 h at 100° C. in a microwave oven. The reaction mixture was then filtered, the solvent evaporated and the residue was taken up in ethyl acetate and water. The organic phase was separated off, washed with water until neutral, dried over sodium sulfate and filtered, and the filtrate was concentrated in vacuo. The residue was chromatographed on silica gel using a dichloromethane/ethyl acetate gradient, and the appropriate fractions were combined and concentrated.
Reaction SMILES: Br[C:2]1[CH:24]=[C:23]2[C:5]([CH2:6][C:7]3([C:16]42[N:20]=[C:19]([NH2:21])[C:18]([CH3:22])=[N:17]4)[CH2:12][CH2:11][CH:10]([CH:13]([F:15])[F:14])[CH2:9][CH2:8]3)=[CH:4][CH:3]=1.[Cl:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[N:30][CH:31]=1.CC([PH+](C(C)(C)C)CCCS([O-])(=O)=O)(C)C.C([O-])([O-])=O.[K+].[K+]>[Na+].[Na+].Cl[Pd+2](Cl)(Cl)Cl>[Cl:25][C:26]1[CH:27]=[C:28]([C:2]2[CH:24]=[C:23]3[C:5]([CH2:6][C:7]4([C:16]53[N:20]=[C:19]([NH2:21])[C:18]([CH3:22])=[N:17]5)[CH2:8][CH2:9][CH:10]([CH:13]([F:14])[F:15])[CH2:11][CH2:12]4)=[CH:4][CH:3]=2)[CH:29]=[N:30][CH:31]=1
Reactant: CC1=NC2(N=C1N)c1cc(Br)ccc1CC21CCC(C(F)F)CC1
Reactant: OB(O)c1cncc(Cl)c1
Agent: Cl[Pd]Cl
Agent: CC(C)(C)[PH+](CCCS(=O)(=O)[O-])C(C)(C)C
Agent: O=C([O-])[O-]
Product: CC1=NC2(N=C1N)c1cc(-c3cncc(Cl)c3)ccc1CC21CCC(C(F)F)CC1
Temperature: 100 °C
Yield: 11.2 %

Procedure:
6′-Bromo-4-(difluoromethyl)-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine (Example 128, 0.1 g, 0.25 mmol), 5-chloropyridin-3-yl boronic acid (0.048 g, 0.30 mmol), 3-(di-tert-butylphosphonium)propane sulfonate (6.77 mg, 0.03 mmol), sodium tetrachloro-palladate(II) (3.71 mg, 0.01 mmol), 2-Me THF (2 mL) and aq. K2CO3 (2.0 M, 0.379 mL, 0.76 mmol) were added to a microwave vial. The vial was sealed and evacuated and refilled with Ar (g) and then heated in the microwave reactor for 30 min at 100° C. The same amount of Pd-catalyst, ligand and boronic ester were added and the vial was sealed and evacuated and refilled with Ar (g). The vial was heated in the microwave reactor for 30 min at 100° C. EtOAc and water were added and the organic phase was extracted, dried through a phase separator and evaporated to dryness. The crude product was purified using preparative chromatography to give the title compound (12 mg, 11% yield): 1H NMR (500 MHz, CD3CN) δ ppm 1.24-1.41 (m, 4 H), 1.45-1.54 (m, 3 H), 1.71-1.86 (m, 1 H), 2.00 (dt, 1 H), 2.24 (s, 3 H), 2.98 (d, 1 H), 3.07 (d, 1 H), 5.32 (br. s., 2 H), 5.64 (d, 1 H), 6.86 (d, 1 H), 7.38 (d, 1 H), 7.50 (dd, 1 H), 7.93 (t, 1 H), 8.49 (d, 1 H), 8.65 (d, 1 H); MS (MM−ES+APCI)+ m/z 429 [M+H]+.
Reaction SMILES: [F:1][CH2:2][C:3]([CH2:7][F:8])([CH3:6])[CH2:4][OH:5].[CH2:9]([O:16][C@@H:17]([C@@H:43]1[NH:48][C@@H:47]([CH3:49])[CH:46](O)[O:45][CH2:44]1)[C@@H:18]([N:28]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[CH:21]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:36]([N:28]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C@@H:18]([CH2:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[CH:21]=1)[C@@H:17]([O:16][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C@H:43]1[CH2:44][O:45][C@@H:46]([O:5][CH2:4][C:3]([CH2:7][F:8])([CH2:2][F:1])[CH3:6])[C@H:47]([CH3:49])[NH:48]1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CC(CO)(CF)CF
Reactant: C[C@@H]1N[C@@H]([C@H](OCc2ccccc2)[C@H](Cc2cc(F)cc(F)c2)N(Cc2ccccc2)Cc2ccccc2)COC1O
Product: C[C@@H]1N[C@@H]([C@H](OCc2ccccc2)[C@H](Cc2cc(F)cc(F)c2)N(Cc2ccccc2)Cc2ccccc2)CO[C@H]1OCC(C)(CF)CF
Yield: 42.1 %

Procedure:
React 2,2-di-(fluoromethyl)propanol (2.172 g, 17.5 mmol) with (3S,5R)-5-[(1S,2S)-1-benzyloxy-2-dibenzylamino-3-(3,5-difluorophenyl)-propyl]-3-methylmorpholin-2-ol (2.004 g, 3.5 mmol) essentially as described in Preparation 307 to provide 1.0 g of the desired compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][C@@H:6]([CH3:8])[N:5](CC2C=CC=CC=2)[CH2:4][C@H:3]1[CH3:16]>CO>[CH3:1][N:2]1[CH2:7][C@@H:6]([CH3:8])[NH:5][CH2:4][C@H:3]1[CH3:16]
Reactant: C[C@@H]1CN(Cc2ccccc2)[C@H](C)CN1C
Solvent: CO
Product: C[C@@H]1CN(C)[C@H](C)CN1
Yield: 62.9 %

Procedure:
(2R,5R)-1,2,5-Trimethyl-4-(phenylmethyl)piperazine (680 mg, 3.11 mmol) was dissolved in 50 mL of MeOH, degassed and placed under argon. 10% Pd/C (170 mg) was added, and the contents were thoroughly degassed and placed under a hydrogen balloon for approximately 3 hrs. The contents were then degassed and filtered through Celite, and the Celite pad was washed with DCM and MeOH. After 6.5 mL 1N HCl was added, the resulting filtrate was concentrated in vacuo to provide the hydrochloride salt of (2R,5R)-1,2,5-trimethylpiperazine (251 mg, 100%). LCMS: (M+H)+: 129.1.