Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:3][C:4]1[CH:5]=[C:6]([CH2:14][O:15][Si:16]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([F:13])[F:12])=[CH2:2].Cl[CH2:27]I.C([Zn]CC)C>ClCCl>[CH:1]1([O:3][C:4]2[CH:5]=[C:6]([CH2:14][O:15][Si:16]([CH:17]([CH3:18])[CH3:19])([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])[CH:7]=[CH:8][C:9]=2[O:10][CH:11]([F:12])[F:13])[CH2:27][CH2:2]1
Reactant: ClCI
Reactant: C=COc1cc(CO[Si](C(C)C)(C(C)C)C(C)C)ccc1OC(F)F
Agent: CC[Zn]CC
Solvent: ClCCl
Product: CC(C)[Si](OCc1ccc(OC(F)F)c(OC2CC2)c1)(C(C)C)C(C)C
Temperature: 5 °C
Reaction time: 0.25 h

Procedure:
To a solution of the alkene, 3-Ethenyloxy-4-difluoromethoxy-1-(triisopropylsilyloxy)methylbenzene, from Step 3 (67 g, 179 mmol) and chloroiodomethane (78 mL, 1.07 mol) in dichloromethane (1.5 L) at 5° C. (ice bath) was added diethyl zinc (55 mL, 537 mmol) in 5 mL portions over 1.2 h. During the addition, the internal temperature was maintained at <20° C. After the addition was complete, the mixture was stirred for 15 min and then the cooling bath was removed and stirring was continued for a further 2.5 h. The mixture was re-cooled to 5° C. (ice bath) and MeOH (2 mL) was added over 15 min, followed by the addition of water (30 mL) over 15 min and finally, the addition of 6N HCl (5 mL). The mixture was partitioned between ether (IL) and water (500 mL). The aqueous layer was extracted with ether (500 mL) and the combined organics were washed with brine, dried (Na2SO4) and concentrated. Flash chromatography of the residue (silica gel; hexane/ethyl acetate 98:2 to 95:5) provided 3-Cyclopropyloxy-4-difluoromethoxy-1-(triisopropylsilyloxy)methylbenzene (71 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][C@H:11]([OH:13])[CH2:10][N:9]2[C:14]2[CH:19]=[CH:18][N:17]3[N:20]=[CH:21][C:22]([C:23](O)=[O:24])=[C:16]3[N:15]=2)[CH:5]=[CH:6][CH:7]=1.[CH:26]([NH2:29])([CH3:28])[CH3:27]>>[F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][C@H:11]([OH:13])[CH2:10][N:9]2[C:14]2[CH:19]=[CH:18][N:17]3[N:20]=[CH:21][C:22]([C:23]([NH:29][CH:26]([CH3:28])[CH3:27])=[O:24])=[C:16]3[N:15]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cnn2ccc(N3C[C@@H](O)C[C@@H]3c3cccc(F)c3)nc12
Reactant: CC(C)N
Product: CC(C)NC(=O)c1cnn2ccc(N3C[C@@H](O)C[C@@H]3c3cccc(F)c3)nc12

Procedure:
Prepared according to the method of Example 212, Step F, using 5-((2R,4S)-2-(3-fluorophenyl)-4-hydroxypyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Example 216, Step B) and isopropyl amine. The title compound was obtained as a white solid (5.5 mg, 49% yield). MS (apci) m/z=384.1 (M+H).
Reaction SMILES: [C:1](Cl)(=[O:8])[CH2:2][O:3][CH2:4][C:5](Cl)=[O:6].[F:10][C:11]([F:23])([F:22])[C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][C:18]=1[N+:19]([O-:21])=[O:20])[NH2:15]>C1C=CC=CC=1>[F:10][C:11]([F:22])([F:23])[C:12]1[CH:13]=[C:14]([NH:15][C:1](=[O:8])[CH2:2][O:3][CH2:4][C:5]([NH:15][C:14]2[CH:16]=[CH:17][C:18]([N+:19]([O-:21])=[O:20])=[C:12]([C:11]([F:10])([F:22])[F:23])[CH:13]=2)=[O:6])[CH:16]=[CH:17][C:18]=1[N+:19]([O-:21])=[O:20]
Reactant: O=C(Cl)COCC(=O)Cl
Reactant: Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Solvent: c1ccccc1
Product: O=C(COCC(=O)Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1)Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1

Procedure:
Reflux a mixture of 11.97 g (0.07 mole) of diglycolic acid dichloride and 28.84 g (0.14 mole) of 3-trifluoromethyl-4-nitroaniline in 250 ml of benzene for 1 hour. Isolate the solid product of this example by filtration and obtain analytically pure material by recrystallization from benzene-methanol followed by crystallizatin from pure methanol, mp 137°-138° C.
Reaction SMILES: O1CCCC1.[S:6]1[CH:10]=[CH:9][C:8]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C:20](Cl)=[N:21][OH:22])=[CH:15][CH:14]=2)=[CH:7]1.[C:24]([C:26]1[C:27]([NH2:32])=[N:28][CH:29]=[CH:30][CH:31]=1)#[CH:25].C(N(CC)CC)C>O>[S:6]1[CH:10]=[CH:9][C:8]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]4[C:27]([NH2:32])=[N:28][CH:29]=[CH:30][CH:31]=4)[O:22][N:21]=3)=[CH:15][CH:14]=2)=[CH:7]1
Reactant: C#Cc1cccnc1N
Reactant: ON=C(Cl)Cc1ccc(OCc2ccsc2)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: Nc1ncccc1-c1cc(Cc2ccc(OCc3ccsc3)cc2)no1
Temperature: 50 °C
Reaction time: 3 h
Yield: 37.3 %

Procedure:
To a tetrahydrofuran (3 mL) solution of (4-(thiophen-3-ylmethoxy)-phenyl)-acetohydroximoyl chloride (150 mg, 0.532 mmol) described in Manufacturing Example 77-1-4 and 3-ethynyl-pyridin-2-ylamine (40 mg, 0.339 mmol) described in Manufacturing Example 1-2-3 was added triethylamine (185 μL, 1.33 mmol), which was stirred for 3 hours at 50° C. Water was added to the reaction solution at room temperature, which was then extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=4:1-2:1-1:1) to obtain the title compound (46 mg, 24%).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[C:5]([C:13]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[O:14])=[CH:4][CH:3]=1.[O:20](S(C(F)(F)F)(=O)=O)[S:21]([C:24]([F:27])([F:26])[F:25])(=O)=[O:22]>>[F:25][C:24]([F:27])([F:26])[S:21]([O:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[C:5]([C:13]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[O:14])=[CH:4][CH:3]=1)(=[O:22])=[O:20]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Cc1cccc2c(O)ccc(C(=O)N3CCCC3)c12
Product: Cc1cccc2c(OS(=O)(=O)C(F)(F)F)ccc(C(=O)N3CCCC3)c12

Procedure:
This compound was prepared by treating (4-hydroxy-8-methylnaphthalen-1-yl) (pyrrolidin-1-yl)methanone (above step-2 intermediate) with Tf2O by following the similar procedure as described in Step-8 of Intermediate-22.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[C:13]([CH2:20][OH:21])=[CH:12][N:11]=2)=[CH:6][CH:5]=1.[S:24](Cl)([Cl:26])=[O:25]>ClCCl>[F:23][C:2]([F:1])([F:22])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:15]=[C:14]([C:16]([F:17])([F:18])[F:19])[C:13]([CH2:20][O:21][S:24]([Cl:26])=[O:25])=[CH:12][N:11]=2)=[CH:6][CH:5]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cnc(-c2ccc(OC(F)(F)F)cc2)nc1C(F)(F)F
Solvent: ClCCl
Product: O=S(Cl)OCc1cnc(-c2ccc(OC(F)(F)F)cc2)nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.2 %

Procedure:
A cooled (0° C.) solution of 0.40 g (1.20 mmol) of [2-(4-trifluoromethoxy-phenyl)-4-trifluoromethyl-pyrimidin-5-yl]-methanol in 12 ml dichloromethane was treated with 0.10 ml (1.32 mmol) thionylchloride and stirred for 30 min at RT. The reaction was cooled (0° C.), treated with 0.08 ml (1.08 mmol) thionylchloride and stirred for 30 min at RT. The solution was evaporated, dissolved in ether and twice in heptane and evaporated to give 0.44 g of the title compound as an off-white powder.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C@@H:17]2[O:35][C@H:18]2C2C=CC(OC)=C(OCC3C=CC=CC=3)C=2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClCCl.[CH3:39][O:40][CH:41]([O:45][CH3:46])[CH2:42][NH:43][CH3:44]>CC(O)CC>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C@H:17]([OH:35])[C@@H:18]([C:11]2[CH:12]=[CH:13][C:14]([O:15][CH3:16])=[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:10]=2)[N:43]([CH2:42][CH:41]([O:45][CH3:46])[O:40][CH3:39])[CH3:44])[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc([C@@H]2O[C@H]2c2ccc(OC)c(OCc3ccccc3)c2)cc1OCc1ccccc1
Reactant: CNCC(OC)OC
Solvent: ClCCl
Solvent: CCC(C)O
Product: COc1ccc([C@H]([C@@H](O)c2ccc(OC)c(OCc3ccccc3)c2)N(C)CC(OC)OC)cc1OCc1ccccc1

Procedure:
Mixture: 51.7 g (0.11 mol) of rel-(S,S)-3,3'-dibenzyloxy-4,4'-dimethoxystilbene oxide, 1800 ml of dichloromethane, 100 ml of 2-butanol, 25 ml (0.19 mol) of methylaminoacetaldehyde dimethyl acetal, 5 g of silica gel
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH2:3][CH:4]([CH2:7][C:8]([F:11])([F:10])[F:9])[CH2:5][OH:6].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.S([O-])([O-])(=O)=S.[Na+].[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl.CCOCC>[F:1][C:2]([F:12])([F:13])[CH2:3][CH:4]([CH2:7][C:8]([F:9])([F:10])[F:11])[CH:5]=[O:6]
Reactant: OCC(CC(F)(F)F)CC(F)(F)F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: CCOCC
Solvent: ClCCl
Product: O=CC(CC(F)(F)F)CC(F)(F)F
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 4,4,4-trifluoro-2-(2,2,2-trifluoroethyl)butan-1-ol (5.0 g, 24 mmol) in CH2Cl2 (80 mL) was added Dess-Martin periodinane reagent (10 g, 24 mmol). The reaction mixture was subsequently stirred for 20 hours at 25° C. The solution was diluted with Et2O (200 mL) and a 1:1 mixture of 10% sodium thiosulfate and saturated NaHCO3 (200 mL) was added. The mixture was stirred rapidly for 10 min until both phases were clear. The layers were separated and the aqueous phase was extracted with Et2O (100 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated to 50% of its original volume to give 4,4,4-trifluoro-2-(2,2,2-trifluoro-ethyl)-butyraldehyde that was used as is for the subsequent reaction.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7][NH2:8])([O-:4])=[O:3].[OH:13][CH:14]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:15][C:16](O)=[O:17].C(N(CC)CC)C.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.O.Cl>O1CCCC1>[OH:13][CH:14]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:15][C:16]([NH:8][CH2:7][C:6]1[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=1[N+:2]([O-:4])=[O:3])=[O:17]
Reactant: NCc1ccccc1[N+](=O)[O-]
Reactant: O=C(O)CC(O)c1ccccc1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: O=C(CC(O)c1ccccc1)NCc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 5 h
Yield: 92.1 %

Procedure:
2-Nitrobenzyl amine hydrochloride (2.27 g, 12.0 mmol), 3-hydroxy-3-phenyl propionic acid (2.00 g, 12.0 mmol), triethylamine (1.34 g, 13.3 mmol) were added to tetrahydrofuran (50 ml) and the reaction mixture was ice cooled. Under ice cooled condition, 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (3.33 g, 12.0 mmol) was added thereto and stirred at room temperature for five hours. The reaction mixture was poured into dilute hydrochloric acid water and extracted with ethyl acetate. The organic layer was washed with a saturated brine and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained crude crystal was washed with a mixture of hexane-ether (2:1) to obtain 3-hydroxy-N-(2-nitrobenzyl)-3-phenyl propionic acid amide (3.32 g).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([O:15][C:16]3[CH:17]=[CH:18][CH:19]=[C:20]4[C:25]=3[NH:24][C:23](=[O:26])[CH:22]=[N:21]4)[CH:10]=2)=[CH:5][CH:4]=1.[BH4-].[Na+]>CCO>[F:27][C:2]([F:1])([F:28])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([O:15][C:16]3[CH:17]=[CH:18][CH:19]=[C:20]4[C:25]=3[NH:24][C:23](=[O:26])[CH2:22][NH:21]4)[CH:10]=2)=[CH:5][CH:4]=1
Reactant: O=c1cnc2cccc(Oc3cc(-c4ccc(C(F)(F)F)cc4)ncn3)c2[nH]1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: O=C1CNc2cccc(Oc3cc(-c4ccc(C(F)(F)F)cc4)ncn3)c2N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 8-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-1H-quinoxalin-2-one, (Example 32(e)), (0.25 g, 0.65 mmol) in EtOH (5 mL) was added sodium borohydride (0.11 mg, 2.8 mmol, Aldrich). After stirring at room temperature for 2 h, the mixture was quenched with satd aq. NaHCO3 and extracted with 25% i-PrOH/CHCl3 (3×). The combined organic layers were dried over Na2SO4, filtered and concentrated. Purification by flash chromatography (0→1.5% 2M NH3/MeOH in CH2Cl2) gave the title compound as a light-yellow powder. Mp: 305° C., MS (ESI, pos. ion) m/z: 387 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([O:24]C)=[O:23])[CH:17]=1)[CH2:10][C:9]2([CH3:27])[CH3:26])=[O:5])[CH3:2].Cl>O1CCCC1.[OH-].[Li+].O.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([OH:24])=[O:23])[CH:17]=1)[CH2:10][C:9]2([CH3:26])[CH3:27])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2c(c1)C(C)(C)CC(c1cccc(C(=O)OC)c1)N2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1ccc2c(c1)C(C)(C)CC(c1cccc(C(=O)O)c1)N2
Temperature: 25 °C
Reaction time: 4 h
Yield: 49.9 %

Procedure:
A mixture of 2-(3-methoxycarbonyl-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (2.5 g, 6.8 mmol) in tetrahydrofuran (20 mL), 2M lithium hydroxide in water (10 mL) was stirred for 4 h at 25° C. The mixture was neutralized with a 2 N aqueous hydrochloric acid solution, diluted with ethyl acetate (100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-(3-carboxy-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (1.2 g, 50%) as a light white solid which was used for next step without further purification: MS (ESI) M+1=354.2.
Reaction SMILES: Br[C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH2:3]1)[CH2:9]2>C1C=CC=CC=1.[Fe](Cl)(Cl)Cl>[C:2]1([C:2]23[CH2:11][CH:6]4[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]4)[CH2:3]2)[CH2:9]3)[CH:11]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrC12CC3CC(CC(C3)C1)C2
Agent: Cl[Fe](Cl)Cl
Solvent: c1ccccc1
Product: c1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Reaction time: 3 h
Yield: 80 %

Procedure:
Heat 0.068 mol of iron(III) chloride to boiling in 20 ml of absolute benzene. Drop 0.0186 mol of 1-bromo-adamantane, dissolved in 30 ml of absolute benzene, to the solution. Then heat to boiling for 3 hrs. After cooling, pour the reaction mixture onto ice/hydrochloric acid, separate the organic phase, and extract the aqueous phase with two portions of benzene. Wash the combined organic phases with water, dry with calcium chloride, filter and evaporate to dryness under vacuum. Recrystallize the residue from methanol. (Yield: 80%).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:11]([N:12]2[CH2:24][CH2:23][N:15]3[C:16]4[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=4[CH:22]=[C:14]3[C:13]2=[O:25])=[CH:10][C:9]([F:26])=[CH:8][C:7]=1N1CCN2C3CCCCC=3C=C2C1=O)(=[O:3])[CH3:2].Br[C:42]1[CH:43]=[C:44]([NH:50][C:51]2[CH:62]=[C:54]3[CH2:55][N:56]([CH:59]4[CH2:61][CH2:60]4)[CH2:57][CH2:58][N:53]3[N:52]=2)[C:45](=[O:49])[N:46]([CH3:48])[CH:47]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC([O-])=O.[Na+]>CC#N.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:1]([O:4][CH2:5][C:6]1[C:11]([N:12]2[CH2:24][CH2:23][N:15]3[C:16]4[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=4[CH:22]=[C:14]3[C:13]2=[O:25])=[CH:10][C:9]([F:26])=[CH:8][C:7]=1[C:42]1[CH:43]=[C:44]([NH:50][C:51]2[CH:62]=[C:54]3[CH2:55][N:56]([CH:59]4[CH2:61][CH2:60]4)[CH2:57][CH2:58][N:53]3[N:52]=2)[C:45](=[O:49])[N:46]([CH3:48])[CH:47]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1c(N2CCn3c(cc4c3CCCC4)C2=O)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Reactant: Cn1cc(Br)cc(Nc2cc3n(n2)CCN(C2CC2)C3)c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: CC(=O)OCc1c(-c2cc(Nc3cc4n(n3)CCN(C3CC3)C4)c(=O)n(C)c2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Temperature: 110 °C
Yield: 60.1 %

Procedure:
A mixture of 4-fluoro-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate 210d (105 mg, 0.26 mmol), 135c (100 mg, 0.28 mmol), PdCl2(dppf) (29 mg, 0.039 mmol), K3PO4 (100 mg), and NaOAc (50 mg) in MeCN (10 mL) and water (3 mL) was heated at 110° C. for 2 h. The solvent was evaporated in vacuo. The residue was purified on reverse phase Combi-flash to give 135d (100 mg, 60%). MS: [M+H]+ 640.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[H-].[Na+].Cl[C:16]1[N:17]([CH2:24][C:25]2([CH3:28])[CH2:27][O:26]2)[CH:18]=[C:19]([N+:21]([O-:23])=[O:22])[N:20]=1>CN(C=O)C>[CH3:27][C:25]1([CH2:28][O:10][C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:11])([F:12])[F:1])=[CH:9][CH:8]=2)[O:26][C:16]2=[N:20][C:19]([N+:21]([O-:23])=[O:22])=[CH:18][N:17]2[CH2:24]1
Reactant: Oc1ccc(OC(F)(F)F)cc1
Reactant: CC1(Cn2cc([N+](=O)[O-])nc2Cl)CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(COc2ccc(OC(F)(F)F)cc2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 46.9 %

Procedure:
4-Trifluoromethoxyphenol (198 mg, 1.11 mmol) was dissolved in DMF (5 ml). To the solution, sodium hydride (48 mg, 1.21 mmol) was added at room temperature, and the solution was stirred for 20 minutes at 80° C. To the resulting solution, 2-chloro-1-(2-methyloxiran-2-ylmethyl)-4-nitroimidazole prepared in Example 6 (220 mg, 1.01 mmol) was added with cooling on ice-bath, and the solution was stirred for 15 minutes at 80° C. The reaction mixture was poured into ice-water, and the mixture was extracted with ethyl acetate. The organic phase was washed with a saturated saline solution, dried over magnesium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/ethyl acetate=10/1) and then crystallized from methylene chloride-diisopropyl ether to afford 2-methyl-6-nitro-2-(4-trifluoromethoxyphenoxymethyl)-2,3-dihydroimidazo[2,1-b]oxazole (170 mg, yield 47%) as a white powder.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18](Cl)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:23]([O:27][C:28](=[O:36])[NH:29][C@H:30]1[CH2:34][CH2:33][C@H:32]([NH2:35])[CH2:31]1)([CH3:26])([CH3:25])[CH3:24].C(N(C(C)C)CC)(C)C>CC(O)C>[C:23]([O:27][C:28](=[O:36])[NH:29][C@H:30]1[CH2:34][CH2:33][C@H:32]([NH:35][C:18]2[C:17]([N+:20]([O-:22])=[O:21])=[CH:16][N:15]=[C:14]3[N:10]([S:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)(=[O:9])=[O:8])[CH:11]=[CH:12][C:13]=23)[CH2:31]1)([CH3:26])([CH3:24])[CH3:25]
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1Cl
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)C1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2c([N+](=O)[O-])cnc3c2ccn3S(=O)(=O)c2ccccc2)C1
Yield: 94.7 %

Procedure:
A mixture of 1-benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine (16.9 g, 49.9 mmol), racemic trans (3-amino-cyclopentyl)-carbamic acid tert-butyl ester (10.0 g, 49.9 mmol: Prepared according to J. Org. Chem. 2004, 69(13), 4538; Tetrahedron 1997, 53(9), 3347; WO94/17090 and Org. Lett. 2000, 2, 4169) and diisopropylethylamine (12.0 mL, 69.9 mmol) in propan-2-ol (175 mL) was heated at reflux for 4 hours. After cooling, the mixture was concentrated in vacuo and the residue triturated (water) to give 23.7 g (94%) of racemic trans [3-(1-benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-cyclopentyl]-carbamic acid tert-butyl ester as a yellow solid. LCMS (Method B, ESI): RT=4.25 min, m+H=502.3; 1H NMR (400 MHz, DMSO) δ: 8.89 (s, 1H), 8.87 (d, 1H), 8.12 (d, 2H), 7.83 (d, 1H), 7.76 (m, 1H), 7.65 (t, 2H), 7.17 (d, 1H), 7.06 (br d, 1H), 4.62 (m, 1H), 3.99 (m, 1H), 2.24 (m, 1H), 1.97 (m, 3H), 1.56 (m, 2H), 1.38 (s, 9H).
Reaction SMILES: [CH:1]12[CH2:8][CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][NH:2]2.[C:9](Cl)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>[OH-].[Na+]>[C:9]([N:2]1[CH2:3][CH:4]2[CH2:7][CH2:8][CH:1]1[CH:6]=[CH:5]2)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C1=CC2CCC1CN2
Reactant: O=C(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(c1ccccc1)N1CC2C=CC1CC2
Reaction time: 1 h
Yield: 55 %

Procedure:
To a solution of 2-azabicyclo[2,2,2]-oct-5-ene (M. P. Cava et al, J. Org. Chem., 30, 3772 (1965)) (3.3 g) in aqueous 2.5N sodium hydroxide (50 ml) was added benzoyl chloride (6 ml) and the mixture stirred vigourously for 1 hour. Extraction into ether (2×100 ml), drying (Na2SO4) and concentration afforded the 2-benzoyl-2-azabicyclo[2,2,2]oct-5-ene (D1a) (3.7 g, 55%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([O:16][CH3:17])[C:12]=1[O:13][CH2:14][CH3:15])[C:6]([NH:8][NH2:9])=[O:7].[C:18]1([CH:24]=[C:25]2[CH2:29][CH2:28][CH2:27][C:26]2=O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C>[CH3:17][O:16][C:11]1[CH:10]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:12]=1[O:13][CH2:14][CH3:15])[C:6]([NH:8][N:9]=[C:26]1[CH2:27][CH2:28][CH2:29][C:25]1=[CH:24][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:7]
Reactant: CCOc1c(OC)cc(C(=O)NN)cc1OC
Reactant: O=C1CCCC1=Cc1ccccc1
Solvent: CCO
Product: CCOc1c(OC)cc(C(=O)NN=C2CCCC2=Cc2ccccc2)cc1OC
Reaction time: 1 h

Procedure:
A solution of 30.2 g (0.126 moles) of 3,5-dimethoxy-4-ethoxybenzoic acid hydrazide in 250 cm3 of anhydrous ethanol is added to a solution of 21.8 g (0.126 moles) of 2-phenylmethylenecyclopentan-1-one in 50 cm3 of ethanol. The reaction mixture is boiled for one hour, then cooled. The separated crystals are filtered off and dried. Yield: 39.78 g (80.0%). M.p.: 239°-240° C.
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].O1CCCC1.C([Li])CCC.O[CH:38]1[CH2:42][C:41]2[C:43]([Cl:48])=[C:44]([Cl:47])[CH:45]=[CH:46][C:40]=2[O:39]1>CCCCCC>[CH2:42]([C:41]1[C:43]([Cl:48])=[C:44]([Cl:47])[CH:45]=[CH:46][C:40]=1[OH:39])[CH:38]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OC1Cc2c(ccc(Cl)c2Cl)O1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCCC=CCc1c(O)ccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Twenty-five grams of n-hexyltriphenylphosphonium bromide were dissolved in 350 ml. of dry tetrahydrofuran and cooled to -10° C. To the solution were added 37 ml. of a 1.6M solution of n-butyllithium in hexane. The solution was slowly warmed to room temperature and stirred for one hour. The solution was then cooled to 0° C. and a solution of 2.38 g. of 2,3- dihydro-2-hydroxy-4,5-dichlorobenzofuran in 20 ml. of tetrahydrofuran was added. The reaction was allowed to reflux for approximately 18 hours. The solution was then cooled and evaporated to dryness. Ethyl acetate and water were added and the pH was adjusted to 2.5. The layers were separated. The organic layer was washed with a saturated sodium chloride solution, filtered through sodium sulfate, and evaporated to dryness. The residue was purified by high pressure liquid chromatography giving 2.51 g. of the desired intermediate as a mixture of cis and trans isomers.
Reaction SMILES: [NH2:1][C:2]([CH3:9])([CH2:7][CH3:8])[C:3]([O:5][CH3:6])=[O:4].[Cl:10][C:11]1[N:16]=[C:15](Cl)[CH:14]=[CH:13][N:12]=1.CN1C(=O)CCC1>O>[Cl:10][C:11]1[N:16]=[C:15]([NH:1][C:2]([CH3:9])([CH2:7][CH3:8])[C:3]([O:5][CH3:6])=[O:4])[CH:14]=[CH:13][N:12]=1
Reactant: CCC(C)(N)C(=O)OC
Reactant: Clc1ccnc(Cl)n1
Solvent: O
Solvent: CN1CCCC1=O
Product: CCC(C)(Nc1ccnc(Cl)n1)C(=O)OC
Temperature: 80 °C
Yield: 98.1 %

Procedure:
A 250 mL flask was charged with methyl 2-amino-2-methylbutanoate (8.4 g, 54.4 mmol), 2,4-dichloropyrimidine (8.9 g, 59.8 mmol), TEA (5.5 g, 54.4 mmol) and 80 mL NMP. The reaction mixture was heated to 80° C. for ˜18 hours. After cooling, water (300 mL) was added and the mixture extracted with MTBE. The organic extracts were washed with water and dried over sodium sulfate. Filtration and evaporation under vacuum afforded 13 g of an orange oil which was purified by flash chromatography, (0-100% ethyl acetate-hexane affording 4.6 g (34%) methyl 2-((2-chloropyrimidin-4-yl)amino)-2-methylbutanoate as an oil. 1H NMR: (CDCl3) δ 8.05-7.88 (m, 1H), 6.28 (δ, 1H), 5.95 (δ, 1H), 4.2-4.0 (μ, 1H), 3.86 (m, 1H), 2.46 (m, 1H), 2.10 (m, 1H), 2.01 (m, 1H), 1.72 (m, 3H), 0.89 (m, 3H). m/e, m+1 244.1