Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:14]=[CH:15][C:16]4[N:17]([C:19]([C:22]([O:24]C)=O)=[CH:20][N:21]=4)[CH:18]=3)=[CH:11][N:10]([C:26]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:9]=2)=[CH:4][CH:3]=1.O.[NH2:46][NH2:47]>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:14]=[CH:15][C:16]4[N:17]([C:19]([C:22]([NH:46][NH2:47])=[O:24])=[CH:20][N:21]=4)[CH:18]=3)=[CH:11][N:10]([C:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1cnc2ccc(-c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)nc3-c3ccc(F)cc3)cn12
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNC(=O)c1cnc2ccc(-c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)nc3-c3ccc(F)cc3)cn12

Procedure:
A mixture of 740 mg methyl 6-[3-(4-fluorophenyl)-1-trityl-1H-pyrazol-4-yl]imidazo[1,2-a]pyridine-3-carboxylate (compound in Production Example 273), 0.32 mL hydrazine monohydrate and 20 mL ethanol was heated for 6 hours under reflux. The reaction solution was evaporated, and the resulting residue was purified by NH silica gel column chromatography (ethyl acetate/hexane) to give 283 mg of the title compound as a color amorphous.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[O:10]1[CH2:15][CH2:14][CH:13]([NH2:16])[CH2:12][CH2:11]1>>[Br:1][C:2]1[C:3]([NH:16][CH:13]2[CH2:14][CH2:15][O:10][CH2:11][CH2:12]2)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: NC1CCOCC1
Product: Clc1ncc(Br)c(NC2CCOCC2)n1
Yield: 83 %

Procedure:
In the reaction of 5-bromo-2,4-dichloropyrimidine (300 mg, 1.32 mmol) with tetrahydropyran-4-ylamine (144 mg, 1.42 mmol) according to GP 2, the desired product is obtained in 83% yield (320 mg) after chromatographic purification (silica gel, ethyl acetate/hexane with ethyl acetate: 0-100%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:22]=[CH:21][CH:20]=[CH:19][C:6]=1[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=O)=[CH:11][CH:10]=1)=[O:4].[CH2:23]([NH:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].C(Cl)CCl.Cl>C(Cl)Cl.CN(C1C=CN=CC=1)C.O>[CH2:30]([N:29]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:16](=[O:18])[CH2:15][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:7][C:6]2[CH:19]=[CH:20][CH:21]=[CH:22][C:5]=2[C:3]([O:2][CH3:1])=[O:4])=[CH:14][CH:13]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: COC(=O)c1ccccc1COc1ccc(CC(=O)O)cc1
Reactant: CCCCCCNCc1ccccc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Solvent: O
Solvent: ClCCl
Product: CCCCCCN(Cc1ccccc1)C(=O)Cc1ccc(OCc2ccccc2C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(4-{[2-(Methoxycarbonyl)benzyl]oxy}phenyl)acetic acid (50 mg, 0.166 mmol) was dissolved in DCM (2 ml), N-hexylbenzylamine (38.2 mg, 0.2 mmol) was added, then EDC (38.3 mg, 0.2 mmol) was added and then DMAP (24.4 mg, 0.2 mmol) was added. The mixture was stirred at room temperature overnight. 1% HCl (1 ml) and water (1 ml) were added into the mixture. The two phases were separated by using a Whatman Filter Tube. The obtained organic solution was evaporated in vacuum and the oil product (71 mg) was left. It was then used directly in next step.
Reaction SMILES: Cl.[CH3:2][Si:3]1([CH3:9])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.C(N(CC)CC)C.[F:17][C:18]1[CH:19]=[C:20]([N+:25]([O-:27])=[O:26])[CH:21]=[CH:22][C:23]=1F.O>C(OC(=O)C)C>[F:17][C:18]1[CH:19]=[C:20]([N+:25]([O-:27])=[O:26])[CH:21]=[CH:22][C:23]=1[N:6]1[CH2:7][CH2:8][Si:3]([CH3:9])([CH3:2])[CH2:4][CH2:5]1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: C[Si]1(C)CCNCC1
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C[Si]1(C)CCN(c2ccc([N+](=O)[O-])cc2F)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 69.8 %

Procedure:
To a solution of 4 (500 mg, 3.85 mmol) in ethylacetate, triethylamine (973 mg, 9.63 mmol) is added and stirred at 25° C. for 10 min. The reaction mixture is cooled to 0° C. and 3,4-difluoronitrobenzene (612 mg, 3.85 mmol) is added dropwise and allowed to stir at 25° C. for 6 h. Water is then added and the organic layer is separated. The aqueous layer is extracted with EtOAc and the solvent is removed. The product is purified by column chromatography using hexanes-EtOAc mixtures to obtain the product as a crystalline yellow solid 9 (721 mg) in 70% isolated yield.
Reaction SMILES: O.NN.[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:34]=[N:35][NH:36][CH:37]=3)=[CH:29][CH:28]=2)[O:12][CH2:13][CH2:14][NH:15]C(=O)C2C(=CC=CC=2)C(O)=O)=[CH:7][CH:6]=1>CO>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:37]=[N:36][NH:35][CH:34]=3)=[CH:29][CH:28]=2)[O:12][CH2:13][CH2:14][NH2:15])=[CH:7][CH:6]=1
Reactant: O=C(O)c1ccccc1C(=O)NCCOC(c1ccc(Cl)cc1)c1ccc(-c2cn[nH]c2)cc1
Agent: NN
Solvent: O
Solvent: CO
Product: NCCOC(c1ccc(Cl)cc1)c1ccc(-c2cn[nH]c2)cc1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
Hydrazine monohydrate (159 □l, 3.28 mmol) was added to a solution of N-(2-{(4-Chloro-phenyl)-[4-(1H-pyrazol-4-yl)-phenyl]-methoxy}-ethyl)-phthalamic acid (260 mg, 0.55 mmol) in methanol (6 ml) and the reaction mixture stirred at 80° C. for 16 hours. Upon cooling, the solvent was removed under reduced pressure and the crude product was purified by column chromatography (SiO2), eluting with dichloromethane:methanol:acetic acid:water (90:18:3:2). Further purification by Phenomenex_Strata_SCX column chromatography, eluting with methanol followed by 2N ammonia in methanol, afforded the desired product as the free base (120 mg). LC/MS: (FL-A) Rt 2.07 [M-NH2CH2CH2O+H]+ 267. 1H NMR (Me-d3-OD) δ 2.85 (2H, t), 3.55 (2H, t), 5.45 (1H, s), 7.35-7.40 (6H, m), 7.58 (2H, d), 7.95 (2H, s).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][C:17]2=[O:26])[CH2:10][CH2:9]1)(C)(C)C.Cl.O.Cl.O1CCOCC1>O1CCOCC1>[NH2:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][C:17]2=[O:26])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)ccc3ccccc32)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: NC1CCN(CCn2c(=O)ccc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl{1-[2-(2-oxoquinolin-1(2H)-yl)ethyl]piperidin-4-yl}carbamate (Intermediate 164, 220 mg, 0.59 mmol) in dioxane (5 mL) was added a solution of HCl in dioxane (4M, 9 mL), followed by water (1 mL) and it was stirred at room temperature over night. An addition 5 mL of HCl/dioxane was added to the reaction. After 1 hr, the reaction was concentrated to dryness. The crude product was partitioned between 10% methanol/dichloromethane (50 mL) and 1M sodium hydroxide (50 mL). The aqueous phase was back extracted with 10% methanol/dichloromethane (50 mL) and the combined organic phases were washed with brine, dried over sodium sulfate and concentrated under reduced pressure to give 170 mg (quantitative) of the crude product as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[CH:4][C:3]=1[S:10]([N:13]([CH2:17][CH2:18]Cl)[CH:14]([CH3:16])[CH3:15])(=[O:12])=[O:11].[F:20][C:21]1[CH:35]=[CH:34][C:24]2[NH:25][C:26]([CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[N:27][C:23]=2[CH:22]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[CH:4][C:3]=1[S:10]([N:13]([CH2:17][CH2:18][N:31]1[CH2:30][CH2:29][CH:28]([C:26]2[NH:25][C:24]3[CH:34]=[CH:35][C:21]([F:20])=[CH:22][C:23]=3[N:27]=2)[CH2:33][CH2:32]1)[CH:14]([CH3:15])[CH3:16])(=[O:11])=[O:12]
Reactant: CC(C)N(CCCl)S(=O)(=O)c1cc(Cl)c(Cl)cc1Cl
Reactant: Fc1ccc2[nH]c(C3CCNCC3)nc2c1
Product: CC(C)N(CCN1CCC(c2nc3cc(F)ccc3[nH]2)CC1)S(=O)(=O)c1cc(Cl)c(Cl)cc1Cl

Procedure:
The title compound was prepared using the procedure described in Example 1 using D7 and 4-(5-fluoro-1H-benzimidazol-2-yl)piperidine (D17). MH+ 547/549/551/553.
Reaction SMILES: [OH:1][CH2:2][C@H:3]([NH:10]C(=O)OC(C)(C)C)[C:4]1[N:5]=[N:6][N:7]([CH3:9])[N:8]=1.[ClH:18].O1CCOCC1>CO>[ClH:18].[NH2:10][C@H:3]([C:4]1[N:5]=[N:6][N:7]([CH3:9])[N:8]=1)[CH2:2][OH:1]
Reactant: Cn1nnc([C@H](CO)NC(=O)OC(C)(C)C)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cn1nnc([C@@H](N)CO)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 106 mg of tert-butyl [(1R)-2-hydroxy-1-(2-methyl-2H-tetrazol-5-yl)ethyl]carbamate in 3 ml of methanol was added to 1.5 ml of a 4 M hydrogen chloride/1,4-dioxane solution, followed by stirring at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain 78 mg of (2R)-2-amino-2-(2-methyl-2H-tetrazol-5-yl)ethanol hydrochloride.
Reaction SMILES: N1C=CC=CC=1.[CH3:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([C:17]#[C:18][CH2:19][F:20])=[CH:13][CH:12]=1)(=[O:10])=[O:9].[H][H]>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].C(OCC)(=O)C.[Pd]>[CH3:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17]/[CH:18]=[CH:19]\[F:20])=[CH:13][CH:12]=1)(=[O:10])=[O:9]
Reactant: [H][H]
Reactant: CS(=O)(=O)c1ccc(C#CCF)cc1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(C/C=C\F)cc1
Yield: 99.3 %

Procedure:
cis-hydrogenation using Lindlar catalyst and pyridine: Stir a mixture of 533 mg, 2.51 mmoles of the title compound of Example 1 (recrystallized from dichloromethane-hexane), 211 mg, 2.67 mmoles of pyridine and 127 mg of Lindlar catalyst (palladium on calcium carbonate, poisoned with lead (obtained from Aldrich) in 25 mL of ethyl acetate under hydrogen at atomospheric pressure at 26° C. for 1 hr until the theoretical amount of hydrogen (62 mL) is consumed. Remove the catalyst by filtration and wash it with ethyl acetate. Wash the ethyl acetate solution successively with ice-cold 4% HCl solution, saturated NaHCO3 solution and water, and dry over anhydrous MgSO4. Evaporate solvent under vacuum to give the title compound as an oil (534 mg).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[NH:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][C:24]2([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:28][CH2:27][NH:26][CH2:25]2)[CH2:18][CH2:17]1)[CH3:2].C([N:38](CC)C(C)C)(C)C.[CH3:44][O:45][C:46]1[CH:54]=[CH:53][C:52]([CH2:55][N:56]2[CH:60]=C[N:58]=[N:57]2)=[CH:51][C:47]=1[C:48](Cl)=[O:49]>O1CCCC1.C(OCC)(=O)C>[CH3:44][O:45][C:46]1[CH:54]=[CH:53][C:52]([CH2:55][N:56]2[CH:60]=[N:38][N:58]=[N:57]2)=[CH:51][C:47]=1[C:48]([N:26]1[CH2:27][CH2:28][C:24]([CH2:23][CH2:22][N:19]2[CH2:20][CH2:21][CH:16]([NH:15][C:7]3[N:6]([CH2:5][CH2:4][O:3][CH2:1][CH3:2])[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[N:8]=3)[CH2:17][CH2:18]2)([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:25]1)=[O:49]
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1ccc(Cn2ccnn2)cc1C(=O)Cl
Reactant: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(Cn5cnnn5)ccc4OC)C3)CC2)nc2ccccc21
Reaction time: 18 h

Procedure:
Combine 3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl-amino)piperidin-1-yl)ethyl)-3-phenylpyrrolidine (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt) (1.0 mmol), N,N-diisopropylethylamine (0.35 mL), and 2-methoxy-5-(1H-triazol-1-ylmethyl)benzoyl chloride (0.22 g, 0.94 mmol) in tetrahydrofuran (50 mL). After 18 hours, dilute the reaction mixture with ethyl acetate and extract with a saturated aqueous sodium bicarbonate solution and then brine. Dry the organic layer over Na2SO4, filter, and concentrate in vacuo to give a residue. Chromatograph the residue to give the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([N+:25]([O-])=O)[CH:16]=2)[CH:9]=1)([O-])=O.[H][H].Cl>C(O)(C)C.[Pd]>[NH2:25][C:17]1[CH:16]=[C:15]([CH:20]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:18]=1)[O:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([O:7][C:6]2[CH:28]=[C:29]([C:31]([F:32])([F:34])[F:33])[CH:30]=[C:4]([NH2:1])[CH:5]=2)[CH:9]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc(Oc2cccc(Oc3cc([N+](=O)[O-])cc(C(F)(F)F)c3)c2)cc(C(F)(F)F)c1
Agent: [Pd]
Agent: Cl
Solvent: CC(C)O
Product: Nc1cc(Oc2cccc(Oc3cc(N)cc(C(F)(F)F)c3)c2)cc(C(F)(F)F)c1

Procedure:
Into a reducing device equipped with a thermometer, a reflux condenser and an agitator were charged 72 g of 1,3-bis(3-nitro-5-trifluoromethylphenoxy)benzene (0.147 mol), 500 mL of isopropyl alcohol and 7.2 g of 5%-Pd/C (50% of water content), and the mixture was reacted at 50° C. for 5 hours in an atmosphere of hydrogen. At the end of the reaction, the catalyst was filtered out, the filtrate was condensed under a reduced pressure and the residue was dissolved in 200 g of isopropanol and 400 g of 36% HCl was added to the solution to precipitate the desired hydrochloride. The hydrochloride was suspended in 150 g of water and 200g of 1,2-dichloroethane (EDC), the mixture was neutralized with 28% ammonium hydroxide aq. and separated, and the EDC layer was washed with water and evaporated to give 1,3-bis(3-amino-5-trifluoromethylphenoxy)benzene as a brown viscous liquid; Yield: 33.8 g (53.7%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:21])[C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([CH:18]([CH3:20])[CH3:19])[CH:12]=1)[CH2:5]O.B(Br)(Br)[Br:23]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:21])[C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([CH:18]([CH3:20])[CH3:19])[CH:12]=1)[CH2:5][Br:23]
Reactant: CC(C)c1cc(Oc2c(Cl)cc(CO)cc2Cl)ccc1O
Reactant: BrB(Br)Br
Solvent: ClCCl
Product: CC(C)c1cc(Oc2c(Cl)cc(CBr)cc2Cl)ccc1O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3,5-dichloro-4-(4′-hydroxy-3′-iso-propylphenoxy)benzyl alcohol in CH2Cl2 (5.0 mL) at −78° C. is added BBr3. The reaction mixture is stirred at room temperature for 16 h, poured into ice water and extracted with ethyl acetate. The organic layer is dried over MgSO4, filtered and concentrated under reduced pressure. The crude product is purified by column chromatography on silica gel, eluting with acetone-hexanes to afford 3,5-dichloro-4-(4′-hydroxy-3′-iso-propylphenoxy)benzyl bromide.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([N:9]2[C:14]3[N:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][NH:11][C:10]2=[O:19])[CH:6]=[CH:7][CH:8]=1.CN(C)C=O.[CH2:27](OC(OCC)N(C)C)[CH3:28]>O>[F:21][C:2]([F:20])([F:1])[C:3]1[CH:4]=[C:5]([N:9]2[C:14]3[N:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]([CH2:27][CH3:28])[C:10]2=[O:19])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C1NCc2cccnc2N1c1cccc(C(F)(F)F)c1
Reactant: CCOC(OCC)N(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CCN1Cc2cccnc2N(c2cccc(C(F)(F)F)c2)C1=O
Yield: 18.9 %

Procedure:
To a mixture of 2.9 g of 1-(m-trifluoromethylphenyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine, 25 ml of dimethylformamide and 4.4 g of dimethylformamide diethylacetal was reacted at 145° - 150° C for 5 hours. After the reaction was complete, the solvent was distilled off from the mixture under reduced pressure. The residue thus obtained was diluted with water, extracted with ether and dehydrated. The ether solution was applied on a column of alumina and then eluted with ether. The eluate was concentrated by evaporation to leave a residue, which was then recrystallized from a mixture of ether and petroleum ether to give 0.6 g of 1-(m-trifluoromethylphenyl)-3-ethyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine as colorless prisms, melting at 155° - 157° C.
Reaction SMILES: Cl[C:2]1[C:3]([N+:16]([O-:18])=[O:17])=[CH:4][C:5]([C:12]([F:15])([F:14])[F:13])=[C:6]([CH3:11])[C:7]=1[N+:8]([O-:10])=[O:9].[CH:19]([NH2:23])([CH2:21][CH3:22])[CH3:20]>C1C=CC=CC=1>[CH:19]([NH:23][C:2]1[C:3]([N+:16]([O-:18])=[O:17])=[CH:4][C:5]([C:12]([F:15])([F:14])[F:13])=[C:6]([CH3:11])[C:7]=1[N+:8]([O-:10])=[O:9])([CH2:21][CH3:22])[CH3:20]
Reactant: Cc1c(C(F)(F)F)cc([N+](=O)[O-])c(Cl)c1[N+](=O)[O-]
Reactant: CCC(C)N
Solvent: c1ccccc1
Product: CCC(C)Nc1c([N+](=O)[O-])cc(C(F)(F)F)c(C)c1[N+](=O)[O-]

Procedure:
A nitration mixture, consisting of 16.1 ml. of H2SO4 (d 1.84) and 1.9 ml. of HNO3 (d 1.5), is heated to 55° C. and 3.5 grams of 5-chloro-2-(trifluoromethyl)toluene is slowly added. The mixture is heated for one hour at 55° C. followed by one hour at 110° C. The reaction mixture is cooled and poured onto ice to give 5-chloro-2-(trifluoromethyl)-4,5-dinitrotoluene as a cream-colored solid. The product is crystallized from cyclohexane to give 3.6 grams of cream-colored crystals, melting point 81° C. to 82° C. 1.8 Grams of 5-chloro-2-(trifluoromethyl)-4,6-dinitrotoluene is refluxed for 15 minutes with 3 ml. of mono-sec-butylamine and 30 ml. of benzene, cooled, filtered, washed with water until neutral, dried and vacuum stripped to give 1.5 grams of N-sec-butyl-3-methyl-2,6-dinitro-4-(trifluoromethyl)aniline as a yellow solid, melting point 38° C. to 39° C.
Reaction SMILES: [CH2:1]([O:7][CH:8]1[CH2:13][C:12]([CH3:15])([CH3:14])[NH:11][C:10]([CH3:17])([CH3:16])[CH2:9]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C(N(CC)CC)C.[C:25]1([C:31](=[O:35])[C:32](Cl)=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(Cl)Cl>[CH2:1]([O:7][CH:8]1[CH2:9][C:10]([CH3:16])([CH3:17])[N:11]([C:32](=[O:33])[C:31]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:35])[C:12]([CH3:15])([CH3:14])[CH2:13]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: O=C(Cl)C(=O)c1ccccc1
Reactant: CCCCCCOC1CC(C)(C)NC(C)(C)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCOC1CC(C)(C)N(C(=O)C(=O)c2ccccc2)C(C)(C)C1
Temperature: -10 °C
Reaction time: 4 h
Yield: 76 %

Procedure:
24.1 g (0.1 mole) of 4-hexyloxy-2,2,6,6-tetramethylpiperidine are dissolved in 100 ml of absolute methylene chloride. To this solution are added 15.2 g (0.15 mole) of absolute triethylamine and the whole solution is cooled to -10° C. At this temperature a solution of 16.8 g (0.1 mole) of phenylglyoxylyl chloride in 100 ml of methylene chloride is slowly added dropwise. When this addition is complete, the reaction mixture is allowed to warm to room temperature and stirred for about 4 hours. Precipitated hydrochloride is removed by filtration and the solution is clarified by filtration over a small amount of silica gel and concentrated by evaporation, affording 28.4 g of 1-(4-hexyloxy-2,2,6,6-tetramethylpiperidino)-2-phenylethane-1,2-dione as a yellow oil (stabiliser 1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH3:11])=[CH:5]2.[C:12]([O:16][C:17](=O)[O:18]C(C)(C)C)([CH3:15])([CH3:14])[CH3:13].CC#N>CN(C)C1C=CN=CC=1.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:17]([O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:18])[C:6]([CH3:11])=[CH:5]2
Reactant: Cc1cc2cc(Br)ccc2[nH]1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1cc2cc(Br)ccc2n1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.5 %

Procedure:
5-Bromo-2-methylindole (4.2 g, 200.0 mmol), di-t-butylcarbonate (4.37 g, 20 mmol), 4-dimethylaminopyridine (2.93 g, 24 mmol) and CH3CN (50 mL) were mixed and stirred at room temperature for 16 h. The reaction mixture was diluted with EtOAc (300 mL) and the organic solution was washed successively with water (50 mL), a 1N HCl solution (50 mL), a saturated NaHCO3 solution (2×50 mL) and brine (25 mL). The organic layer was dried over MgSO4, filtered and concentrated in vacuo to afford an oil (6.11 g, 99% yield): 1H NMR (CDCl3, 300 MHz): 7.98 (d, 1H, J=9), 7.56 (d, 1H, J=1), 7.32 (dd, H, J=9, 1), 6.27 (s, 1H), 2.60 (d, 3H, J=1), 1.69 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[O:5][CH:6]=1.[CH:9](/B(O)O)=[CH:10]/[CH3:11].C(C1OC(C=O)=CC=1)C1C=CC=CC=1>CN(C=O)C>[CH:9](/[C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[O:5][CH:6]=1)=[CH:10]/[CH3:11]
Reactant: C/C=C\B(O)O
Reactant: O=Cc1cc(Br)co1
Agent: O=Cc1ccc(Cc2ccccc2)o1
Solvent: CN(C)C=O
Product: C/C=C\c1coc(C=O)c1
Yield: 48.2 %

Procedure:
The title compound was synthesized from 4-bromo-furan-2-carboxaldehyde (1.1 g, 6.3 mmol, 1 equiv) and cis-propene boronic acid (0.65 g, 7.5 mmol, 1.2 equiv) using the conditions to synthesize 5-benzyl-furan-2-carbaldehyde, with the exception that the reaction was run in DMF (20 mL). The resulting residue was purified via ISCO Companion (0-25% EtOAc/heptane over 30 min, retention time of product: 23-26 min) to give (Z)-4-(prop-1-enyl)furan-2-carbaldehyde (0.4130 g, 48% yield). LC/MS m/e 136.8 (M+H). 1H NMR (400 MHz, CD3CN) δ (ppm): 9.59 (d, J=0.63 Hz, 1 H), 7.83 (s, 1 H), 7.42 (s, 1 H), 6.23 (dd, J=11.40, 1.68 Hz, 1 H), 5.79-5.89 (m, 1 H), 1.87 (dd, J=7.10, 1.78 Hz, 3 H).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Br[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=1[F:16].[Cl:17][C:18]1[C:19](B2OC(C)(C)C(C)(C)O2)=[CH:20][C:21]2[N:25]=[C:24]([O:26][C:27]3[CH:28]=[CH:29][C:30]([CH3:36])=[C:31]([CH:35]=3)[C:32]([OH:34])=[O:33])[N:23]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[C:22]=2[CH:45]=1>CN(C=O)C.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>[Cl:17][C:18]1[C:19]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=2[F:16])=[CH:20][C:21]2[N:25]=[C:24]([O:26][C:27]3[CH:28]=[CH:29][C:30]([CH3:36])=[C:31]([CH:35]=3)[C:32]([OH:34])=[O:33])[N:23]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[C:22]=2[CH:45]=1
Reactant: Cc1ccc(Oc2nc3cc(B4OC(C)(C)C(C)(C)O4)c(Cl)cc3n2COCC[Si](C)(C)C)cc1C(=O)O
Reactant: COc1ccc(Br)c(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2cc3nc(Oc4ccc(C)c(C(=O)O)c4)n(COCC[Si](C)(C)C)c3cc2Cl)c(F)c1
Temperature: 150 °C

Procedure:
K2CO3 (0.293 mL, 0.585 mmol) followed by Pd(PPh3)4 (6.76 mg, 5.85 μmol) were added to a solution of 4-Bromo 3-fluoro anisole (0.027 mL, 0.195 mmol) and 5-[(6-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazol-2-yl)oxy]-2-methylbenzoic acid (122 mg, 0.219 mmol) in DMF (2 mL). The reaction was heated at 150° C. under microwave irradiation for 10 min. Volatiles were removed to afford the desired product, which was used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([C@@H:13]([OH:25])[C@@H:14]([NH2:24])[CH2:15][C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[CH:17]=2)[CH2:11][O:10][C:9]1([CH3:27])[CH3:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:35](OC(=O)C)(=[O:37])[CH3:36]>O1CCCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([C@@H:13]([OH:25])[C@@H:14]([NH:24][C:35](=[O:37])[CH3:36])[CH2:15][C:16]2[CH:17]=[C:18]([F:23])[CH:19]=[C:20]([F:22])[CH:21]=2)[CH2:11][O:10][C:9]1([CH3:27])[CH3:26])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N1[C@@H]([C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)COC1(C)C
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 72.4 %

Procedure:
Dissolve (R)-4-[(1S,2S)-2-amino-3-(3,5-difluorophenyl)-1-hydroxypropyl]-2,2-dimethyloxazolidine-3-carboxylic acid tert-butyl ester (920 mg, 2.38 mmol) in dry tetrahydrofuran (20 ml) under an atmosphere of nitrogen. Add to the resulting solution triethylamine (400 μl, 2.87 mmol) and acetic anhydride (235 μL, 2.49 mmol). After 1 hour, dilute with ethyl acetate and wash with water (twice), 0.1 N hydrochloric acid, and saturated aqueous sodium chloride. Dry (magnesium sulfate), filter, concentrate and purify (silica gel chromatography 0:100 to 70:30 ethyl acetate:hexanes) to give the desired compound as a white solid (738 mg, 72% yield).