Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH2:15][O:16][CH2:17][CH2:18][OH:19])[C:13]([CH3:20])=[N:12][C:11]=2[CH:21]([CH3:23])[CH3:22])[CH:5]=[C:6]([CH3:8])[CH:7]=1.O.[C:25]1(C)[CH:30]=[CH:29][C:28](S(O)(=O)=O)=[CH:27][CH:26]=1.C1(C)C=CC=CC=1.COC1CCCCC=1>C(Cl)Cl>[C:25]1([O:19][CH2:18][CH2:17][O:16][CH2:15][N:14]2[C:10]([S:9][C:4]3[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[CH:5]=3)=[C:11]([CH:21]([CH3:23])[CH3:22])[N:12]=[C:13]2[CH3:20])[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Cc1cc(C)cc(Sc2c(C(C)C)nc(C)n2COCCO)c1
Agent: COC1=CCCCC1
Solvent: O
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Cc1cc(C)cc(Sc2c(C(C)C)nc(C)n2COCCOC2=CCCCC2)c1
Yield: 74.8 %

Procedure:
A solution of the compound 1 (33.4 mg, 0.1 mmol) and p-toluenesulfonic acid hydrate (20.0 mg, 0.105 mmol) in a mixture of methylene chloride (1 mL) - toluene (0.1 mL) was concentrated under reduced pressure. The residue was dissolved in a mixture of dioxane (2 mL) - benzene (0.5 mL), to which was added 1-methoxycyclohexene (112 mg, 1.00 mmol). The reaction mixture was heated under reflux, and concentrated to a small volume over 1 hour. A drop of triethylamine was added to the reaction mixture, and the mixture was concentrated under reduced pressure. Hexane was added to the residue, the mixture was filtered to remove the insoluble matter, and the filtrate was purified by chromatography on an alumina column (eluate: hexane - ethyl acetate (2:1)) to give the same compound 6 (31 mg, 75%) as oil. Rf 0.62 (Al2O3 60, Type E, 2:1 hexane -EtOAc).
Reaction SMILES: [CH2:1]([C@H:8]([NH:30]C(=O)OC)[C@H:9]([OH:29])[CH2:10][N:11]1[C@H:20]([C:21](=[O:28])[NH:22]OC(C)(C)C)[CH2:19][C@H:18]2[C@H:13]([CH2:14][CH2:15][CH2:16][CH2:17]2)[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C.O>[NH2:30][C@@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C@H:9]([OH:29])[CH2:10][N:11]1[C@H:20]([C:21]([NH:22][C:2]([CH3:7])([CH3:3])[CH3:1])=[O:28])[CH2:19][C@H:18]2[C@H:13]([CH2:14][CH2:15][CH2:16][CH2:17]2)[CH2:12]1
Reactant: COC(=O)N[C@@H](Cc1ccccc1)[C@H](O)CN1C[C@H]2CCCC[C@H]2C[C@H]1C(=O)NOC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCCC[C@@H]2CN1C[C@@H](O)[C@@H](N)Cc1ccccc1
Yield: 202.4 %

Procedure:
A suspension of 41.37 g of methyl (1 S,2R)-[1 -benzyl-3-[(3 S,4aS,8aS)-3-tert-butoxycarbamoyl-octahydro-isoquinolin-2-yl]-2-hydroxy-propyl]-carbamate and 23.0 g of sodium hydroxide in 90 ml of ethanol and 90 ml of water was heated at reflux for 3.5 hours, diluted with 45 ml of water and cooled to 22°, and the separated solid was filtered off, washed with a 1:4 mixture of ethanol/water and dried, there being obtained 35.35 g (98%) of pure 2-[3(S)-amino-2(R)-hydroxy-4-phenyl-butyl]-N-tert.butyl-decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide, m.p. 1730-1750C. IR (KBr):
Reaction SMILES: [Li+].[AlH4-].[F:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]3[CH2:15][CH2:16][CH2:17][C:13]=3[C:12]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](O)=[O:24])=[N:11]2)=[CH:6][CH:5]=1>C1COCC1>[F:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:14]3[CH2:15][CH2:16][CH2:17][C:13]=3[C:12]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][OH:24])=[N:11]2)=[CH:8][CH:9]=1
Reactant: O=C(O)CCCCCc1nn(-c2ccc(F)cc2)c2c1CCC2
Agent: [AlH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCCCCCc1nn(-c2ccc(F)cc2)c2c1CCC2
Temperature: 60 °C
Yield: 44.8 %

Procedure:
Lithium tetrahydridoaluminate (0.345 g, 9.1 mmol) in THF (75 ml) was treated with the compound of Example 31 (1.0 g, 3.1 mmol) and the mixture was heated at 60° C. for 2 hours. Excess reagent was quenched, the mixture filtered and the combined filtrate and ethyl acetate washes were evaporated to a colorless oil (0.76 g). Polar impurities were removed on silica gel (40 g) with 1:1 ethyl acetate-Skelly B eluent to provide title compound (0.42 g) as an oil.
Reaction SMILES: O=C[C@@H]([C@H]([C@@H](CO)O)O)O.[O:11]=[CH:12][C@@H:13]([C@H:15]([C@@H:17]([C@@H:19]([CH2:21][OH:22])[OH:20])[OH:18])[OH:16])[OH:14]>>[O:11]=[CH:12][C@H:13]([C@H:15]([C@@H:17]([C@@H:19]([CH2:21][OH:22])[OH:20])[OH:18])[OH:16])[OH:14]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)CO
Product: O=C[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Temperature: 80 °C

Procedure:
A mixture of 5.7 g (38.4 mmole) of D-xylose of mp. 153° C. and 6.9 g (38.4 mmole) of D-glucose of mp. 143° C. is heated to approximately 80° C. with 52.7 g (176.8 mmole) of BEPDIB. The readily volatile constituents are then removed in vacuo (10-3Torr). Subsequent distillation gives 7.3 g of bp. 78° C./10-3Torr in addition to 11 g of yellowish residue.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].I[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=1.C([O-])([O-])=O.[Cs+].[Cs+].CN(C)CC(O)=O.Cl>O1CCOCC1.[Cu]I>[Cl:19][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6]
Reactant: Clc1cccc(I)c1
Reactant: COc1ccc(C=O)cc1O
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc(C=O)cc1Oc1cccc(Cl)c1
Temperature: 98 °C
Reaction time: 0.08 h
Yield: 19 %

Procedure:
To a 250 mL pressure resistant vial which contained a mixture of 3-hydroxy-4-methoxy-benzaldehyde (1520 mg, 10 mmole), 1-Iodo-3-chloro-benzene (2390 mg, 10 mmole), Cs2CO3 (1600 mg, 10 mmole) and N,N-dimethylglycine.HCl (280 mg, 2 mmole) in dioxane (40 mL) was added CuI (380 mg, 2 mmole) at rt. The reaction mixture was bumbled with Ar for 5 min at rt and then the vial was sealed. The reaction mixture was heated to 98° C. and stirred for 24 h and then 110° C. for 20 h. After cooling to rt, the reaction mixture was poured onto 250 mL ice-water which was extracted with ethyl acetate (3×50 mL), washed with water (2×50 mL), brine (50 mL) and dried over Na2SO4. After removal of solvent, the residue was purified by silica gel column chromatography with ethyl acetate/hexane as eluent to give 500 mg (24% yield) of product (12).
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][CH:9]([C:15](=[O:17])[CH3:16])[CH2:10][C:11]([O:13][CH3:14])=[O:12])=O)=[CH:4][CH:3]=1.OS(O)(=O)=O>C(OC(=O)C)(=O)C>[CH3:14][O:13][C:11](=[O:12])[CH2:10][C:9]1[N:8]=[C:6]([C:5]2[CH:18]=[CH:19][C:2]([CH3:1])=[CH:3][CH:4]=2)[O:17][C:15]=1[CH3:16]
Reactant: COC(=O)CC(NC(=O)c1ccc(C)cc1)C(C)=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Product: COC(=O)Cc1nc(-c2ccc(C)cc2)oc1C
Reaction time: 1 h
Yield: 85.8 %

Procedure:
The intermediate prepared in Example 8 (280 g, 1.06 mol) was dissolved in acetic anhydride (650 mL) followed by slow addition of conc. H2SO4 (60 ml). The pot temperature reached 80° C. The reaction was then held at 85° C. for 1 hour, cooled, and the acetic anhydride removed in vacuo. The residue was poured into ice water (2 L) and extracted with EtOAc (4 L total). The organic layer was then stirred with 1 N NaOH (500 mL) for 1 hour, separated, then dried with MgSO4 and concentrated to afford the title ester as a clear oil (223 g, 87%), which slowly solidified to a white solid.
Reaction SMILES: C(O)C.[CH:4]([C:7]1[CH:20]=[CH:19][C:10]([O:11][CH:12]2[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]2)=[CH:9][CH:8]=1)([CH3:6])[CH3:5].O.Cl.[NH2:23][C@H:24]([C:27]([OH:29])=[O:28])[CH2:25][SH:26].C([O-])(=O)C.[Na+]>O>[CH:4]([C:7]1[CH:20]=[CH:19][C:10]([O:11][CH:12]2[CH2:17][CH2:16][C:15]3([S:26][CH2:25][C@@H:24]([C:27]([OH:29])=[O:28])[NH:23]3)[CH2:14][CH2:13]2)=[CH:9][CH:8]=1)([CH3:6])[CH3:5]
Reactant: CC(C)c1ccc(OC2CCC(=O)CC2)cc1
Reactant: N[C@@H](CS)C(=O)O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)c1ccc(OC2CCC3(CC2)N[C@H](C(=O)O)CS3)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 54.7 %

Procedure:
In a solvent mixture consisting of 21 ml of ethanol and 9 ml of water were dissolved 3.10 g of 4-(4-isopropylphenoxy)-1-cyclohexanone, 2.35 g of L-cysteine hydrochloride monohydrate and 1.10 g of sodium acetate. The mixture was stirred at ambient temperature for 6 hours. The reaction mixture was concentrated under reduced pressure, and water and ethyl ether were added to the concentrate. The deposited crystal was collected by filtration, and there was obtained 2.45 g of (3R)-8-(4-isopropylphenoxy)-1-thia-4-azaspiro[4.5]decan-3-carboxylic acid as a colorless crystalline product.
Reaction SMILES: [F:1][C:2]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([S:14][CH3:15])[S:13][C:6]=12.C1C=C(Cl)C=C(C(OO)=[O:31])C=1.O>C(Cl)Cl>[F:1][C:2]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([S:14]([CH3:15])=[O:31])[S:13][C:6]=12
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Solvent: ClCCl
Solvent: O
Product: CS(=O)c1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98.8 %

Procedure:
To a solution of 230 (400 mg, 1.189 mmol, scheme 50) in DCM (12 mL) at 0° C. was added m-CPBA (77%, 272 mg, 1.189 mmol). The reaction mixture was stirred at 0° C. for 30 minutes, water was added and the phases were separated. The organic phase was collected, washed with a 1% sodium hydroxide solution, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography, eluent DCM/MeOH (20:1), to afford title compound 233 (414 mg, 90% yield, crude), which was used in the next step without further purification. MS (m/z): 353.0 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].[Br-:11].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>ClCCl.CO>[Br:11][C:6]1[CH:5]=[C:4]([CH3:9])[C:3]([OH:10])=[C:2]([CH3:1])[C:7]=1[CH3:8]
Reactant: [Br-]
Reactant: Cc1ccc(C)c(O)c1C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(Br)c(C)c(C)c1O
Reaction time: 5 h

Procedure:
10 g (71 mmol) of 2,3,6-trimethylphenol are initially introduced in a solvent mixture consisting of 250 ml of dichloromethane and 190 ml of methanol, and 35.4 g (72 mmol) of tetrabutylammonium tribromide in 170 ml of dichloromethane and 130 ml of methanol are added. After 5 h at room temperature, the batch is evaporated in a rotary evaporator, and the residue remaining is taken up in MTB. The organic solution is washed three times with water, dried over sodium sulfate and evaporated in a rotary evaporator. The crystalline residue obtained is employed in the next step without further work-up.
Reaction SMILES: [CH:1]([NH:4][CH:5]([CH3:11])[CH2:6][O:7][CH:8]([OH:10])[CH3:9])([CH3:3])[CH3:2].[CH2:12]=O>[Pd].CO>[CH:1]([N:4]([CH:5]([CH3:11])[CH2:6][O:7][CH:8]([OH:10])[CH3:9])[CH3:12])([CH3:3])[CH3:2]
Reactant: CC(C)NC(C)COC(C)O
Reactant: C=O
Agent: [Pd]
Solvent: CO
Product: CC(O)OCC(C)N(C)C(C)C
Temperature: 80 °C
Yield: 94.4 %

Procedure:
A total of 155 g of 2-(isopropylamino) propoxyethanol, 122 g of 37% aqueous formaldehyde, 5 g of 10% Pd/C and 1 l of methanol were charged to an autoclave, pressured to 1000 psi with H2 and heated at 80° C. for 3 hours. Filtration and distillation of the reaction mixture yielded 159 g of 2-(N-isopropyl-N-methylamino)propoxyethanol with b.p. of 125° C. at 20 mm.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:21])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]=2[O:19][CH3:20])=[N:7][CH:8]=1.Cl[C:24]1[C:33]2[C:28](=[CH:29][C:30]([O:36][CH3:37])=[C:31]([O:34][CH3:35])[CH:32]=2)[N:27]=[CH:26][N:25]=1.C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[CH3:22][N:2]([CH3:1])[C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:21])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][C:24]3[C:33]4[C:28](=[CH:29][C:30]([O:36][CH3:37])=[C:31]([O:34][CH3:35])[CH:32]=4)[N:27]=[CH:26][N:25]=3)=[CH:14][C:13]=2[O:19][CH3:20])=[N:7][CH:8]=1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: COc1cc(O)ccc1CC(=O)Nc1ccc(N(C)C)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1cc(Oc2ncnc3cc(OC)c(OC)cc23)ccc1CC(=O)Nc1ccc(N(C)C)cn1
Temperature: 140 °C
Yield: 83.8 %

Procedure:
A mixture of N-(5-dimethylaminopyridin-2-yl)-2-(4-hydroxy-2-methoxyphenyl) acetamide (0.111 g), 4-chloro-6,7-dimethoxyquinazoline (0.075 g), potassium carbonate (0.2 g) and DMA (2 ml) was stirred and heated to 140° C. in a microwave oven for 20 minutes. The reaction mixture was purified by preparative HPLC using a Waters ‘β Basic Hypersil’ reversed-phase column (5 microns silica, 30 mm diameter, 250 mm length) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. There was thus obtained the title compound (0.137 g); 1H NMR: (CDCl3) 2.92 (s, 6H), 3.75 (s, 2H), 3.91 (s, 3H), 4.07 (s, 3H), 4.08 (s, 3H), 6.86 (s, 1H), 6.88 (m, 1H), 7.10 (m, 1H), 7.33 (s, 1H), 7.41 (d, 1H), 7.55 (s, 1H), 7.73 (d, 1H), 8.09 (d, 1H), 8.16 (br s, 1H), 8.64 (s, 1H); Mass Spectrum: M+H+ 490.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[OH-].[Na+].Cl[CH2:12][CH2:13][C:14]([OH:16])=[O:15]>O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:4][CH:3]=1
Reactant: O=C(O)CCCl
Reactant: Cc1ccc(S)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(SCCC(=O)O)cc1

Procedure:
With caution 210 g (1.5 moles) of 4-methylthio-phenol and 120 g (3.0 moles) of sodium hydroxide in 200 ml of water was slowly added to 163 g (1.51 mole) of 3-chloropropionic acid. The mixture was heated to reflux for 20 hours. After reflux the unreacted 4-methylthiophenol was removed by distillation and the hot reaction mixture poured with stirring onto ice and concentrated hydrochloric acid. The slurry was filtered and collected on a buchner funnel. The wet mass was added to a solution of 300 ml of 1% sodium hydroxide solution and 300 ml of ethyl acetate. The resulting mixture was poured into a one liter separatory funnel, and after extraction with 1% sodium hydroxide, the aqueous layer was drawn off. The organic layer was extracted a second and third time with 1% sodium hydroxide. The extracts were added to a two liter separatory funnel, acidified with concentrated hydrochloric acid after the ethyl acetate was layered on. The organic extract was collected and dried over anhydrous Na2SO4, and two heaping teaspoons of activated charcoal were added to the yellow solution. Filtering removed insolubles and the resulting light yellow solution was reduced to a white sticky solid using a rotary evaporator at 65° C. and reduced pressure. Recrystallization from hot benzene yields white needles of 3-(4-methylthiophenoxy)-propionic acid with a melting point of 129°-131° C. (uncorrected).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[C:11]([N:30]1[CH:34]=[C:33]([CH2:35][CH2:36][C:37](OC)=[O:38])[N:32]=[CH:31]1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C)C=CC=CC=1.C(Cl)Cl>[C:11]([N:30]1[CH:34]=[C:33]([CH2:35][CH2:36][CH:37]=[O:38])[N:32]=[CH:31]1)([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)CCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=CCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Yield: 50.8 %

Procedure:
A solution of 44.4 mmole of diisobutylaluminium hydride in 29 ml of toluene is added to a solution of 8.79 g of methyl 3-(1-tritylimidazol-4-yl)propionate in 175 ml of methylene chloride at -72° under nitrogen. After 5 min the reaction is quenched by adding 14 ml of methanol followed by 90 ml of water. The reaction mixture is allowed to warm to room temperature and is filtered through celite. The organic phase is separated, dried over sodium sulfate and evaporated to a yellow oil which is chromatographed on 280 g of silica with ether to yield 4.13 g of 3-(1-tritylimidazol-4-yl)propionaldehyde as an oil. IR (CDCl3): 2830, 2740, 1730 cm-1.
Reaction SMILES: [NH2:1][NH2:2].[CH2:3]([NH:10][C:11](=[O:19])[C:12]1[CH:17]=[CH:16][C:15](Cl)=[N:14][CH:13]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(O)C>[CH2:3]([NH:10][C:11](=[O:19])[C:12]1[CH:17]=[CH:16][C:15]([NH:1][NH2:2])=[N:14][CH:13]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(NCc1ccccc1)c1ccc(Cl)nc1
Reactant: NN
Solvent: CCO
Product: NNc1ccc(C(=O)NCc2ccccc2)cn1
Yield: 61.4 %

Procedure:
Combined hydrazine (1.67 mL, 53.3 mmol) and a solution of N-benzyl-6-chloronicotinamide (2.19 g, 8.88 mmol) in ethanol (70 mL) and heated overnight at 100° C. The reaction mixture was then cooled and evaporated to give a solid. The solid was collected by filtration, washed with 70 mL water, and recrystallized from hot ethanol to give the title compound (1.32 g, 61%) as an off-white solid. MS m/z [M+H]+ 243.2.
Reaction SMILES: [F:1][C:2](F)(F)[CH2:3][O:4][C:5]1[N:10]=[CH:9][C:8]([CH:11]([NH2:13])[CH3:12])=[CH:7][CH:6]=1.ClC1C=CC(C#N)=CN=1.FC(F)CO>>[F:1][CH2:2][CH2:3][O:4][C:5]1[N:10]=[CH:9][C:8]([CH:11]([NH2:13])[CH3:12])=[CH:7][CH:6]=1
Reactant: CC(N)c1ccc(OCC(F)(F)F)nc1
Agent: N#Cc1ccc(Cl)nc1
Agent: OCC(F)F
Product: CC(N)c1ccc(OCCF)nc1

Procedure:
The title compound was synthesised according to the 2-step procedure described for the synthesis of 1-[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]ethanamine starting from 6-chloronicotinonitrile and 2,2-difluoroethanol.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C@@H:8]1[NH2:13])=[O:6])[CH3:3].S([O-])([O-])(=O)=O.[Mg+2].C(N(CC)CC)C.[F:27][C:28]1[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=1.[BH4-].[Na+].C(=O)(O)[O-].[Na+]>O1CCCC1>[CH2:2]([O:4][C:5]([CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]1[NH:13][CH2:32][C:31]1[CH:34]=[CH:35][C:28]([F:27])=[CH:29][CH:30]=1)=[O:6])[CH3:3]
Reactant: CCOC(=O)[C@@H]1CCCC[C@@H]1N
Reactant: O=Cc1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCCCC1NCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of cis-2-amino-cyclohexanecarboxylic acid ethyl ester hydrochloride (2.80 g, 12.81 mmol) in tetrahydrofuran (100 mL) at 25° C. was added magnesium sulfate (4.0 g), triethylamine (1.36 g, 13.48 mmol), and 4-fluorobenzaldehyde (3.26 g, 26.29 mmol) sequentially. The reaction was stirred at 25° C. for 16 h. The mixture was passed through a short pad of Celite and the filtrate was concentrated and dried in vacuo. The residue was re-dissolved in methanol (100 mL) at 25° C. To this solution was slowly added sodium borohydride (1.0 g, 26.29 mmol). The mixture was stirred at 25° C. for 1 h. It was then poured into a 1/2 saturated aqueous sodium bicarbonate solution and the mixture was extracted into ethyl acetate (3×100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford a clear oil. Purification by flash column chromatography (Teledyne Isco RediSep Column; 0-50% ethyl acetate in hexanes) afforded the desired product, 2-(4-fluoro-benzylamino)-cyclohexanecarboxylic acid ethyl ester (4.47 g, 16.0 mmol, >100%, product still contains ethyl acetate), as a clear oil which was directly used in the next step. LC-MS (ESI) calcd for C16H22FNO2 279.16, found 280.0 [M+H+].
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10](=[O:38])[C@H:11]([NH:27][C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])[CH2:12][C:13]1[CH:18]=[C:17]([Cl:19])[C:16]([NH2:20])=[C:15]([CH3:21])[C:14]=1[CH2:22][O:23][C:24](=[O:26])[CH3:25].[N:39](OCCC(C)C)=O.C([O-])(=O)C.[K+]>C(O)(=O)C.C(Cl)(Cl)Cl.ClCCl>[CH3:8][O:9][C:10](=[O:38])[C@H:11]([NH:27][C:28]([O:30][CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)=[O:29])[CH2:12][C:13]1[C:14]([CH2:22][O:23][C:24](=[O:26])[CH3:25])=[C:15]2[C:16](=[C:17]([Cl:19])[CH:18]=1)[NH:20][N:39]=[CH:21]2
Reactant: CC(C)CCON=O
Reactant: COC(=O)[C@@H](Cc1cc(Cl)c(N)c(C)c1COC(C)=O)NC(=O)OCc1ccccc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H](Cc1cc(Cl)c2[nH]ncc2c1COC(C)=O)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 83 %

Procedure:
Trifluoroacetic acid (70 μL, 0.91 mmol) was added to a solution of 3-(2-acetoxymethyl-4-amino-5-chloro-3-methyl-phenyl)-2-(R)-benzyloxycarbonylamino-propionic acid methyl ester (345 mg, 0.77 mmol) in 5% acetic acid in chloroform (5.2 mL). Isoamyl nitrite (120 μL, 0.89 mmol) was added to the mixture drop-wise. Reaction mixture was stirred at room temperature for 40 minutes. Potassium acetate (300 mg, 3.1 mmol) was added to the mixture. Reaction mixture was stirred at room temperature for 45 minutes. Mixture was diluted with dichloromethane (10 mL) then washed successively with water (2×10 mL), and saturated aqueous sodium bicarbonate (2×10 mL). Organic was dried (magnesium sulfate), filtered and concentrated in vacuo. Crude product was obtained as an orange solid in 83% yield. Material was carried forward without further purification. 1H NMR (300 MHz, CDCl3): δ=8.20 (s, 1H); 7.29 (m, 5H); 7.21 (s, 1H); 5.53 (d, J=7.7, 1H); 5.40 (s, 2H); 5.04 (s, 2H); 4.67 (m, 1H); 3.74 (s, 3H); 3.34 (m, 1H); 3.21 (m, 1H); 2.02 (s, 3H). MS m/e (M+H)+=460.1.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[N:10]2[CH:11]=[CH:12][C:13]([C:15]([F:18])([F:17])[F:16])=[N:14][C:9]2=[N:8][CH:7]=1)CCC.Br[C:28]1[N:33]=[C:32]([C:34]2[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:35]=2[C:36]#[N:37])[CH:31]=[CH:30][CH:29]=1>>[F:42][C:40]1[CH:39]=[CH:38][C:35]([C:36]#[N:37])=[C:34]([C:32]2[CH:31]=[CH:30][CH:29]=[C:28]([C:6]3[N:10]4[CH:11]=[CH:12][C:13]([C:15]([F:16])([F:17])[F:18])=[N:14][C:9]4=[N:8][CH:7]=3)[N:33]=2)[CH:41]=1
Reactant: N#Cc1ccc(F)cc1-c1cccc(Br)n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2nc(C(F)(F)F)ccn12
Product: N#Cc1ccc(F)cc1-c1cccc(-c2cnc3nc(C(F)(F)F)ccn23)n1
Yield: 14 %

Procedure:
3-Tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine was coupled with 2-(6-bromopyridin-2-yl)-4-fluorobenzonitrile as in Example 1 to give 4-fluoro-2-[6-(7-trifluoromethylimidazo[1,2-α]pyrimidin-3-yl)pyridin-2-yl]benzonitrile as a pale pink solid (16 mg, 14%): δH (400 MHz, CDCl3) 7.29-7.32 (1H, m), 7.40 (1H, d, J 7), 7.53 (1H, dd, J 9 and 2), 7.66 (1H, dd, J 8 and 1), 7.88-8.03 (3H, m), 8.59 (1H, s), 10.56 (1H, d, J 7).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[CH:12]=[C:13]([S:17](Cl)(=[O:19])=[O:18])[S:14][C:15]=2[Br:16])=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[NH2:28][C:29]1[NH:33][N:32]=[N:31][N:30]=1>C(Cl)Cl>[Br:16][C:15]1[S:14][C:13]([S:17](=[O:19])(=[O:18])[NH:28][C:29]2[NH:33][N:32]=[N:31][N:30]=2)=[CH:12][C:11]=1[C:7]1[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=1[CH3:10]
Reactant: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)Cl)sc2Br)s1
Reactant: Nc1nnn[nH]1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)Nc3nnn[nH]3)sc2Br)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
4-[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]-5-bromothiophene-2-sulfonyl chloride, prepared as in Step III of Example 23 (500 mg; 1.2 mmol; 1 eq), is dissolved in anhydrous DCM (30 ml). The reaction is put under nitrogen. Triethylamine (0.34 ml; 2.41 mmol; 2 eq) and 5-amino-1H-tetrazole (204.6 mg; 2.41 mmol; 2 eq) are added successively and the reaction mixture is stirred overnight at room temperature. It is then washed with water, NH4Cl sat., brine and dried over MgSO4, affording the title compound (550 mg; 64%).