Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:14][CH:15]1[C:30](=[O:31])[N:17]2[C:18]([C:27]([OH:29])=[O:28])=[C:19]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[CH2:20][S:21][C@H:16]12.C[Si](C)(C)Cl.C[C:38](OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=[O:39].CN(C)C>C1COCC1.O.C(N(CC)CC)C>[C:24]([O:23][CH2:22][C:19]1[CH2:20][S:21][C@@H:16]2[CH:15]([NH:14][CH:38]=[O:39])[C:30](=[O:31])[N:17]2[C:18]=1[C:27]([OH:29])=[O:28])(=[O:26])[CH3:25]
Reactant: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Agent: CN(C)C
Agent: C[Si](C)(C)Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC=O)[C@H]2SC1
Reaction time: 2.5 h

Procedure:
To a stirred suspension of 7-amino-3-acetoxymethylceph-3-em-4-carboxylic acid toluene-p-sulphonate dihydrate (19.2 g., 40 mmole) in anhydrous THF (500 ml.) under nitrogen in a 1 liter flask was added triethylamine (dried over potassium, 27.76 ml., 200 mmole) then trimethylchlorosilane (20.18 ml., 17.36 g., 160 mmole) while maintaining the temperature at 20° with a cooling bath. After 30 minutes a further 10% of triethylamine and 10% of trimethylchlorosilane were added and the reaction mixture was allowed to stir for a further 2.5 hours. To the mixture was then added acetic formic mixed anhydride (7.04 g., 80 mmole) with cooling in an ice bath. A further 10% trimethylamine, 10% trimethylchlorosilane and 20% acetic formic mixed anhydride, and then yet a further 10% of all three reagents were added to achieve complete disappearance of starting material on t.l.c. Water was then added, the suspension was filtered on a sintered glass disc and the solid dried to give 3-acetoxymethyl-7-formylaminoceph-3-em-4-carboxylic acid.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([CH:14]=[CH:15][CH2:16][CH:17]3[O:22][CH2:21][CH2:20][CH2:19][O:18]3)[CH:5]=[CH:4][C:3]1=2.Br[C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1.P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:31][C:28]1[CH:29]=[CH:30][C:25](/[C:15](=[CH:14]/[C:6]2[CH:5]=[CH:4][C:3]3[C:2]([CH3:23])([CH3:1])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]=3[CH:7]=2)/[CH2:16][CH:17]2[O:18][CH2:19][CH2:20][CH2:21][O:22]2)=[CH:26][CH:27]=1
Reactant: Cc1ccc(Br)cc1
Reactant: CC1(C)CCC(C)(C)c2cc(C=CCC3OCCCO3)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1ccc(/C(=C/c2ccc3c(c2)C(C)(C)CCC3(C)C)CC2OCCCO2)cc1

Procedure:
1.5 g (5 mmoles) of 2-[3-(5,6,7,8-tetrahydro-5,5, 8,8-tetramethyl-2-naphthyl)-allyl]-1,3-dioxane, 850 mg (5 mmoles) of 4-bromotoluene, 25 mg (0.1 mmole) of Pd (OAc)2, 55 mg (0.2 mmole) of P(C6H5)3 and 1.4 g (10 mmoles) of potassium carbonate are heated at 180° C. for 2 hours under passage of nitrogen.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]([NH:13][NH2:14])=[O:12])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:15]1([C:18](O)=O)[CH2:17][CH2:16]1>P(Cl)(Cl)(Cl)=O>[C:1]1([S:7]([CH2:10][C:11]2[O:12][C:18]([CH:15]3[CH2:17][CH2:16]3)=[N:14][N:13]=2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)C1CC1
Reactant: NNC(=O)CS(=O)(=O)c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: O=S(=O)(Cc1nnc(C2CC2)o1)c1ccccc1
Yield: 40.3 %

Procedure:
To 3.0 g (14.0 mmol) of benzenesulfonyl-acetic acid hydrazide in 30 mL of phosphorus oxychloride, 1.47 g (17.0 mmol, 1.2 eq) of cyclopropanecarboxylic acid were added, and heated at reflux for 2 hours. The reaction mixture was very carefully poured onto ice, extracted with EtOAc, filtered and evaporated. Column chromatography on silica gel with EtOAc/heptane 2:1 yielded 1.49g (41%) of 2-benzenesulfonylmethyl-5-cyclopropyl-[1,3,4]oxadiazole as a white solid, MS: 265 (MH+).
Reaction SMILES: Br[C:2]1[CH:27]=[CH:26][C:5]([CH2:6][O:7][CH2:8][C@@H:9]2[CH2:11][C@@H:10]2[CH:12]2[CH2:17][CH2:16][N:15]([C:18]3[N:23]=[CH:22][C:21]([CH2:24][CH3:25])=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[CH2:28]1[O:31][C@H:29]1[CH3:30]>>[CH2:24]([C:21]1[CH:20]=[N:19][C:18]([N:15]2[CH2:16][CH2:17][CH:12]([C@H:10]3[CH2:11][C@H:9]3[CH2:8][O:7][CH2:6][C:5]3[CH:26]=[CH:27][C:2]([CH2:28][C@@H:29]([OH:31])[CH3:30])=[CH:3][CH:4]=3)[CH2:13][CH2:14]2)=[N:23][CH:22]=1)[CH3:25]
Reactant: C[C@H]1CO1
Reactant: CCc1cnc(N2CCC([C@H]3C[C@H]3COCc3ccc(Br)cc3)CC2)nc1
Product: CCc1cnc(N2CCC([C@H]3C[C@H]3COCc3ccc(C[C@H](C)O)cc3)CC2)nc1

Procedure:
This compound was prepared from the product of example 54 (step A), and (S)-propylene oxide according to the procedure from example 58. MS (ESI) m/z 410 [M+H]+. GPR119 Human EC50: 1.6 nM
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=[N:33][C:28]2[CH:29]=CC=N[C:27]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.C(N)(C)C>C(#N)C>[CH2:1]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([NH:33][CH:28]([CH3:29])[CH3:27])=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1cccc(NCc2ccccc2)c1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)N
Solvent: CC#N
Product: CC(C)NC(=O)c1cccc(NCc2ccccc2)c1
Yield: 60.1 %

Procedure:
A solution of 3-benzylamino-benzoic acid (500 mg, 1.5 mmol), HATU (832 mg, 2 mmol), diisopropylethylamine (0.38 ml, 2 mmol) and isopropylamine (0.19 ml, 2 mmol) in acetonitrile was heated to 50° C. for 16 hrs. On cooling, solvents were removed in vacuo and the residue partitioned between dichloromethane and water (50 ml/50 ml). The organic layer was separated, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/dichloromethane 0% to 50% v/v) to afford the title compound as a white solid (242 mg). HPLC retention time 2.69 min. Mass spectrum (ES+) m/z 269.9 (M+H).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][C:15]1[CH:16]=[N:17][C:18]([Cl:23])=[C:19]([F:22])[C:20]=1[I:21])(C)(C)C>ClCCl>[Cl:23][C:18]1[N:17]=[CH:16][C:15]([NH2:14])=[C:20]([I:21])[C:19]=1[F:22]
Reactant: CC(C)(C)OC(=O)Nc1cnc(Cl)c(F)c1I
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1cnc(Cl)c(F)c1I
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98.4 %

Procedure:
Trifluoroacetic acid (50 mL) was added to a solution of (6-chloro-5-fluoro-4-iodo-pyridin-3-yl)-carbamic acid tert-butyl ester (31 g, 83.2 mmol) in dichloromethane (150 mL) and the resultant reaction mixture was stirred at ambient temperature for 90 minutes. The solvent was evaporated and the resultant residue was treated with ice/water (200 mL), layered with diethyl ether (300 mL) and the pH of the aqueous phase was adjusted to 10 by the addition of solid potassium carbonate solution. The organic phase was separated, dried (Na2SO4), filtered and concentrated in-vacuo to afford a residue. The resultant residue was triturated with pentane:diethyl ether (9:1) to afford the title compound as a cream coloured solid (22.3 g, 98%). 1H NMR (400 MHz, CDCl3): 7.63 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](O)[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[N:3]=1.P(Cl)(Cl)([Cl:17])=O.CN(C)C1C=CC=CC=1>>[Cl:17][C:6]1[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[N:3]=[C:2]([NH2:1])[N:7]=1
Reactant: Nc1nc(O)cc(-c2ccncc2)n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: Nc1nc(Cl)cc(-c2ccncc2)n1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
32 g (170.04 mmol) of the compound (from example XXVIII) are dissolved in 87.1 ml (0.93 mmol) of phosphoryl chloride. 2.80 ml (22.11 mmol) of N,N-dimethylaniline are slowly added dropwise, and the mixture is stirred at 100° C. for one hour. The reaction solution is then stirred at room temperature for another two hours. The phosphoryl chloride is removed under reduced pressure using a rotary evaporator. Water/dichloromethane 9:1 is added to the residue, which is then boiled for 5 minutes. The mixture is then neutralized using saturated sodium bicarbonate solution and the product is filtered off with suction and dried under high vacuum.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].[F:7][C:8]([F:19])([F:18])[C:9]([C:14]([F:17])([F:16])[F:15])([OH:13])[CH2:10]C=C>ClCCl>[F:7][C:8]([F:18])([F:19])[C:9]([OH:13])([C:14]([F:16])([F:15])[F:17])[CH2:10]/[CH:3]=[CH:2]/[C:1]([O:5][CH3:6])=[O:4]
Reactant: C=CC(=O)OC
Reactant: C=CCC(O)(C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)/C=C/CC(O)(C(F)(F)F)C(F)(F)F
Yield: 65.3 %

Procedure:
To a 250 mL 3 neck roundbottom flask with reflux condenser and Teflon-coated magnetic stir bar was added methyl acrylate (9.10 g, 105.7 mmol, 1.1 eq.), 1,1,1-trifluoro-2-trifluoromethyl-pent-4-ene-2-ol (20 g, 96.1 mmol, 1 eq.) and 100 mL of anhydrous dichloromethane. The solution was heated to reflux under nitrogen and 300 mg of the Hoveyda-Grubbs 2nd generation ruthenium metathesis catalyst (0.048 mmol, 0.005 eq.) was added in 4 portions over 4 hours. The reaction was heated an additional 12 hours after which the product was purified by vacuum distillation (65° C., 6 Torr) and column chromatography (silica gel, 80:20 hexane:ethyl acetate eluent) to afford 16.7 g of methyl 6,6,6-trifluoro-5-hydroxy-5-(trifluoromethyl)hex-2-enoate (I) as colorless liquid (E/Z=2.15:1) contaminated with a small amount (0.15 eq.) of 1,1,1,8,8,8-hexafluoro-2,7-di(trifluoromethyl)-oct-4-ene-2,7-diol (E/Z=6.7:1).
Reaction SMILES: [OH:1][C@@H:2]1[O:10][C@@H:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@@H:5]([OH:6])[C@@H:3]1[OH:4].[CH3:13]O>>[O:1]([CH3:13])[CH:2]1[O:10][C@@H:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@@H:5]([OH:6])[C@@H:3]1[OH:4]
Reactant: CO
Reactant: OC[C@@H]1O[C@@H](O)[C@@H](O)[C@H](O)[C@H]1O
Product: COC1O[C@@H](CO)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C

Procedure:
A mixture of α-L-glucopyranose (5.4 g.), methanol (30 ml.) and cation-exchange resin [(2 g., Dowex® 50W-X8 (H+), 50-100 mesh, previously prepared by treatment with methanol] was stirred magnetically at reflux temperature for 24 hours in a 50-ml. round-bottomed flask. The solution, which gave a negative test, was then cooled and filtered. The resin was washed several times with methanol and the filtrate and washings were evaporated at reduced pressure to a syrup (5.63 g., 96%) containing no L-glucose (paper chromatography, n-butanol/ethanol water v/v 40:11:19). A sample (1.0 g.) was dissolved in boiling methanol (2 ml.) and the mixture was allowed to slowly cool to room temperature to give crystalline methyl L-glucopyranoside. The crystals were suspended in enough ethanol to make a 10% (w/v) mixture, and this mixture was boiled to effect dissolution. On cooling of the mixture pure methyl α-L-glucopyranoside was obtained, m.p. 166.5°-168°, [α]D -156° (c 2.5, water). These values compare favourably with those for methyl α-D-glucopyranoside, m.p. 167°-169°, [α]D +157° (c 2, water).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C(=O)=O.[CH2:14]([P:23](=[O:30])([O:27][CH2:28][CH3:29])[O:24][CH2:25][CH3:26])P(=O)(OCC)OCC.[CH:31]([C:33]1[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][CH:34]=1)=O>O1CCCC1.C(OCC)(=O)C>[CH3:40][O:39][C:37]([C:36]1[CH:41]=[CH:42][C:33](/[CH:31]=[CH:14]/[P:23](=[O:30])([O:24][CH2:25][CH3:26])[O:27][CH2:28][CH3:29])=[CH:34][CH:35]=1)=[O:38]
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C=O
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOP(=O)(/C=C/c1ccc(C(=O)OC)cc1)OCC
Reaction time: 0.5 h
Yield: 86.1 %

Procedure:
A 1.0 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (17 ml) is diluted with anhydrous tetrahydrofuran (81 ml) under a nitrogen atmosphere and dry ice cooling, and then a solution of tetraethyl methylenebis(phosphonate) (4.6 g) in anhydrous tetrahydrofuran (8 ml) is added dropwise thereto. The mixture is stirred under dry ice cooling for 30 minutes, and then a solution of methyl 4-formylbenzoate (2.64 g) in anhydrous tetrahydrofuran (12 ml) is added dropwise thereto. The mixture is stirred under dry ice cooling for 1.5 hours and further under ice cooling for 2.5 hours. Ethyl acetate is added to the reaction mixture. The organic layer is washed with water and saturated brine successively, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting precipitate is filtered off to give 4.1 g (86%) of diethyl (E)-2-[4-(methoxycarbonyl)phenyl]vinylphosphonate as crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9](=[CH:14][N:15]([CH3:17])[CH3:16])[N:8]=[C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:6]=2[CH:25]=1.O1CCCC1.CCOCC.N(C[C:39]([N:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1)=[O:40])C>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9](=[CH:14][N:15]([CH3:16])[CH2:17][C:39]([N:41]3[CH2:46][CH2:45][O:44][CH2:43][CH2:42]3)=[O:40])[N:8]=[C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:6]=2[CH:25]=1
Reactant: CNCC(=O)N1CCOCC1
Reactant: CN(C)C=C1N=C(c2ccccc2Cl)c2cc(Br)ccc2N(C)C1=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CN(C=C1N=C(c2ccccc2Cl)c2cc(Br)ccc2N(C)C1=O)CC(=O)N1CCOCC1
Temperature: 160 °C

Procedure:
A suspension of 8.4 gm of 7-bromo-5-(2'-chlorophenyl)-1,3-dihydro-3-(dimethylamino-methylene)-1-methyl-2H-1,4-benzodiazepin-2-one in 45 gm of sarcosine morpholide was heated to 160°C, while stirring, whereby a clear solution was formed after some time, which was stirred for 90 minutes more at 160°C. Thereafter, the reaction mixture was allowed to cool and was then taken up in a mixture consisting of 150 ml each of tetrahydrofuran and ether. The resulting solution was washed three times with 100 ml of water each, and the organic phase was dried over magnesium sulfate and evaporated in vacuo. The residue was purified on a silicagel column, using a 19:1-mixture of chloroform and methanol as the flow agent. Those fractions containing the desired compound were combined, the solvent mixture was distilled off in vacuo, and the residue was recrystallized from tetrahydrofuran, yielding the compound of the formula ##SPC8##
Reaction SMILES: [C:1]1([C:6]2[CH:18]=[CH:17][C:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH:2]=1>CO.[Pd]>[CH:1]1([C:6]2[CH:7]=[CH:8][C:9]([C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])=[CH:17][CH:18]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(C)OC(=O)c1ccc(C2=CCCC2)cc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)c1ccc(C2CCCC2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 86.6 %

Procedure:
To a solution of tert-butyl 4-cyclopentenylbenzoate (400 mg, 1.64 mmol) in methanol (20 mL) was added palladium on carbon (10%, 100 mg). The mixture was stirred for 24 hours at room temperature under hydrogen atmosphere. The mixture was filtered and concentrated in vacuo to give tert-butyl 4-cyclopentylbenzoate (350 mg, 86%) as a white solid. LRMS (M+H+) m/z: calcd 246.16. found 246
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]2[N:11]([C:15]([CH2:19][C:20]([NH2:22])=O)=[C:16]([CH3:18])[N:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>O1CCOCC1>[CH2:1]([O:8][C:9]1[C:10]2[N:11]([C:15]([CH2:19][C:20]#[N:22])=[C:16]([CH3:18])[N:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc2c(OCc3ccccc3)cccn2c1CC(N)=O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1COCCO1
Product: Cc1nc2c(OCc3ccccc3)cccn2c1CC#N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of 8-benzyloxy-2-methyl-imidazo[1,2-a]pyridine-3-acetamide (3 g) in dioxane was cooled to 5°-10° C. To the suspension there was added over a period of 5 minutes a solution of trifluoroacetic anhydride (6 g) in dioxane. The mixture was maintained cool and stirred for 30 minutes. Thereafter the mixture was allowed to warm to room temperature and was stirred for a further four hours. The mixture was thendiluted with ice water and the precipitate was filtered. After recrystallization from ethylacetate the desired compound was obtained (m.p. 163°-166° C.).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:12])[CH3:11])=[C:5]([O:13][C:14]([F:17])([F:16])[F:15])[CH:4]=1)#[N:2].Cl.[NH2:19][OH:20].C([O-])(=O)C.[Na+]>C(O)(C)C>[OH:20][NH:19][C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:12])[CH3:11])=[C:5]([O:13][C:14]([F:15])([F:17])[F:16])[CH:4]=1)=[NH:2]
Reactant: NO
Reactant: CC(=O)Nc1ccc(C#N)cc1OC(F)(F)F
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(C)O
Product: CC(=O)Nc1ccc(C(=N)NO)cc1OC(F)(F)F

Procedure:
The mixture consisting of 610 mg of N-(4-cyano-2-trifluoromethoxyphenyl)-acetamide, 15 ml of isopropanol, 255 mg of hydroxylamine hydrochloride and 410 mg of sodium acetate was heated to reflux for 5 hours. After cooling, the insoluble fraction was filtered off, and the filtrate is concentrated and taken up in a little isopropanol, the product was precipitated, filtered off with suction and dried by adding water until the first cloudiness and subsequent stirring.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([F:8])[C:5]([Cl:9])=[C:4](F)[N:3]=1.[CH3:11][CH:12]1[CH2:17][CH:16]([CH3:18])[CH2:15][NH:14][CH2:13]1>O1CCCC1>[Cl:9][C:5]1[C:6]([F:8])=[N:7][C:2]([F:1])=[N:3][C:4]=1[N:14]1[CH2:15][CH:16]([CH3:18])[CH2:17][CH:12]([CH3:11])[CH2:13]1
Reactant: Fc1nc(F)c(Cl)c(F)n1
Reactant: CC1CNCC(C)C1
Solvent: C1CCOC1
Product: CC1CC(C)CN(c2nc(F)nc(F)c2Cl)C1

Procedure:
Into 6 ml of tetrahydrofuran solution of 0.5 g of 2,4,6-trifluoro-5-chloropyrimidine was added dropwise 0.34 g or 3,5-dimethylpiperidine (cis/trans diastereomer=about 4/1) at room temperature, and the mixture was stirred for one-and-half hour at same temperature. The reaction mixture was subjected to silica gel column chromatography to obtain 0.56 g of 5-chloro-2,4-difluoro-6-(3,5-dimethylpiperidino)pyrimidine. This compound had the cis/trans diastereomer originated two ethyls on the pyperidine ring. The ratio of the cis/trans diastereomer was about 5/1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([CH:13]3OCC[O:14]3)[N:10]=[C:9]2[CH3:18])=[CH:4][CH:3]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[C:11]([CH:13]=[O:14])[N:10]=[C:9]2[CH3:18])=[CH:6][CH:7]=1
Reactant: Cc1nc(C2OCCO2)cn1-c1ccc(Cl)cc1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(C=O)cn1-c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 68.5 %

Procedure:
A solution of 1-(4-chlorophenyl)-4-(1,3-dioxolan-2-yl)-2-methyl-1H-imidazole (1.05 g, 3.97 mmol) and camphorsulfonic acid (92 mg, 0.40 mmol, 0.1 equiv) in THF (26.5 mL) and water (13.3 mL) was heated at 60° C. for 1 hour. The reaction was then cooled to room temperature and quenched with saturated aqueous sodium bicarbonate (100 mL). The mixture was extracted with ethyl acetate (100 mL) and the organic layer was washed with saturated aqueous sodium chloride (50 mL), dried (Na2SO4), filtered, and concentrated in vacuo. Silica gel column chromatography (EtOAc with 7% methanol) provided 1-(4-chlorophenyl)-2-methyl-1H-imidazole-4-carbaldehyde (0.600 g, tan solid) in 69% yield. 1H NMR (400 MHz, CDCl3) δ 9.89 (s, 1H), 7.67 (s, 1H), 7.53 (d, J=8.7 Hz, 2H), 7.27 (d, J=8.7 Hz, 2H), 2.40 (s, 3H). MS m/z 221.0 (M+H)+; Rt-0.47 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[S:9]([C@H:12]1[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:14]([C:24]([O:26][CH3:27])=[O:25])[CH2:13]1)(=[O:11])=[O:10].[F:28][C:29]([F:33])([F:32])[CH2:30][OH:31].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:31][CH2:30][C:29]([F:33])([F:32])[F:28])[CH:5]=[CH:4][C:3]=1[S:9]([C@H:12]1[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[C@H:14]([C:24]([O:26][CH3:27])=[O:25])[CH2:13]1)(=[O:11])=[O:10]
Reactant: OCC(F)(F)F
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(F)cc2Cl)CN1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(OCC(F)(F)F)cc2Cl)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 53.2 %

Procedure:
Under an atmosphere of argon, (2S,4R)-1-tert-butyl 2-methyl 4-(2-chloro-4-fluorophenylsulfonyl)pyrrolidine-1,2-dicarboxylate ([prepared in analogy to General Procedure C, steps C1-C3, using 2-chloro-4-fluorothiophenol in step C2] 1.5 g, 1.0 eq.) was combined with N,N-dimethylacetamide (15 ml) to give a light yellow solution. 2,2,2-Trifluoroethanol (854 mg, 617 μl, 8.53 mmol, Eq: 2.4) and cesium carbonate (2.09 g, 6.4 mmol, Eq: 1.8) were added. The reaction mixture was stirred over night at RT. The crude reaction mixture was concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 50 g, 0% to 50% ethyl acetate in heptane) to yield the title compound as a white foam (0.95 g, 53.2%, MS (m/e)=502.09 [M+H+]).
Reaction SMILES: [CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][C@@H:3]([CH2:14][NH:15][CH2:16][C@@H:17]2[O:31][C:21]3=[C:22]4[C:27](=[CH:28][CH:29]=[C:20]3[O:19][CH2:18]2)[N:26]=[C:25]([CH3:30])[CH:24]=[CH:23]4)[CH2:2]1.Cl>CCOCC>[CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][C@H:3]([CH2:14][NH:15][CH2:16][C@@H:17]2[O:31][C:21]3=[C:22]4[C:27](=[CH:28][CH:29]=[C:20]3[O:19][CH2:18]2)[N:26]=[C:25]([CH3:30])[CH:24]=[CH:23]4)[CH2:2]1
Reactant: Cc1ccc2c3c(ccc2n1)OC[C@H](CNC[C@H]1CCc2[nH]c4ccccc4c2C1)O3
Agent: Cl
Solvent: CCOCC
Product: Cc1ccc2c3c(ccc2n1)OC[C@H](CNC[C@@H]1CCc2[nH]c4ccccc4c2C1)O3

Procedure:
Diastereomer 2: 30 mg of the amine was isolated and converted into its di-hydrochloride salt by treating a methanolic solution of the amine with 145 μL of 1 N HCl in ether. The yellow solid was collected by vacuum filtration, washed with ethyl acetate and hexane, and dried under vacuum to afford N-{[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]methyl}-N-{[(2S)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl}amine as a yellow powder; mp 218-221 (d); MS (ES) m/z=414 [M+H]+.
Reaction SMILES: [O:1]=[S:2]1(=[O:25])[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:20]4[N:21]=[C:22]([NH2:24])[N:23]=[C:19]4[CH:18]=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.Br[C:27]1[CH:28]=[C:29]([N:33]2[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]2)[CH:30]=[CH:31][CH:32]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[O:25]=[S:2]1(=[O:1])[CH2:3][CH2:4][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:20]4[N:21]=[C:22]([NH:24][C:27]5[CH:32]=[CH:31][CH:30]=[C:29]([N:33]6[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]6)[CH:28]=5)[N:23]=[C:19]4[CH:18]=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:6][CH2:7]1
Reactant: CN1CCN(c2cccc(Br)c2)CC1
Reactant: Nc1nc2cccc(-c3ccc(CN4CCS(=O)(=O)CC4)cc3)n2n1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCN(c2cccc(Nc3nc4cccc(-c5ccc(CN6CCS(=O)(=O)CC6)cc5)n4n3)c2)CC1

Procedure:
5-{4-[(1,1-dioxidothiomorpholin-4-yl)methyl]phenyl}-N-[3-(4-methylpiperazin-1-yl)phenyl][1,2,4]triazolo[1,5-a]pyridin-2-amine was prepared from 5-{4-[(1,1-dioxidothiomorpholin-4-yl)methyl]phenyl}[1,2,4]triazolo[1,5-a]pyridin-2-amine (75.0 mg, 0.210 mmol) and 1-(3-bromo-phenyl)-4-methyl-piperazine (65.0 mg, 0.255 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (22.0 mg, 0.0402 mmol) as the ligand in a manner analogous to Step 2d and was isolated as an off-white solid (0.052 g, 47%). MP=150-152° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.02 (d, J=7.7 Hz, 2H), 7.55-7.42 (m, 5H), 7.17 (t, J=7.8 Hz, 1H), 6.97 (d, J=7.0 Hz, 1H), 6.87-6.80 (m, 2H), 6.55 (d, J=8.3 Hz, 1H), 3.76 (s, 2H), 3.24-3.19 (m, 4H), 3.14-3.03 (m, 8H), 2.58-2.53 (m, 4H), 2.36 (s, 3H). MS=532 (MH)+.