Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5]C(N1CCNCC1)=O)(C)(C)C.[Cl:14]CC(Cl)=O.CONC.[ClH:23].Cl.COC[CH:28]([NH:30][C:31](=[O:39])[CH2:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)C>>[ClH:14].[ClH:23].[CH3:1][O:5][N:30]([CH3:28])[C:31](=[O:39])[CH2:32][N:33]1[CH2:34][CH2:35][NH:36][CH2:37][CH2:38]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COCC(C)NC(=O)CN1CCNCC1
Reactant: O=C(Cl)CCl
Agent: CNOC
Agent: Cl
Product: CON(C)C(=O)CN1CCNCC1

Procedure:
N-Methoxy-N-methyl-2-piperazin-1-yl-acetamide dihydrochloride was prepared from 1-tert-butyloxycarbonyl-piperazine, chloroacetylchloride and N-methoxy-N-methylamine in an analogous manner as described for the preparation of N-(2-methoxy-1-methyl-ethyl)-2-piperazin-1-yl-acetamide dihydrochloride (example 40).
Reaction SMILES: [OH-:1].[Na+].[F:3][C:4]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:5]=1[CH:6]=O.FC1C=CC(C)=[C:18]([CH:21]=1)[CH:19]=O.Cl>CC(C)=O.O>[F:3][C:4]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:5]=1[CH:6]=[CH:21][C:18](=[O:1])[CH3:19]
Reactant: [OH-]
Reactant: Cc1ccc(F)c(C=O)c1
Reactant: Cc1ccc(F)cc1C=O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)C=Cc1cc(C)ccc1F
Reaction time: 1 h

Procedure:
To a mixture of acetone (160 ml), sodium hydroxide (6.4 g) and water (200 ml) was added dropwise at 0° C. a mixture of 2-fluoro-5-methylbenzaldehyde and 5-fluoro-2-methylbenzaldehyde (about 1:7) (28.1 g) in acetone (40 ml), and the mixture was stirred at the same temperature for 1 hour. To the mixture was added 1N hydrochloric acid (160 ml), and acetone was evaporated under reduced pressure. The residue was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate-hexane) to give 4-(2-fluoro-5-methylphenyl)-3-buten-2-one (18.2 g).
Reaction SMILES: C(C1N=C(N2CCOCC2)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.[C:28]([C:32]1[N:33]=[C:34](Cl)[C:35]2[N:40]=[N:39][N:38]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[Cl:48])[C:36]=2[N:37]=1)([CH3:31])([CH3:30])[CH3:29].[CH3:50][N:51]([CH:55]1[CH2:59][CH2:58][NH:57][CH2:56]1)[C:52](=[O:54])[CH3:53]>>[C:28]([C:32]1[N:33]=[C:34]([N:57]2[CH2:58][CH2:59][CH:55]([N:51]([CH3:50])[C:52](=[O:54])[CH3:53])[CH2:56]2)[C:35]2[N:40]=[N:39][N:38]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[Cl:48])[C:36]=2[N:37]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(=O)N(C)C1CCNC1
Reactant: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Agent: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Product: CC(=O)N(C)C1CCN(c2nc(C(C)(C)C)nc3c2nnn3Cc2ccccc2Cl)C1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chlorobenzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and N-methyl-N-(pyrrolidin-3-yl)acetamide. MS (m/e): 442.4 (MH+).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]4[CH:24]=[CH:23][N:22]=[N:21]4)[O:16][C:15]3=[O:25])=[CH:10][C:9]=2[F:26])=[CH:4][CH2:3]1.C(=O)(O)[O-].[Na+].[CH:32]([S:35](Cl)(=[O:37])=[O:36])([CH3:34])[CH3:33].S(Cl)(Cl)(=O)=O>O.CC(C)=O>[CH:32]([S:35]([N:2]1[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]4[CH:24]=[CH:23][N:22]=[N:21]4)[O:16][C:15]3=[O:25])=[CH:10][C:9]=2[F:26])=[CH:4][CH2:3]1)(=[O:37])=[O:36])([CH3:34])[CH3:33]
Reactant: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(C2=CCNCC2)c(F)c1
Reactant: CC(C)S(=O)(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O=S(=O)(Cl)Cl
Solvent: O
Product: CC(C)S(=O)(=O)N1CC=C(c2ccc(N3C[C@H](Cn4ccnn4)OC3=O)cc2F)CC1
Temperature: 0 °C
Reaction time: 18 h
Yield: 45.6 %

Procedure:
(5R)-3-(4-(1,2,5,6-Tetrahydropyridin-4-yl)-3-fluorophenyl)-5-(1,2,3-triazol-1-ylmethyl)-oxazolidin-2-one hydrochloride (380 mg, 1 mM) was dissolved in water (5 ml), which was then diluted with acetone (10 ml), and solid sodium bicarbonate (0.84 g, 10 mM) added. The mixture was stirred and cooled to 0° C., and isopropylsulfonyl chloride (285 mg, 2 mM) added dropwise. After stirring for 5 hours, an equal portion of sulfonyl chloride was added, and stirring continued for 18 hours. Most acetone was removed by evaporation, the residue diluted with water (50 ml), and extracted with ethyl acetate (3×20 ml). The extracts were washed with brine and dried (magnesium sulfate). The residual oil after evaporation was purified by chromatography on a 10 g silica Mega Bond Elut® column, eluting with a gradient increasing in polarity from 0 to 5% methanol in dichloromethane. Relevant fractions were combined and evaporated to give the desired product (205 mg).
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][NH2:7].[F:12][C:13]([F:27])([F:26])[C:14]1[CH:15]=[C:16]([N:20]=[C:21]([S-])[S-](C)C)[CH:17]=[CH:18][CH:19]=1.CC#N>CS(C)=O.C(O)(C(F)(F)F)=O>[N:3]1[C:4]2[C:5](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][NH:7][C:21]=1[NH:20][C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([C:13]([F:12])([F:26])[F:27])[CH:15]=1
Reactant: NCc1ccccc1N
Reactant: C[S-](C)C([S-])=Nc1cccc(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: FC(F)(F)c1cccc(NC2=Nc3ccccc3CN2)c1
Temperature: 190 °C
Reaction time: 0.5 h
Yield: 22.9 %

Procedure:
Under an atmosphere of nitrogen, sodium hydroxide (0.1 ml, solution in water, 20 mol/l, 2 mmol) was added to a solution of 2-aminobenzylamine (92 mg, 0.75 mmol) in DMSO (1 ml). After 30 min, a solution of (3-trifluoromethyl-phenyl)-dimethyl-dithiocarbonimidate (200 mg, 0.75 mmol) in DMSO (1 ml) was added, and the mixture was heated to 190° C. for 3 h. The title compound (50 mg, 23%, MS: m/e=292.1 [M+H+]) was isolated from the reaction mixture by preparative, reverse phase HPLC (YMC CombiPrep C18 column 50×20 mm, solvent gradient 5-95% CH3CN in 0.1% TFA(aq) over 6.0 min, λ=230 nm, flow rate 40 ml/min).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:8][C:7]2=[O:14])([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]>C(#N)C.CN(C=O)C>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:7]2=[O:14])([O-:3])=[O:2]
Reactant: O=C1NC(=O)c2cc([N+](=O)[O-])ccc21
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)CN1C(=O)c2ccc([N+](=O)[O-])cc2C1=O
Yield: 95.7 %

Procedure:
To a solution of 5-nitroisoindoline-1,3-dione (10.5 g, 53.6 mmol) in a mixture of acetonitrile (80 ml) and DMF (20 ml), potassium carbonate (9.99 g, 72.3 mmol) and tert-butyl 2-bromoacetate (10.29 ml, 69.6 mmol) were added, and the reaction was heated to reflux for 3 hours. The insoluble inorganic salts were filtered off, and the filtrate was evaporated to dryness. The residue was diluted with EtOH (60 ml) and precipitation of the desired product was observed. The precipitate was collected by filtration affording tert-butyl 2-(5-nitro-1,3-dioxoisoindolin-2-yl)acetate (15.7 g, 51.3 mmol, 96% yield, MS/ESI+ 328.9 [MNa]+).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2.[C:12](OC(=O)C)(=[O:14])[CH3:13].Cl.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1.O.CCOCC>[C:12]([O:1][CH2:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2)(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: OCc1cccc2[nH]ccc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)OCc1cccc2[nH]ccc12

Procedure:
4-Hydroxymethylindole (17 g) is heated in pyridine (12 ml) with acetic anhydride (11.9 ml) for three hours on the steam bath. After dilution with ether, the reaction mixture is first shaken out with 1N hydrochloric acid, then with saturated sodium bicarbonate solution and finally with water. The ether solution is evaporated. 20 g of 4-acetoxymethylindole remains.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-])=O)=[CH:10][CH:11]=2)[CH:6]=[C:5]1[C:16]([CH3:21])([CH3:20])[CH2:17][CH2:18][OH:19]>[Ni].CO>[NH2:13][C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][CH:10]=1)[N:4]([CH2:3][CH2:2][OH:1])[C:5]([C:16]([CH3:21])([CH3:20])[CH2:17][CH2:18][OH:19])=[CH:6]2
Reactant: CC(C)(CCO)c1cc2cc([N+](=O)[O-])ccc2n1CCO
Agent: [Ni]
Solvent: CO
Product: CC(C)(CCO)c1cc2cc(N)ccc2n1CCO
Yield: 25.9 %

Procedure:
A solution of 3-[1-(2-hydroxy-ethyl)-5-nitro-1H-indol-2-yl]-3-methyl-butan-1-ol (300 mg, 1.03 mmol) and Raney Nickel (200 mg,) in CH3OH (30 mL) was stirred for 5 h at room temperature under a H2 atmosphere. The catalyst was filtered through a celite pad and the filtrate was evaporated under vacuum to give a residue, which was purified by preparative TLC to afford 3-[5-amino-1-(2-hydroxy-ethyl)-1H-indol-2-yl]-3-methyl-butan-1-ol (70 mg, 26%). 1H NMR (300 MHz, CDCl3) δ 7.07 (d, J=8.7 Hz, 1H), 6.83 (d, J=2.1 Hz, 1H), 6.62 (dd, J=2.1, 8.4 Hz, 1H), 6.15 (s, 1H), 4.47 (t, J=5.4 Hz, 2H), 4.07 (t, J=5.4 Hz, 2H), 3.68 (t, J=5.7 Hz, 2H), 2.16 (t, J=5.7 Hz, 2H), 4.00-3.91 (m, 4H), 2.76 (s, 2H), 1.61 (s, 6H), 1.42 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C([O-])([O-])=O.[K+].[K+]>CCO>[CH2:9]([N:1]([CH2:6][CH2:7][CH2:2][CH2:3][CH2:4][CH3:5])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCI
Reactant: Nc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCCCCCN(CCCCCC)c1ccccc1

Procedure:
A mixture of aniline (5.90 ml, 6.47×10−2 mol), 1-iodohexane (20.0 ml, 0.136 mol) and K2CO3 (18.80 g, 0.136 mol) in 80 ml of EtOH was refluxed for 27 h under Ar. The precipitate was filtered off and washed with CH2Cl2. The filtrate was washed with water and dried over Na2SO4. The residue was chromatographed on silica gel with 4:1 hexane:CHCl3 as the eluent. Yield=14.735 g (87% based on 5.90 ml of aniline). 1H NMR (250 MHz, CDCl3): δ 7.20 (dd, 2H, J=7.1, 8.8 Hz, Ph), 6.57-6.66 (m, 3H, Ph), 3.24 (t, 4H, J=7.7 Hz, —NCH2—), 1.48-1.65 (m, 4H, —NCH2CH2—), 1.22-1.40 (m, 12H, —CH2—), 0.90 (t, 6H, J=6.6 Hz, —CH3). CI MS m/z: 262.253 ((M+H)+) (calcd 262.253).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH2:20][C:21](O)=[O:22])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][C:15]([F:18])([F:17])[F:16])[CH:7]=1.[CH:24]([NH:27][NH:28][C:29]([C:31]1[O:32][CH:33]=[CH:34][C:35]=1[CH3:36])=[O:30])([CH3:26])[CH3:25].C(NC(C)C)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH2:20][C:21]([N:27]([CH:24]([CH3:26])[CH3:25])[NH:28][C:29]([C:31]2[O:32][CH:33]=[CH:34][C:35]=2[CH3:36])=[O:30])=[O:22])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][C:15]([F:18])([F:17])[F:16])[CH:7]=1
Reactant: Cc1ccoc1C(=O)NNC(C)C
Reactant: O=C(O)COc1ccc(F)cc1-c1ccccc1OC(F)(F)F
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: Cc1ccoc1C(=O)NN(C(=O)COc1ccc(F)cc1-c1ccccc1OC(F)(F)F)C(C)C
Yield: 56.9 %

Procedure:
A solution of (5-fluoro-2′-trifluoromethoxy-biphenyl-2-yloxy)-acetic acid (211 mg, 0.64 mmol) and 3-methyl-furan-2-carboxylic acid N′-isopropyl-hydrazide (140 mg, 0.768 mmol) in DMF (3 ml) was treated with diisopropyl amine (0.278 ml, 1.6 mmol) and PyBroP (448 mg, 0.96 mmol) at room temperature overnight. The reaction mixture was partitioned between 1N HCl and ethyl acetate. The organic layer was successively washed with saturated sodium bicarbonate and brine, then dried over sodium sulfate, filtered and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 50-100% ethyl acetate in hexanes gradient to afford the product as a white solid (180 mg, 57%). MS m/e 495.19 (M+H+)
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH3:13].C([O-])([O-])=O.[K+].[K+].Cl[CH2:21][C:22]([CH3:24])=[CH2:23]>CN(C=O)C>[CH3:13][O:12][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=1[O:1][CH2:23][C:22]([CH3:24])=[CH2:21])[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(O)c(OC)c1
Reactant: C=C(C)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=C(C)COc1ccc(C(=O)OC)cc1OC
Temperature: 60 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a suspension of methyl 4-hydroxy-3-methoxybenzoate (100 g, 0.55 mol) and K2CO3 (92 g, 0.66 mol) in DMF (800 ml) was added drop wise 3-chloro-2-methyl-propene (55 g, 0.60 mol). The mixture was stirred at 60° C. overnight. TLC (EtOAc/petroleum ether=1/3) showed no starting material was present. The reaction mixture was filtered and the filtrate was added water (400 ml). The mixture was extracted with EtOAc (400 ml×3). The combined organic phase was washed with brine (400 mL), dried (Na2SO4) and concentrated to give the product (130 g, 100%) as yellow oil. The oil was used directly to the next step without further purification. 1H NMR (400 MHz, CDCl3): δ 7.54 (d, 1H), 7.19 (s, 1H), 6.80 (d, 1H), 5.00 (d, 2H), 4.50 (s, 2H), 3.83 (d, 6H), 1.76 (s, 3H).
Reaction SMILES: Cl.[C:2]1([C@:8]23[CH2:16][NH:15][CH2:14][C@H:13]2[CH2:12][S:11][C:10]([NH:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:9]3)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.Cl[C:36]1[N:41]=[C:40]([CH:42]([CH3:44])[CH3:43])[C:39]([F:45])=[CH:38][N:37]=1>O1CCOCC1.O.C(=O)(O)[O-].[Na+]>[F:45][C:39]1[C:40]([CH:42]([CH3:44])[CH3:43])=[N:41][C:36]([N:15]2[CH2:14][C@@H:13]3[C@@:8]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)([N:9]=[C:10]([NH:17][C:18](=[O:25])[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[S:11][CH2:12]3)[CH2:16]2)=[N:37][CH:38]=1
Reactant: O=C(NC1=N[C@@]2(c3ccccc3)CNC[C@H]2CS1)c1ccccc1
Reactant: CC(C)c1nc(Cl)ncc1F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1COCCO1
Product: CC(C)c1nc(N2C[C@H]3CSC(NC(=O)c4ccccc4)=N[C@@]3(c3ccccc3)C2)ncc1F
Yield: 3090.6 %

Procedure:
A solution of N-[(4aR,7aS)-7a-phenyl-4a,5,6,7-tetrahydro-4H-pyrrolo[3,4-d][1,3]thiazin-2-yl]benzamide hydrochloride (285 mg, 7.62 μmol), diisopropylethylamine (798 μL, 4.57 mmol) and 2-chloro-5-fluoro-4-isopropyl-pyrimidine (0.798 g, 4.57 mmol) in 1,4-dioxane (15 mL) is heated to 100° C. for eight hours under nitrogen. The reaction mixture is cooled and diluted with water and aqueous saturated sodium bicarbonate. The mixture is extracted with ethyl acetate (3×). The combined organic layers are dried over sodium sulfate and the solvent is removed under vacuum. The crude product is purified over silica gel eluting with a 5% to 100% ethyl acetate in hexanes gradient, to give the title compound (112 mg, 31%). ES/MS (m/e): 476 (M+H).
Reaction SMILES: [CH3:1][C:2]1([CH3:5])[CH2:4][NH:3]1.C(N(CC)CC)C.[CH2:13]([O:20][C:21](Cl)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[C:21]([N:3]1[CH2:4][C:2]1([CH3:5])[CH3:1])([O:20][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:22]
Reactant: CC1(C)CN1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2,2-Dimethyl aziridine is dissolved in CH2Cl2 and triethylamine under argon at 0° C. Benzylchloroformate is added and the contents of the flask are stirred at room temperature overnight. The mixture is poured into 10% citric acid and extracted with CHCl3. The organic layer is washed with dilute aqueous NaHCO3 and dried over MgSO4. The solution is evaporated to yield N-Cbz-2,2-dimethylaziridine.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=1)=O.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:24]=[C:25]([CH2:29][CH:30]=O)[CH:26]=[CH:27][CH:28]=1>>[F:9][C:8]([F:11])([F:10])[C:7]1[CH:6]=[CH:5][CH:4]=[C:3]2[C:2]=1[N:1]=[CH:30][C:29]([C:25]1[CH:26]=[CH:27][CH:28]=[C:23]([C:22]([F:21])([F:32])[F:33])[CH:24]=1)=[C:12]2[C:14]1[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=1
Reactant: O=CCc1cccc(C(F)(F)F)c1
Reactant: Nc1c(C(=O)c2cccc(O)c2)cccc1C(F)(F)F
Product: Oc1cccc(-c2c(-c3cccc(C(F)(F)F)c3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
The title compound was prepared from [2-amino-3-(trifluoromethyl)phenyl]-(3-hydroxy-phenyl)methanone and (3-Trifluoromethyl-phenyl)-acetaldehyde following the procedure of Example 457: HRMS: calcd for C23H13F6NO+H+, 434.09741; found (ESI, [M+H]+), 434.0993.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9](Cl)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH2:13]([O:17][C:18](=[O:22])[CH:19]([CH3:21])[NH2:20])[CH:14]([CH3:16])[CH3:15]>>[CH2:13]([O:17][C:18](=[O:22])[CH:19]([CH3:21])[NH:20][C:9](=[O:10])[CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH:14]([CH3:16])[CH3:15]
Reactant: O=C(Cl)CCc1ccccc1
Reactant: CC(C)COC(=O)C(C)N
Agent: Cl
Product: CC(C)COC(=O)C(C)NC(=O)CCc1ccccc1

Procedure:
Following General Procedure A above and using 3-phenylpropionyl chloride (Aldrich) and D,L-alanine iso-butyl ester hydrochloride (from Example B above), the title compound was prepared as a solid having a melting point of from 51°-54° C. The reaction was monitored by tlc on silica gel and purification was by extraction with Et2O followed by washes with aqueous K2CO3 and aqueous HCl.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6].O.C[N+]1([O-])CC[O:12]CC1.[O:16]1C[CH2:19][CH2:18][CH2:17]1>[Os](=O)(=O)(=O)=O>[OH:12][CH:18]([CH2:17][OH:16])[CH2:19][N:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6]
Reactant: C[N+]1([O-])CCOCC1
Reactant: C1CCOC1
Reactant: O=C1NCCN1
Agent: O=[Os](=O)(=O)=O
Solvent: O
Product: O=C1NCCN1CC(O)CO
Reaction time: 18 h

Procedure:
In the fourth step, a 0.4M solution of osmium tetroxide (0.05 mole for each mole of XI) is added dropwise to a solution in tetrahydrofuran of the intermediate (XI) and 4-methylmorpholine-4-oxide monohydrate (two moles for each mole of intermediate) and the resulting mixture stirred for 16 to 20 hours to obtain the 3-(2,3-dihydroxypropyl)imidazolidinone intermediate (XII) in the reaction mixture which may then be recovered employing conventional procedures.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[CH:10](=[O:14])[CH:11]([CH3:13])[CH3:12].Cl.C(Cl)Cl>C(OCC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:10]([OH:14])[CH:11]([CH3:13])[CH3:12])=[CH:4][CH:3]=1
Reactant: CC(C)C=O
Reactant: Clc1ccc([Mg]Br)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)C(O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 1 M solution of p-chlorophenylmagnesium bromide in diethyl ether (100 mL) is added to a solution of isobutyraldehyde (9.08 mL, 0.1 mol) in diethyl ether at −5° C. After the addition is complete, the reaction mixture is stirred overnight at room temperature, diluted with an ice-water mixture, and acidified with 10% hydrochloric acid. The phases are separated and the aqueous phase is extracted with diethyl ether. The organic phase and extracts are combined, washed sequentially with saturated sodium hydrogen carbonate solution, water and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain an oil. Column chromatography of the oil using silica gel and a 33% methylene chloride in hexanes solution gives the title product as a colorless oil (14 g) which is identified by NMR spectral analyses.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][C:5]1[CH:6]=[C:7]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:8]([N:10]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1[O:25][CH3:26])[CH3:11])=[O:9].CCN(C(C)C)C(C)C.[CH3:43][S:44](Cl)(=[O:46])=[O:45].[NH4+].[Cl-]>C(Cl)Cl>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C:17]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[N:10]([CH3:11])[C:8](=[O:9])[C:7]2[CH:27]=[C:28]([C:30]([F:32])([F:33])[F:31])[CH:29]=[C:5]([S:4][CH2:3][CH2:2][NH:1][S:44]([CH3:43])(=[O:46])=[O:45])[CH:6]=2)=[C:19]([O:25][CH3:26])[CH:20]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(SCCN)cc(C(F)(F)F)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(SCCNS(C)(=O)=O)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
To an ice-cold solution of 3-(2-aminoethylthio)-N-(4-(4-fluoro-2-methoxyphenyl)pyridin-3-yl)-N-methyl-5-(trifluoromethyl)benzamide (0.12 g, 250 μmol, example 237) and DIPEA (64.7 mg, 87.4 μL, 501 μmol) in CH2Cl2 (2 mL) was added methanesulfonyl chloride (35.8 mg, 24.4 μL, 313 μmol) and the clear colorless solution was stirred at 0° C. for 2.5 hours. The reaction mixture was poured on saturated aqueous NH4Cl solution and CH2Cl2 and the layers were separated. The aqueous layer was extracted three times with CH2Cl2. The organic layers were dried over MgSO4, filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 5 g column using an MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Colorless foam (0.121 g; 86%). MS (ESI): m/z=558.11 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]([O:23][C:24]([F:43])([F:42])[C:25]([F:41])([F:40])[O:26][C:27]([F:39])([F:38])[C:28]([F:37])([F:36])[C:29]([F:35])([F:34])[C:30]([F:33])([F:32])[F:31])([F:22])[F:21])=[CH:10][CH:9]=2)=[N:6][CH:7]=1.Br[CH2:45][CH2:46][O:47][CH2:48][CH2:49][O:50][CH2:51][CH2:52][CH2:53][CH3:54]>>[CH2:51]([O:50][CH2:49][CH2:48][O:47][CH2:46][CH2:45][O:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]([O:23][C:24]([F:43])([F:42])[C:25]([F:40])([F:41])[O:26][C:27]([F:38])([F:39])[C:28]([F:36])([F:37])[C:29]([F:34])([F:35])[C:30]([F:31])([F:32])[F:33])([F:22])[F:21])=[CH:12][CH:13]=2)=[N:4][CH:3]=1)[CH2:52][CH2:53][CH3:54]
Reactant: Oc1cnc(-c2ccc(OCCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc2)nc1
Reactant: CCCCOCCOCCBr
Product: CCCCOCCOCCOc1cnc(-c2ccc(OCCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc2)nc1

Procedure:
The title compound was prepared essentially as in Example 1 by combining 5-hydroxy-2-[4-(3-(2-(2-(nonafluorobutoxy)tetrafluoroethoxy)-2,2-difluoroethoxy)propoxy)phenyl]pyrimidine (1.22 g, 1.85 mmol, Example 10) and 1-bromo-2-(2-butoxyethoxy)ethane (0.81 g, 3.62 mmol). The resulting crude product was isolated and further purified essentially as described in Example 3, eluting with 30 volume percent ethyl acetate/hexane, to yield 1.13 g of purified product.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([NH2:11])[C:7]([NH2:10])=[CH:8][CH:9]=1)[CH2:2][CH3:3].S(=O)(O)[O-].[Na+].[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([CH:26]=O)=[N:18]1>CN(C)C=O>[CH2:1]([C:4]1[CH:9]=[CH:8][C:7]2[NH:10][C:26]([C:19]3[C:20]4[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=4)[NH:17][N:18]=3)=[N:11][C:6]=2[CH:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1ccc(N)c(N)c1
Reactant: O=Cc1n[nH]c2ccccc12
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1ccc2[nH]c(-c3n[nH]c4ccccc34)nc2c1
Temperature: 200 °C

Procedure:
A stirred solution of 4-propyl-benzene-1,2-diamine [57 mg, Reference Example 30(d)] and sodium bisulfite (40 mg) in dimethylformamide (2 ml) was treated with indazole-3-carboxaldehyde [Reference Example 6(l)]. The reaction mixture was heated in a Smith Creator microwave at 200° C. for 13 minutes then partitioned between ethyl acetate and water. The organic layer was washed with brine, then dried over magnesium sulfate and then evaporated. The residue was subjected to flash column chromatography on silica eluting with a mixture of ethyl acetate and hexane (3:1) to give 3-(5-n-propyl-1H-benzoimidazol-2-yl)-1H-indazole (74 mg) as a pale brown solid. MS: 277.3 (M+H)+. HPLC (METHOD B1): RT=12.81 minutes. (b) 2-(1H-Indazol-3-yl)-1H-benzoimidazole-5-sulfonic acid benzylamide