Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([Cl:9])[C:5](=O)[CH2:6][CH3:7].[Cl-].[CH:12]([NH2:14])=[NH2+:13].C[O-].[Na+]>CO>[Cl:9][C:4]1[C:3]([OH:2])=[N:13][CH:12]=[N:14][C:5]=1[CH2:6][CH3:7]
Reactant: CCC(=O)C(Cl)C(=O)OC
Reactant: NC=[NH2+]
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CCc1ncnc(O)c1Cl

Procedure:
To a solution of 8.6 g (0.049 mol) of 2-chloro-3-oxopentanoic acid methylester (content 94 percent) and 6.04 g (0.075 mol) of formamidinium chloride in 10 ml of methanol, there was added within 2 hours at 20° to 22° C., while stirring, 21.6 g of sodium methylate solution (30 percent in methanol, 0.12 mol). After another 3 hours of stirring, neutralization with conc. hydrochloric acid (pH about 5) and evaporation to dryness on the rotary evaporator were performed. The residue was taken up with 20 ml of water and extracted out three times with ethyl acetate. The combined organic phases were dried on sodium sulfate, the solvent was distilled off and the solid residue was dried at 50° C. and 100 torr. The following data concerns the product of this example:
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]([F:14])([F:13])[F:12])=[CH:6][CH:5]=1)=[O:3].[S:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[C:20](OCC)=[O:21].[H-].[Na+].Cl>O.O1CCCC1>[S:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[C:20](=[O:21])[CH2:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]([F:12])([F:13])[F:14])=[CH:8][CH:9]=1)=[O:3]
Reactant: CCOC(=O)c1cccs1
Reactant: CC(=O)c1ccc(OC(F)(F)F)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(CC(=O)c1cccs1)c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Yield: 99.4 %

Procedure:
4-Trifluoromethoxyacetophenone (4.1 g, 20 mM) and ethyl 2-thiophenecarboxylate (3.1 g, 20 mM) were placed in a 300 ml eggplant type flask, and 100 ml of dehydrated tetrahydrofuran was added thereto. After this mixture was stirred at room temperature, a 60% oil suspension of sodium hydride (1.1 g, 26 mM) was slowly added thereto. Thereafter, the resulting mixture was heated under reflux for 6 hours and allowed to cool to room temperature. After 100 ml of water was added to the reaction mixture under cooling with ice, the reaction mixture was adjusted to pH 1.0 with a concentrated aqueous solution of hydrochloric acid and then extracted with 100 ml of ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled off under reduced pressure to obtain 6.2 g of 1-(2-thienyl)-3-(4-trifluoromethoxyphenyl)-1,3-propanedione in an almost quantitative yield.
Reaction SMILES: N1C=CC=C[CH:2]=1.[F:7][C:8]([F:19])([C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])[C:9]([OH:11])=[O:10]>CO>[F:7][C:8]([F:19])([C:12]([F:17])([F:18])[C:13]([F:14])([F:15])[F:16])[C:9]([O:11][CH3:2])=[O:10]
Reactant: O=C(O)C(F)(F)C(F)(F)C(F)(F)F
Reactant: c1ccncc1
Solvent: CO
Product: COC(=O)C(F)(F)C(F)(F)C(F)(F)F

Procedure:
Cationic fluorochemical surfactants useful as antistatic agents and lubricants for polymeric shapes are prepared from 2,2,3,4,4,4-hexafluorobutanol or perfluorobutyric acid. Hexafluorobutanol is reacted with bromoundecanoic acid to obtain a bromoester which is then reacted with pyridine to obtain a cationic surfactant. Perfluorobutyric acid is esterified with methanol to obtain methyl perfluorobutyrate which is then reacted with dimethylaminopropylamine to obtain an amino-amide which is then reacted with hydrogen peroxide to obtain the N-oxide derivative which is neutralized with glycolic acid to obtain a cationic surfactant, a salt of the N-oxide derivative.
Reaction SMILES: [N:1]([CH:4]1[CH2:21][CH2:20][C:7]2=[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[S:9][C:10]([S:11][CH:12]([CH3:14])[CH3:13])=[C:6]2[C:5]1=[O:22])=[N+]=[N-].[C:23](OC(=O)C)(=[O:25])[CH3:24]>[C].[Pd].C(O)(=O)C>[C:23]([NH:1][CH:4]1[CH2:21][CH2:20][C:7]2=[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[S:9][C:10]([S:11][CH:12]([CH3:14])[CH3:13])=[C:6]2[C:5]1=[O:22])(=[O:25])[CH3:24]
Reactant: CCOC(=O)c1sc(SC(C)C)c2c1CCC(N=[N+]=[N-])C2=O
Reactant: CC(=O)OC(C)=O
Agent: [Pd]
Solvent: CC(=O)O
Product: CCOC(=O)c1sc(SC(C)C)c2c1CCC(NC(C)=O)C2=O
Yield: 77.8 %

Procedure:
A mixture of ethyl 5-azido-4,5,6,7-tetrahydro-3-isopropylthio-4-oxobenzo[c]thiophene-1-carboxylate (1.60 g), palladium-carbon (5%, 50% wet, 1.6 g), acetic acid (30 ml) and acetic anhydride (15 ml) was subjected to a catalytic reduction reaction at room temperature under 1 atm. The insoluble substances were filtered off; the filtrate was poured over water and extracted with ethyl acetate. The organic layer was washed with water, a saturated aqueous solution of sodium hydrogen carbonate and water in that order, and dried (MgSO4), after which the solvent was distilled off to yield ethyl 5-acetylamino-4,5,6,7-tetrahydro-3-isopropylthio-4-oxobenzo[c]thiophene-1-carboxylate (1.30 g, 77.8%), which was then recrystallized from ethyl acetate-hexane. Colorless prisms. Melting point 170-171° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH:9]([C:11]1[CH:12]=[CH:13][C:14]([O:20][CH3:21])=[C:15](B(O)O)[CH:16]=1)=[O:10]>>[Cl:1][C:2]1[N:7]=[C:6]([C:13]2[CH:12]=[C:11]([CH:16]=[CH:15][C:14]=2[O:20][CH3:21])[CH:9]=[O:10])[CH:5]=[CH:4][N:3]=1
Reactant: COc1ccc(C=O)cc1B(O)O
Reactant: Clc1ccnc(Cl)n1
Product: COc1ccc(C=O)cc1-c1ccnc(Cl)n1
Yield: 70 %

Procedure:
2,4 dichloropyrimidine and 5-formyl-2-methoxyphenylboronic acid was coupled following procedure A. The yield was 70%. LC-MS showed the product was >95% pure and had the expected M+H+ of 249. 1H NMR (Varian 300 MHz, MeOD-d6, shifts relative to the solvent peak at 3.33 ppm) δ 9.9 (s, 1H) 8.7 (d, 1H) 8.4 (s, 1H) 8.0 (d, 2H) 7.4 (d, 1H) 3.9 (s, 3H).
Reaction SMILES: CN(C)CCCN=C=NCC.[NH2:12][C:13]1[C:14](=[O:26])[N:15]([CH3:25])[C:16](=[O:24])[N:17]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:18]=1[NH2:19].[CH3:27][O:28][C:29]1[C:38]([O:39][CH3:40])=[CH:37][CH:36]=[C:35]2[C:30]=1[C:31]([CH2:41][C:42](O)=O)=[CH:32][N:33]=[CH:34]2.ON1C2C=CC=CC=2N=N1>ClCCl.O>[CH2:20]([N:17]1[C:18]2[N:19]=[C:42]([CH2:41][C:31]3[C:30]4[C:35](=[CH:36][CH:37]=[C:38]([O:39][CH3:40])[C:29]=4[O:28][CH3:27])[CH:34]=[N:33][CH:32]=3)[NH:12][C:13]=2[C:14](=[O:26])[N:15]([CH3:25])[C:16]1=[O:24])[CH:21]([CH3:22])[CH3:23]
Reactant: COc1ccc2cncc(CC(=O)O)c2c1OC
Reactant: CC(C)Cn1c(N)c(N)c(=O)n(C)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: COc1ccc2cncc(Cc3nc4c([nH]3)c(=O)n(C)c(=O)n4CC(C)C)c2c1OC
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (20.6 ml, 0.11 mol) is added to a mixture of 5,6-diamino-1-isobutyl-3-methyl-1H-pyrimidine-2,4-dione (20 g, 0.094 mol), (5,6-dimethoxy-isoquinolin-4-yl)-acetic acid (26.7 g, 0.094 mol), and 1-hydroxybenzotriazole (19.2 g, 0.142 mol) in 1:1 dichloromethane-water (400 ml). The reaction is stirred at ambient temperature for 4.5 hours and the resultant solid collected by filtration. Slurrying in water (500 ml), filtration and washing with water (250 ml) followed by drying, further tritruation with methanol and drying gives an intermediate together with slightly less pure material from concentration of the methanol triturate. The intermediate (16.08 g) is dissolved in water (100 ml) and methanol (100 ml) followed by the addition of 4M aqueous sodium hydroxide (56 ml) and the resultant solution is heated at 70° C. over night. After cooling to ambient temperature, the methanol is evaporated and the residue acidified to pH 1 with concentrated hydrochloric acid. The resultant hydrochloride salt is collected by filtration and dried. The product is then be converted to the free base by treatment with aqueous sodium hydroxide to pH 11 and washing with water to afford 3-isobutyl-8-(5,6-dimethoxy-isoquinolin-4-ylmethyl)-1-methyl-3,7-dihydro-purine-2,6-dione [MH]+ 424.6.
Reaction SMILES: [C:1]([C:4]1[NH:8][CH:7]=[N:6][C:5]=1[O:9][C@@H:10]1[O:18][C@H:17]([C:19]([O:21]C)=O)[C@@H:15]([OH:16])[C@H:13]([OH:14])[C@H:11]1[OH:12])(=[O:3])[NH2:2].[NH3:23]>CO>[C:1]([C:4]1[NH:8][CH:7]=[N:6][C:5]=1[O:9][C@@H:10]1[O:18][C@H:17]([C:19]([NH2:23])=[O:21])[C@@H:15]([OH:16])[C@H:13]([OH:14])[C@H:11]1[OH:12])(=[O:3])[NH2:2]
Reactant: N
Reactant: COC(=O)[C@H]1O[C@@H](Oc2nc[nH]c2C(N)=O)[C@H](O)[C@@H](O)[C@@H]1O
Solvent: CO
Product: NC(=O)c1[nH]cnc1O[C@@H]1O[C@H](C(N)=O)[C@@H](O)[C@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 0.55 g of methyl 1-O-(5-carbamoyl-1H-imidazole-4-yl)-β-D-glucopyranuronate in 50 ml of dry methanol was saturated with ammonia (gas) cooling in an ice bath and the reaction mixture was stirred for 1.5 hours. Then the reaction mixture was heated to room temperature and was concentrated to a residue under reduced pressure. The residue was washed with methanol and ether, and then separated crystals were filtered off and dried to give 0.5 g of 1-O-(5-carbamoyl-1H-imidazole-4-yl)-β-D-glucopyranuronamide which was recrystallized from water-ethanol. m.p. 206° C. (dec.)
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-])=O)[CH:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1>C(O)C.O.[Pd]>[N:1]1([CH2:7][CH2:8][NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([NH2:16])[CH:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1cccc(NCCN2CCOCC2)c1
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: Nc1cccc(NCCN2CCOCC2)c1
Reaction time: 12 h
Yield: 74.9 %

Procedure:
20 g N-2-(morpholin4-yl)ethyl-3-nitroaniline was dissolved in 270 ml ethanol and 30 ml water, and 0.3 Pd/C (5%) was added. After purging with nitrogen, hydrogenation was performed for 12 h at 50° C. under 50 bar of hydrogen pressure. After cooling, nitrogen purging was repeated, the catalyst was filtered off, and the filtrate was reduced on a rotary evaporator. 13.2 g of black oil was obtained; this was distilled twice in a ball tube (180–206° C., 0.06–0.08 mbar). The product obtained was a viscous orange oil (middle fraction).
Reaction SMILES: [C:1]1([CH:7]2[CH2:13][CH2:12][C:11](=[O:14])[C:10]3[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=3[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:19]Br>C(OCC)C>[Br:19][CH:12]1[C:11](=[O:14])[C:10]2[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=2[O:8][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:13]1
Reactant: BrBr
Reactant: O=C1CCC(c2ccccc2)Oc2ccccc21
Solvent: CCOCC
Product: O=C1c2ccccc2OC(c2ccccc2)CC1Br
Yield: 95.8 %

Procedure:
800 mg (3.36 m moles) of 2-phenyl-2,3,4,5-tetrahydro-1-benzoxepin-5-one (compound R1 of Reference Example 1) was dissolved in 80 ml of absolute ethyl ether, and 808 mg (1.5 equivalent amount) of bromine was added to the solution dropwise over 15 minutes under ice-cooling. The reaction mixture was washed with a sodium sulfate aqueous solution followed by water, and then dried with anhydrous magnesium sulfate. After filtrating off the magnesium sulfate, the filtrate was concentrated to obtain a residue, which was then applied to a silica gel column, and eluted with a mixture of hexane/ethyl acetate (98:2) to obtain 1.02 g (yield 95.7%) of the desired compound in a form of a diastereomer mixture (R14a and R14b, ratio 3:1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH3:43][O:44][C:45]1[C:46]2[N:59]=[C:58]([NH2:60])[S:57][C:47]=2[C:48]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)=[N:49][CH:50]=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH:60][C:58]1[S:57][C:47]2[C:48]([C:51]3[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=3)=[N:49][CH:50]=[C:45]([O:44][CH3:43])[C:46]=2[N:59]=1)=[O:8]
Reactant: COc1cccc(C(=O)O)c1
Reactant: COc1cnc(-c2ccccc2)c2sc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COc1cccc(C(=O)Nc2nc3c(OC)cnc(-c4ccccc4)c3s2)c1

Procedure:
From 3-methoxybenzoic acid, HATU and N-methylmorpholine in THF, then treatment with 7-methoxy-4-phenyl-thiazolo[5,4-c]pyridin-2-ylamine. ES-MS m/e (%): 392 (M+H+, 100).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5]Br.[C:7]1([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][O:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: BrCCCCBr
Reactant: OCCCCCc1ccccc1
Product: BrCCCCOCCCCCc1ccccc1

Procedure:
(2.46 g), T.l.c. [K] Rf 0.58 from 1,4-dibromobutane (7.89 g) and benzenepentanol (2 g).
Reaction SMILES: [CH3:1][C:2]1[CH:21]=[CH:20][C:5]([CH:6]=[C:7]2[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][N:24]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][C:2]1[CH:21]=[CH:20][C:5]([CH:6]=[C:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:30])([F:32])[F:31])=[CH:25][N:24]=1
Reactant: Cc1ccc(C=C2CCN(C(=O)OC(C)(C)C)CC2)cc1Oc1ccc(C(F)(F)F)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(C=C2CCNCC2)cc1Oc1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 114.8 %

Procedure:
To a solution of tert-butyl 4-(4-methyl-3-(5-(trifluoromethyl)pyridin-2-yloxy)benzylidene)piperidine-1-carboxylate (0.50 g, 0.0011 mol) in CH2Cl2 (5 mL) cooled to 0° C. under a N2 atmosphere was added TFA (0.85 mL, 0.011 mol) slowly. The resulting mixture was stirred for 2 h at RT. The reaction was concentrated under reduced pressure to give the title compound (440 mg).
Reaction SMILES: [CH3:1][CH:2]([C:19]([NH:21][CH2:22][C:23]([F:29])([F:28])[C:24]([F:27])([F:26])[F:25])=[O:20])[C:3]([NH:5][C@@H:6]1[C:12](=[O:13])[N:11]([CH3:14])[C:10]2[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=2[NH:8][CH2:7]1)=[O:4].ClCCl.[C:33](Cl)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.Cl>C(N(CC)CC)C>[C:33]([N:8]1[CH2:7][C@H:6]([NH:5][C:3](=[O:4])[CH:2]([CH3:1])[C:19]([NH:21][CH2:22][C:23]([F:29])([F:28])[C:24]([F:26])([F:25])[F:27])=[O:20])[C:12](=[O:13])[N:11]([CH3:14])[C:10]2[CH:15]=[CH:16][CH:17]=[CH:18][C:9]1=2)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CC(C(=O)NCC(F)(F)C(F)(F)F)C(=O)N[C@H]1CNc2ccccc2N(C)C1=O
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C(=O)NCC(F)(F)C(F)(F)F)C(=O)N[C@H]1CN(C(=O)c2ccccc2)c2ccccc2N(C)C1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 60.6 %

Procedure:
To a solution of 0.2 g (0.47 mmol) of 2-methyl-N-((3S)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-N′-(2,2,3,3,3-pentafluoro-propyl)-malonamide in 3 ml of dichloromethane 0.096 g (0.95 mmol) of triethylamine and 0.08 mg (0.57 mmol) of benzoylchloride were added. The mixture was stirred for 20 min at room temperature. Hydrochloric acid (10 ml of a 1 N solution) was added and the mixture was extracted two times with dichloromethane. The combined organic layers were extracted with 1N sodiumbicarbonate solution, dried (MgSO4) and concentrated in vacuo. The remaining oil was purified by column chromatography to yield 0.15 g (60%) of a white foam.
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].O[C:7]1[CH2:11][CH:10]([C:12]([O:14][CH3:15])=[O:13])[N:9]([CH3:16])[N:8]=1>C(Cl)(Cl)Cl>[Cl:3][C:7]1[CH2:11][CH:10]([C:12]([O:14][CH3:15])=[O:13])[N:9]([CH3:16])[N:8]=1
Reactant: COC(=O)C1CC(O)=NN1C
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: COC(=O)C1CC(Cl)=NN1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.2 %

Procedure:
To a solution of POCl3 (31.8 ml, 341 mmol) and Net3 (47.6 ml, 341 mmol) in CHCl3 (100 ml) at −5° C. was added a solution of methyl 3-hydroxy-1-methyl-4,5-dihydro-1H-pyrazole-5-carboxylate (36 g, 228 mmol) in CHCl3 (100 ml). After 1 h at this temperature, the mixture was stirred for another 20 h under warming to rt. Then, the reaction mixture was poured on ice water and extracted with CHCl3. The combined organics were washed with water, dried over Na2SO4 and evaporated under reduced pressure. This yielded the title compound (21 g, 52%) which was used in the next step without further purification. [LCMS RtJ=0.63 min; [M+H]+=177.0, 179.0]
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]([C:15]3[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=3[F:23])=O)=[C:9]([CH2:24][CH2:25][CH3:26])[CH:8]=2)=[CH:4][CH:3]=1.Cl.[NH2:30][OH:31].C([O-])(=O)C.[Na+]>C(O)C>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10](/[C:13](/[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=3[F:23])=[N:30]/[OH:31])=[C:9]([CH2:24][CH2:25][CH3:26])[CH:8]=2)=[CH:4][CH:3]=1
Reactant: CCCc1cc(Oc2ccc(Cl)cc2)ccc1C(=O)c1cc(OC)ccc1F
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCCc1cc(Oc2ccc(Cl)cc2)ccc1/C(=N/O)c1cc(OC)ccc1F
Temperature: 60 °C
Reaction time: 48 h

Procedure:
A mixture of the product from Step 3 (1.6 g, 4.0 mmol), hydroxylamine hydrochloride (2.8 g, 40 mmol) and sodium acetate (3.3 g, 40 mmol) in ethanol (40 mL) was stirred in a sealed tube at 60° C. for 48 h. The precipitate was filtered off and the filtrate was concentrated. The residue was purified by chromatography on silica gel to give the oxime product.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl[C:15]([CH3:18])([CH3:17])[CH3:16]>[Cl-].[Cl-].[Zn+2].[N+](C)([O-])=O>[CH3:16][C:15]([C:3]1[CH:2]=[CH:1][C:13]2[NH:12][C:11]3[C:6]([C:5]=2[CH:4]=1)=[CH:7][C:8]([C:5]([CH3:6])([CH3:13])[CH3:4])=[CH:9][CH:10]=3)([CH3:18])[CH3:17]
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: CC(C)(C)Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C[N+](=O)[O-]
Product: CC(C)(C)c1ccc2[nH]c3ccc(C(C)(C)C)cc3c2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a 500 mL three-necked round bottom flask equipped with an over head stirrer, nitrogen gas bubbler, and an addition funnel add 20.02 g (120.8 mmol) of carbazole, 49.82 g (365.5 mmol) of ZnCl2, and 300 mL of nitromethane at room temperature. To the resulting dark brown slurry add 49.82 g (365.5 mmol) of 2-chloro-2-methylpropane (also known as tertiary-butyl chloride or t-BuCl) dropwise from the addition funnel over the period of 2.5 hours. After completing the addition, stir the resulting slurry for an additional 18 hours. Pour the reaction mixture into 800 mL of ice cold water, extract with 3×500 mL methylene chloride, combine and dry the extracts with anhydrous magnesium sulfate, filter, and concentrate the filtrate first by rotary evaporation and then by evaporation under high vacuum to remove nitromethane. Dissolve the resulting residue first in hot methylene chloride (70 mL) followed by hot hexanes (50 mL), allow the resulting solution to cool to room temperature and then placed it in a refrigerator overnight. Isolate the solids formed and wash the isolated solids with cold hexanes and then place them under high vacuum to yield 10.80 g (32.0%) of (P1) as off white crystals.
Reaction SMILES: Br[CH2:2][C:3]#[N:4].[Br:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([CH2:13][CH3:14])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:2][C:3]#[N:4])=[C:8]([CH2:13][CH3:14])[CH:7]=1
Reactant: N#CCBr
Reactant: CCc1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1cc(Br)ccc1OCC#N
Reaction time: 12 h
Yield: 83.8 %

Procedure:
Bromoacetonitrile (1.19 ml, 9.94 mmol) was added to a solution of 4-bromo-2-ethylphenol (2.0 g, 9.94 mmol) and potassium carbonate (1.35 g, 9.94 mmol) in DMF (50 ml). The reaction was stirred for 12 hours and then partitioned between diethyl ether (200 ml) and water (200 ml). The organics were separated, dried over magnesium sulfate, filtered and concentrated in vacuuo to afford the title compound as a yellow oil (2.0 g). 1H NMR (CDCl3): δ 1.13 (t, J=12.07 Hz, 3 H), 2.45 (m, 2H), 4.84 (s, 2H), 7.03–7.10 (m, 2H), 7.21 (m, 1H).
Reaction SMILES: [CH2:1]([O:5][C:6]([NH:8][CH:9]=[CH:10][C:11]1[CH:21]=[CH:20][C:14]([O:15][CH2:16][CH:17]2[O:19][CH2:18]2)=[CH:13][CH:12]=1)=[O:7])[CH2:2][CH2:3][CH3:4].[CH:22]([NH2:25])([CH3:24])[CH3:23]>C(O)(C)C>[CH2:1]([O:5][C:6]([NH:8][CH:9]=[CH:10][C:11]1[CH:21]=[CH:20][C:14]([O:15][CH2:16][CH:17]([OH:19])[CH2:18][NH:25][CH:22]([CH3:24])[CH3:23])=[CH:13][CH:12]=1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)NC=Cc1ccc(OCC2CO2)cc1
Reactant: CC(C)N
Solvent: CC(C)O
Product: CCCCOC(=O)NC=Cc1ccc(OCC(O)CNC(C)C)cc1

Procedure:
Analogously to the description in Example 2, 3.93 g (0.0135 mol) of 1-[p-(2-n-butoxycarbonylaminovinyl)-phenoxy]-2,3-epoxy-propane, on reaction with 1.22 ml (0.0142 mol) of isopropylamine in 50 ml of isopropanol, yield 1-[p-(2-n-butoxycarbonylaminovinyl)-phenoxy]-2-hydroxy-3-isopropylaminopropane of melting point of 125°-126° C. (from acetone-ether).
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[K+].F[B-](F)(F)F.[H+].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[O:20][C:21]3[CH:27]=[CH:26][C:25]([N+]#N)=[CH:24][C:22]=3[N:23]=2)=[CH:15][CH:14]=1>CS(C)=O.O>[C:1](=[O:4])([S:3][C:25]1[CH:26]=[CH:27][C:21]2[O:20][C:19]([C:16]3[CH:17]=[CH:18][C:13]([Cl:12])=[CH:14][CH:15]=3)=[N:23][C:22]=2[CH:24]=1)[CH3:2]
Reactant: CC([O-])=S
Reactant: N#[N+]c1ccc2oc(-c3ccc(Cl)cc3)nc2c1
Agent: F[B-](F)(F)F
Agent: [H+]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)Sc1ccc2oc(-c3ccc(Cl)cc3)nc2c1
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 3.4 %

Procedure:
To a stirred solution of potassium thioacetate (130 mg, 1.13 mmol) in DMSO (2.8 mL) at room temperature was added dropwise a solution of 2-(4-chlorophenyl)benzo[d]oxazole-5-diazonium tetrafluoroboric acid salt (370 mg, 1.08 mmol) in DMSO (1.4 mL). After 15 min, the mixture was heated at 70° C. for 1 h. After cooling, the mixture was diluted with water, and then extracted several times with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous MgSO4 and evaporated. The resulting solid was purified by column chromatography eluting using a gradient (ethyl acetate/hexanes 5:95 v/v to ethyl acetate/hexanes 15:85 v/v) and triturated with diethyl ether/hexanes to afford 11.3 mg (3%) of the title compound (LCMS RT=7.89 min, MH+ 304.2)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH2:20][CH2:19][C:13]3[N:14]=[CH:15][N:16]=[C:17](Cl)[C:12]=3[CH2:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[NH2:21][C@@H:22]([C:25]1[CH:26]=[N:27][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:30]=1)[CH2:23][OH:24].C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH2:20][CH2:19][C:13]3[N:14]=[CH:15][N:16]=[C:17]([NH:21][C@@H:22]([C:25]4[CH:26]=[N:27][C:28]([C:31]([F:34])([F:32])[F:33])=[CH:29][CH:30]=4)[CH2:23][OH:24])[C:12]=3[CH2:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: N#Cc1cc(Cl)ccc1N1CCc2ncnc(Cl)c2C1
Reactant: N[C@H](CO)c1ccc(C(F)(F)F)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: N#Cc1cc(Cl)ccc1N1CCc2ncnc(N[C@H](CO)c3ccc(C(F)(F)F)nc3)c2C1
Yield: 18.9 %

Procedure:
A reaction mixture of 5-chloro-2-(4-chloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)benzonitrile (150 mg, 0.49 mmol) and (S)-2-amino-2-(6-(trifluoromethyl)pyridin-3-yl)ethanol (150 mg, 0.74 mmol) (prepared similarly according to the method for Intermediate 10) in acetonitrile (3 mL) and N,N-diisopropylethylamine (170 μL, 0.98 mmol) was subjected to microwave irradiation at 180° C. for 4 h. The reaction mixture was concentrated and the residue was purified by silica gel column (100% EtOAc and then 0-20% MeOH/CH2Cl2) followed by semi-preparative HPLC (100×20.2 mm, C18 column; 30-70% acetonitrile-water [10 mM Et2NH]) to yield a light yellow foam (44 mg).