Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]([CH2:12][CH3:13])([C:9]([O-:11])=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].O=S(Cl)Cl.[CH2:18]([NH:20][CH2:21][CH3:22])[CH3:19]>C1C=CC=CC=1>[CH2:18]([N:20]([CH2:21][CH3:22])[C:9]([C:3]([CH2:1][CH3:2])([CH2:12][CH3:13])[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:11])[CH3:19]
Reactant: CCNCC
Reactant: CCOC(=O)C(CC)(CC)C(=O)[O-]
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CCOC(=O)C(CC)(CC)C(=O)N(CC)CC
Reaction time: 18 h

Procedure:
To a solution of monoethyl diethylmalonate (28 g. 0.15 mole) in dry benzene (300 ml.) is added SOCl2 (15 ml., 0.21 mole) at 26°-28° in 2 min, with mechanical stirring. The reaction solution is gradually heated to 78° over 25 min, then is heated an additional 45 min at 85°-90° . The mixture is concentrated to dryness under reduced pressure, benzene (100 ml.) is added, and the mixture is again concentrated to dryness. The resultant oily residue dissolved in benzene (200 ml.) is treated dropwise with a solution of diethylamine (30 ml., 0.29 mole) in benzene (90 ml.) at 5°-15° over 17 min, and the reaction mixture is refluxed for 7 hours. The mixture is stored for 18 hours at room temperature and is filtered (to remove insoluble salt), is washed with benzene (50 ml.), is dried over MgSO4 and activated charcoal for 15 min, is filtered, and is concentrated to dryness under reduced pressure (bath at 50°-60°). This will yield 29 g. (79%) of ethyl 2-(N,N-diethylcarbamoyl)-2-ethylbutyrate.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([Cl:34])[C:23]([F:35])=[CH:22][CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CON(C)[C:39]([C:41]1[CH:42]=[N:43][CH:44]=[N:45][CH:46]=1)=[O:40]>>[Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([Cl:34])[C:23]([F:35])=[C:22]([C:39]([C:41]2[CH:42]=[N:43][CH:44]=[N:45][CH:46]=2)=[O:40])[CH:21]=1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CON(C)C(=O)c1cncnc1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc(F)c2Cl)C[C@H](C)O1
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc(C(=O)c3cncnc3)c(F)c2Cl)C[C@H](C)O1

Procedure:
Starting material: (2R,6S)-4-[6-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2-chloro-3-fluorophenyl]-2,6-dimethylmorpholine (Intermediate 42) and N-methoxy-N-methylpyrimidine-5-carboxamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][CH:9]=[C:8]([CH2:12][CH2:13]O)[C:7]=2[CH:6]=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:34]Br.N1C=CC=CC=1>C(Cl)Cl>[Br:34][CH2:13][CH2:12][C:8]1[C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:11]=2[O:10][CH:9]=1
Reactant: BrBr
Reactant: COc1cccc2c(CCO)coc12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cccc2c(CCBr)coc12
Yield: 52.1 %

Procedure:
This compound was prepared by the same method as for intermediate 25, using 4.15 g (21.6 mmol) of 2-(7-methoxybenzofuran-3-yl)-ethanol, 6.8 g (25.9 mmol) of triphenylphosphine, 1.34 mL (25.9 mmol) of bromine, and 3.5 mL (43.2 mmol) of pyridine in 70 mL of CH2Cl2, to afford 2.87 g (52%) of the title compound after flash chromatography on SiO2 (25% CH2Cl2/hexanes to 100% CH2Cl2 gradient): MS (ESI) m/z 254 [M]+.
Reaction SMILES: S(=O)(=O)(O)O.[O:6]1[CH:11]=[CH:10][CH:9]=[CH:8][NH:7]1.[N+:12]([O-])([OH:14])=[O:13].C(=O)([O-])[O-].[Na+].[Na+]>>[N+:12]([C:8]1[NH:7][O:6][CH:11]=[CH:10][CH:9]=1)([O-:14])=[O:13]
Reactant: C1=CNOC=C1
Reactant: O=[N+]([O-])O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=[N+]([O-])C1=CC=CON1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To concentrated sulfuric acid (2 ml) was added portion wise the oxazine XI (0.1 mmol) at 22° C., the solution obtained was cooled to 0° C. and treated with red fuming nitric acid (HNO3) (0.058 ml) and stiffing was continued at 0° C. for 2 h. The reaction mixture was slowly added to crushed ice, the pH was adjusted to 10 using a saturated sodium carbonate solution, the aqueous layer was extracted with AcOEt, the organic layer was dried and evaporated to afford the pure nitro-oxazine XII.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[C:28]([F:38])=[CH:29][C:30]([F:37])=[C:31]([S:33]([NH2:36])(=[O:35])=[O:34])[CH:32]=1>>[F:37][C:30]1[CH:29]=[C:28]([F:38])[C:27]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)=[CH:32][C:31]=1[S:33]([NH2:36])(=[O:34])=[O:35]
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: NS(=O)(=O)c1cc(Br)c(F)cc1F
Product: NS(=O)(=O)c1cc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c(F)cc1F

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 mg, 1.0 mmol) and commercially available 5-bromo-2,4-difluorobenzenesulphonamide (245 mg, 0.9 mmol) according to general procedure II. Obtained as a yellow solid (230 mg, 42%). MS (ISP) 614.3 [(M+H)+]; mp 281-284° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:7]([CH3:15])[S:6][C:5]1=[S:16].[C:17](OC(=O)C)(=[O:19])[CH3:18]>C(Cl)(Cl)Cl>[C:17]([O:1][CH2:2][CH2:3][N:4]1[C:8]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[C:7]([CH3:15])[S:6][C:5]1=[S:16])(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1sc(=S)n(CCO)c1-c1ccccc1
Solvent: ClC(Cl)Cl
Product: CC(=O)OCCn1c(-c2ccccc2)c(C)sc1=S

Procedure:
Intermediate 3-(2-hydroxyethyl)-5-methyl-4-phenyl-3H-thiazole-2-thione was treated with acetic anhydride (1 equiv) and TEA (2 equiv) in CHCl3. After 12 h the product mixture was concentrated and chromatographed (silica gel, 0–40% EtOAc/Hex) to afford the title compound. 1H-NMR (CDCl3): δ 7.50–7.55 (3H, m), 7.28–7.32 (2H, m), 4.32 (2H, t), 4.26 (2H, t), 2.03 (3H, s), 1.93 (3H, s).
Reaction SMILES: ClC1C([F:8])=CN=C(C)C=1.[Cl:10][C:11]1[C:16]([F:17])=[CH:15][N:14]=[C:13]([CH2:18][CH2:19][CH3:20])[CH:12]=1>>[Cl:10][C:11]1[C:16]([F:17])=[CH:15][N:14]=[C:13]([CH2:18][CH2:19][CH3:20])[C:12]=1[F:8]
Reactant: Cc1cc(Cl)c(F)cn1
Reactant: CCCc1cc(Cl)c(F)cn1
Product: CCCc1ncc(F)c(Cl)c1F

Procedure:
By following the procedures described in Example 69 and replacing 4-chloro-5-fluoro-2-picoline (the product of Example 66) with 4-chloro-5-fluoro-2-propyl-pyridine (the product of Example 70), the title compound can be prepared.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:21])[C:11]=1[CH2:12][N:13]1[CH2:17][CH2:16][C@H:15]([N:18]([CH3:20])[CH3:19])[CH2:14]1)[C:5]([O:7]C)=[O:6]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:21])[C:11]=1[CH2:12][N:13]1[CH2:17][CH2:16][C@H:15]([N:18]([CH3:19])[CH3:20])[CH2:14]1)[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1cc(Cl)c(CN2CC[C@H](N(C)C)C2)c(Cl)c1
Solvent: CO
Product: CN(C)[C@H]1CCN(Cc2c(Cl)cc(C(=O)O)cc2Cl)C1

Procedure:
This compound was prepared in the same manner as in Reference Example 1 (step 6), except that methyl 3,5-dichloro-4-[(S)-3-(dimethylamino)pyrrolidin-1-ylmethyl]benzoate obtained in the step 3 was used and methanol was used as the solvent, and that after methanol was added to the residue and the resulting mixture was stirred, insolubles were removed by filtration and the solvent in the filtrate was distilled off under reduced pressure to obtain the objective compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[S:11][C:10]=1[C:18]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SiH](CC)CC)C>ClCCl.FC(F)(F)C(O)=O>[CH2:1]([O:8][C:9]1[CH:13]=[C:12]([C:14]([F:17])([F:15])[F:16])[S:11][C:10]=1[CH2:18][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(C(=O)c2sc(C(F)(F)F)cc2OCc2ccccc2)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(Cc2sc(C(F)(F)F)cc2OCc2ccccc2)cc1
Reaction time: 6.75 h
Yield: 51.3 %

Procedure:
To a solution of (3-benzyloxy-5-trifluoromethylthiophen-2-yl)-(4-methoxy-phenyl)methanone (220.2 mg, 0.56 mmol) as synthesized by the method described in International Publication No. WO04/007517 and triethylsilane (1.34 mL, 8.41 mmol) in dichloromethane (1.1 mL), trifluoroacetic acid (3 mL) was added at 0° C. in a nitrogen stream over five minutes. The reaction mixture was stirred at the same temperature for 6.75 hours, and then triethylsilane (0.9 mL, 5.61 mmol) was added thereto. The reaction mixture was stirred at the same temperature for 16.75 hours, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:10)] to obtain the title compound (108.8 mg, 51%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4](O)=[O:5].C(O)(=O)C.[O-:16][C:17]#[N:18].[K+].[OH-].[Na+]>O>[Cl:11][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[N:1]=[C:17]([OH:16])[N:18]=[C:4]2[OH:5]
Reactant: Nc1ccc(Cl)cc1C(=O)O
Reactant: N#C[O-]
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Oc1nc(O)c2cc(Cl)ccc2n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 65.9 %

Procedure:
To a mixture of 2-amino-5-chlorobenzoic acid (25.3 g), acetic acid (9.0 mL), and water (650 mL) was added an aqueous solution (130 mL) of potassium cyanate (15.5 g), and the mixture was stirred at room temperature for 2 days. Sodium hydroxide (59 g) was added over 30 min. Water (100 mL) was added, and then the precipitated solids were collected by filtration. The resulting solids were suspended in water (700 mL), followed by addition of 4 M hydrochloric acid (55 mL), and then the precipitated solids were collected by filtration to obtain 6-chloroquinazoline-2,4-diol (19.1 g).
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]2[O:7][CH:8]=[C:9]([C:11](=[O:31])[NH:12][C@H:13]3[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=4)=[O:19])[CH2:14]3)[N:10]=2)[CH2:3]1.[CH3:32][S:33](Cl)(=[O:35])=[O:34].C(N(CC)CC)C>C(Cl)Cl>[CH3:32][S:33]([O:1][CH:2]1[CH2:3][N:4]([C:6]2[O:7][CH:8]=[C:9]([C:11](=[O:31])[NH:12][C@H:13]3[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=4)=[O:19])[CH2:14]3)[N:10]=2)[CH2:5]1)(=[O:35])=[O:34]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(N[C@H]1CCN(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1)c1coc(N2CC(O)C2)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC1CN(c2nc(C(=O)N[C@H]3CCN(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)co2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.4 %

Procedure:
To a solution of 3-hydroxy-1-{4-[(3S)-1-(p-nitrobenzyloxycarbonyl)pyrrolidin-3-ylcarbamoyl]-1,3-oxazol-2-yl}azetidine (680 mg, 1.58 mmol) (obtained as described in Reference Example 76(2)) in methylene chloride (34 ml) were added methanesulfonyl chloride (366 μl, 4.73 mmol) and triethylamine (663 μl, 4.73 mmol) in an ice bath and the mixture was stirred for 10 minutes and at room temperature for 2 hours. After checking the completion of the reaction, the mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate→ethyl acetate:methanol (96:4) as the eluant to afford 3-methanesulfonyloxy-1-{4-[(3S)-1-(p-nitrobenzyloxycarbonyl)pyrrolidin-3-ylcarbamoyl]-1,3-oxazol-2-yl}azetidine (760 mg, yield 95%) as a pale yellow solid.
Reaction SMILES: O.NN.[F:4][C:5]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH3:18])=[C:11]2[C:6]=1[C:7](=[O:41])[C:8]([C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=1)=[CH:9][N:10]2[CH2:19][CH2:20][CH2:21][N:22]1C(=O)C2C(=CC=CC=2)C1=O>C(O)C>[NH2:22][CH2:21][CH2:20][CH2:19][N:10]1[C:11]2[C:6](=[C:5]([F:4])[CH:14]=[CH:13][C:12]=2[O:15][CH2:16][CH2:17][CH3:18])[C:7](=[O:41])[C:8]([C:33]2[CH:34]=[CH:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=2)=[CH:9]1
Reactant: CCCOc1ccc(F)c2c(=O)c(-c3ccc(OC)cc3)cn(CCCN3C(=O)c4ccccc4C3=O)c12
Agent: NN
Solvent: CCO
Solvent: O
Product: CCCOc1ccc(F)c2c(=O)c(-c3ccc(OC)cc3)cn(CCCN)c12
Yield: 93.9 %

Procedure:
Hydrazine hydrate (0.62 ml, 12.8 mmol) was added to an ethanol solution (60 ml) of 2-{3-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]propyl}isoindole-1,3-dione (2.0 g, 3.88 mmol) and heated under reflux for 4 hours. The resulting mixture was concentrated under reduced pressure, a 5N aqueous sodium hydroxide solution was added to the thus-obtained residue, and then the resulting mixture was subjected to extraction using dichloromethane. The thus-obtained organic layer was sequentially washed with water and an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure, giving a yellow oily 1-(3-aminopropyl)-5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-one (1.4 g, yield: 94%).
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH2:19][CH:20]([C:22]([OH:24])=O)[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[O:25]1[CH2:30][CH2:29][CH:28]([CH2:31][CH2:32][NH2:33])[CH2:27][CH2:26]1>>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH2:19][CH:20]([C:22]([NH:33][CH2:32][CH2:31][CH:28]3[CH2:29][CH2:30][O:25][CH2:26][CH2:27]3)=[O:24])[N:21]=2)[CH:7]=[N:6]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: NCCC1CCOCC1
Reactant: CC(C)(C)n1ncc(C2=NC(C(=O)O)CS2)c1-c1ccc(F)cc1
Product: CC(C)(C)n1ncc(C2=NC(C(=O)NCCC3CCOCC3)CS2)c1-c1ccc(F)cc1

Procedure:
Using 2-(1-(tert-butyl)-5-(4-fluorophenyl)-1H-pyrazol-4-yl)-4,5-dihydrothiazole-4-carboxylic acid and 2-(tetrahydro-pyran-4-yl)-ethylamine and by reaction and purification in the same manner as in the method described in Example 1, step 7, the title compound was obtained.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH3:5].[OH:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([CH:17]([CH3:21])[C:18]([OH:20])=[O:19])[CH:11]=[CH:10]2>>[CH3:21][CH:17]([C:12]1[CH:11]=[CH:10][C:9]2[C:14](=[CH:15][CH:16]=[C:7]([O:6][CH2:2][CH2:3][CH2:4][CH3:5])[CH:8]=2)[CH:13]=1)[C:18]([OH:20])=[O:19]
Reactant: CC(C(=O)O)c1ccc2cc(O)ccc2c1
Reactant: CCCCI
Product: CCCCOc1ccc2cc(C(C)C(=O)O)ccc2c1

Procedure:
The title compound is prepared according to the method of Example 7 using 1-iodobutane and racemic 6-hydroxy-α-methyl-2-naphthaleneacetic acid. White crystals are obtained having a melting point of 125°-127° c.
Reaction SMILES: O=[CH:2][C@@H:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:4].[NH2:13][CH:14]([C:17]([F:20])([F:19])[F:18])[CH2:15][OH:16].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[F:18][C:17]([F:20])([F:19])[CH:14]([NH:13][CH2:2][C@@H:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:4])[CH2:15][OH:16]
Reactant: C[C@@H](C=O)NC(=O)OC(C)(C)C
Reactant: NC(CO)C(F)(F)F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: C[C@@H](CNC(CO)C(F)(F)F)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 80.9 %

Procedure:
To a stirred solution of (S)-tert-butyl (1-oxopropan-2-yl)carbamate (3.15 g, 18.18 mmol), and DCM (91 ml) was added 2-amino-3,3,3-trifluoropropan-1-ol (2.230 g, 17.28 mmol). Stirred at ambient temperature for 10 minutes and then added sodium triacetoxyborohydride (5.78 g, 27.3 mmol). The mixture was stirred overnight. The reaction was diluted with DCM and then washed with 1 N NaOH, brine dried over MgSO4, filtered and the solvent removed to provide 4.0 grams of tert-butyl ((2S)-1-((1,1,1-trifluoro-3-hydroxypropan-2-yl)amino)propan-2-yl)carbamate as a colorless oil that was used without further purification. LRMS m/z (M+H)+ 287.3 found, 287.3 required.
Reaction SMILES: O1CCCC1.[CH3:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9](Cl)=[O:10].[F:16][C:17]([F:30])([F:29])[O:18][C:19]1[CH:28]=[CH:27][C:22]([O:23][CH2:24][CH2:25][NH2:26])=[CH:21][CH:20]=1>C(N(CC)CC)C>[F:16][C:17]([F:29])([F:30])[O:18][C:19]1[CH:28]=[CH:27][C:22]([O:23][CH2:24][CH2:25][NH:26][C:9](=[O:10])[C:8]2[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=2[CH3:6])=[CH:21][CH:20]=1
Reactant: NCCOc1ccc(OC(F)(F)F)cc1
Reactant: Cc1ccccc1C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccccc1C(=O)NCCOc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A tetrahydrofuran (5 ml) solution of 2-methylbenzoyl chloride (0.77 g) was added dropwise under ice-cooling and stirring to a tetrahydrofuran (20 ml) solution of 2-(4-trifluoromethoxyphenoxy)ethylamine (1.10 g) and triethylamine (0.51 g) and the mixture was further stirred at room temperature for one hour.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH:4]([CH:11]1[CH2:16][CH2:15][N:14](C(OCC2C=CC=CC=2)=O)[CH2:13][CH2:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.CO>CCO>[C:5]1([CH:4]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[C:3]([O:2][CH3:1])=[O:27])[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: COC(=O)C(c1ccccc1)C1CCN(C(=O)OCc2ccccc2)CC1
Solvent: CCO
Solvent: CO
Product: COC(=O)C(c1ccccc1)C1CCNCC1
Yield: 99 %

Procedure:
Following the same procedure as described in Example 10, step 1, but substituting 2-nitro-4-(thiophen-2-yl)aniline for compound 91, and MeOH for EtOH, the title compound 92 (0.384 g, 99%) was obtained as a colorless oil. LRMS (ESI): (calc) 233.31 (found) 234.14 (MH)+
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([C:28]([OH:30])=[O:29])[CH:8]=[C:9]2[C:17]=1[CH:16]([CH2:18][O:19][C:20](=[O:22])[NH2:21])[C:15]1([O:24][C:25](=[O:27])[CH3:26])[O:23][N:10]2[CH2:11][CH:12]2[CH:14]1[NH:13]2)(=[O:3])[CH3:2].[N+](=[CH2:33])=[N-]>CO.C(OCC)C>[C:1]([O:4][C:5]1[CH:6]=[C:7]([C:28]([O:30][CH3:33])=[O:29])[CH:8]=[C:9]2[C:17]=1[CH:16]([CH2:18][O:19][C:20](=[O:22])[NH2:21])[C:15]1([O:24][C:25](=[O:27])[CH3:26])[O:23][N:10]2[CH2:11][CH:12]2[CH:14]1[NH:13]2)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cc(C(=O)O)cc2c1C(COC(N)=O)C1(OC(C)=O)ON2CC2NC21
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Solvent: CO
Product: COC(=O)c1cc(OC(C)=O)c2c(c1)N1CC3NC3C(OC(C)=O)(O1)C2COC(N)=O
Reaction time: 0.33 h

Procedure:
To a solution of 6,9-diacetoxy-8-carbamoyloxymethyl-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-triene-4-carboxylic acid (12 mg) in methanol (2 ml) was added a solution of diazomethane (excess) in diethyl ether at room temperature. The mixture was allowed to stand at room temperature for 20 minutes and then evaporated to dryness in vacuo. The residue was subjected to preparative thin layer chromatography, which was developed with a mixture of chloroform and methanol (15:1, v/v) to afford methyl 6,9-diacetoxy-8-carbamoyloxymethyl-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-triene-4-carboxylate (5 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:8]=1)([O-])=O>CCOC(C)=O.CCO.O=[Pt]=O>[CH2:9]([N:7]1[CH:8]=[C:4]([NH2:1])[CH:5]=[N:6]1)[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=[N+]([O-])c1cnn(CCc2ccccc2)c1
Agent: O=[Pt]=O
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1cnn(CCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-nitro-1-phenethyl-1H-pyrazole (2.78 g, 12.87 mmol), in EtOAc (6 mL, degassed) and EtOH (18 mL, degassed), PtO2 (235 mg, 1.2 mmol) was added and the reaction mixture was stirred at rt under a H2-atmosphere for 18 h. The mixture was diluted with EtOH, filtered over celite and the filter cake was rinsed with EtOH. The filtrate was concentrated to obtain the title compound I-phenethyl-1H-pyrazol-4-ylamine as red solid. LC-MS conditions A: tR=0.54 min, [M+MeCN+H]+=229.04.
Reaction SMILES: CCCCCC.[CH3:7][C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][C:13]([N+:17]([O-:19])=[O:18])=[CH:12][CH:11]=2.[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O>[CH3:7][C:8]1[N:9]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:10]2[C:15]([CH:16]=1)=[CH:14][C:13]([N+:17]([O-:19])=[O:18])=[CH:12][CH:11]=2
Reactant: Cc1cc2cc([N+](=O)[O-])ccc2[nH]1
Reactant: BrCc1ccccc1
Solvent: O
Solvent: CCCCCC
Product: Cc1cc2cc([N+](=O)[O-])ccc2n1Cc1ccccc1
Reaction time: 0.33 h
Yield: 75.1 %

Procedure:
Hexane was used to wash 80 mg 2.0 mmol) of 60% NaH/mineral oil and 6 mL of DMF was added followed by 352 mg (2.0 mmol) of 2-methyl-5-nitro-1H-indole. After 0.33 hours, 0.24 mL (2.0 mol) of benzyl bromide was added, stirred 0.5 hours and diluted with water. The mixture was extracted with EtOAc, the EtOAc washed with a saturated NaCl solution, dried (MgSO4) and on concentrating at reduced pressure, crystals formed. These were washed with MeOH to give 400 mg (75% yield) of 2-methyl-5-nitro-1-(phenylmethyl)-1H-indole, mp, 150-152° C.
Reaction SMILES: CS(O)(=O)=O.[NH2:6][C:7]1(N)[CH:11]=[C:10]([OH:12])[N:9]=[N:8]1.[CH3:14][CH:15](O)[CH3:16]>>[CH:15]([O:12][C:10]1[NH:9][N:8]=[C:7]([NH2:6])[CH:11]=1)([CH3:16])[CH3:14]
Reactant: CC(C)O
Reactant: NC1(N)C=C(O)N=N1
Agent: CS(=O)(=O)O
Product: CC(C)Oc1cc(N)n[nH]1
Temperature: 120 °C
Reaction time: 48 h
Yield: 15 %

Procedure:
Methanesulfonic acid (25 mL) was added to a 2-propanol (250 mL) solution of 3-amino-5-hydroxypyrazolamine (25 g), and stirred at 120° C. for 2 days. The reaction liquid was left cooled, and the solvent was evaporated off under reduced pressure. Aqueous saturated sodium hydrogencarbonate solution was added to the residue, then extracted with ethyl acetate, and dried with sodium sulfate. The drying agent was removed through filtration, and the solvent was evaporated off under reduced pressure to give the intended product (5.35 g, 15%).
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:22]=[C:21]([OH:23])[C:20]4[C:15](=[CH:16][CH:17]=[C:18]([NH:24][C:25](=[O:27])[CH3:26])[CH:19]=4)[N:14]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:28]1(C)C=CC=CC=1.S(OC)(OC)(=O)=O>CCCCCC>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([C:13]3[CH:22]=[C:21]([O:23][CH3:28])[C:20]4[C:15](=[CH:16][CH:17]=[C:18]([NH:24][C:25](=[O:27])[CH3:26])[CH:19]=4)[N:14]=3)=[CH:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(=O)Nc1ccc2nc(-c3ccc(C4CCCCC4)cc3)cc(O)c2c1
Reactant: Cc1ccccc1
Solvent: CCCCCC
Solvent: COS(=O)(=O)OC
Product: COc1cc(-c2ccc(C3CCCCC3)cc2)nc2ccc(NC(C)=O)cc12
Temperature: 70 °C
Yield: 96 %

Procedure:
N-[2-(4-Cyclohexylphenyl)-4-hydroxy-quinolin-6-yl]-acetamide 35.7 g (0.099 moles) was placed in a 500 mL three neck round bottom flask equipped with a condenser, magnetic stirrer and nitrogen inlet with 250 mL of toluene. The material was suspended by stirring and 20.6 mL (0.21 moles) of dimethyl sulfate was added. The suspension was then heated with a silicone oil heating bath, to gentle reflux for 18 hr. After thwas time the reaction was allowed to cool and hexane was added. Solids were collected by vacuum filtration and washed with hexane. After drying, the solids were suspended in a 2 L Erlenmeyer flask with 1 L of 5% sodium hydroxide solution. The suspension was vigorously stirred and heated to 70° C. for 30 min. This converted the salt form of the material to the free base and removed some impurities. After cooling the solids were collected by vacuum filtration and washed with water. The product was dried in a vacuum oven to give 35.8 g (96%) of material, which contained about 30% of side products, with the N-methylated material constituting the major impurity. The material was used without further purification.