Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][CH:12]([N:15]3[CH:19]4[CH2:20][CH2:21][CH:16]3[CH2:17][CH2:18]4)[C:11]2=O)=[CH:6][CH:5]=1)([O-])=O.B.C1COCC1.Cl>C1COCC1.O>[CH:19]12[N:15]([CH:12]3[CH2:13][CH2:14][N:10]([C:7]4[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][CH:8]=4)[CH2:11]3)[CH:16]([CH2:21][CH2:20]1)[CH2:17][CH2:18]2
Reactant: O=C1C(N2C3CCC2CC3)CCN1c1ccc([N+](=O)[O-])cc1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccc(N2CCC(N3C4CCC3CC4)C2)cc1

Procedure:
1-(4-Nitrophenyl)-3-(7-azabicyclo[2.2.1]hept-7-yl)pyrrolidin-2-one (0.25 g) in THF (10 ml) was mixed with borane-THF complex (1M in THF, 0.83 ml) and boiled under reflux for 3 hours. After the reaction was complete, the mixture was diluted with water and adjusted to pH 9-10 with hydrochloric acid (4N). Extraction in ethyl acetate, drying and concentration of the organic phase afforded a crude product that was hydrogenated by method B. This resulted in the product with the molecular weight of 257.38 (C16H23N3); MS (ESI): 258 (M+H+).
Reaction SMILES: [CH:1]1[C:6](/[CH:7]=[CH:8]/[CH:9]=[CH:10]/[C:11](N2CCCCC2)=[O:12])=[CH:5][C:4]2[O:19][CH2:20][O:21][C:3]=2[CH:2]=1.[OH-:22].[K+].Cl>C(O)C>[O:21]1[C:3]2[CH:2]=[CH:1][C:6](/[CH:7]=[CH:8]/[CH:9]=[CH:10]/[C:11]([OH:12])=[O:22])=[CH:5][C:4]=2[O:19][CH2:20]1
Reactant: O=C(/C=C/C=C/c1ccc2c(c1)OCO2)N1CCCCC1
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: O=C(O)/C=C/C=C/c1ccc2c(c1)OCO2
Yield: 79.2 %

Procedure:
Piperine (200 mg, 0.70 mmol) dissolved in anhydrous ethanol and KOH (1.18 g, 21.0 mmol) were mixed and heated to reflux for 12 hours. Upon completion of the experiment, the pH value of the reaction mixture solution was adjusted to 2-3 using hydrochloric acid. After the ethanol was distilled under reduced pressure, the residue was diluted with EtOAC (30 mL) and washed with a saturated solution of NaCl, followed by drying over anhydrous Na2SO4. The solvent was distilled under reduced pressure to give a target compound (121 mg, yield: 79.1%).
Reaction SMILES: C([N:3]([CH2:39]C)[C:4]([C:6]1C=CC=C[C:7]=1[S:12]([C:14]1[C@H:15]([CH3:38])[C@@H:16]2[C@@H:33]([C@H:34]([OH:36])[CH3:35])[C:32](=[O:37])[N:17]2[C:18]=1[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)=[O:20])=O)=[O:5])C.SC1CNC(=O)C1>>[O:5]=[C:4]1[NH:3][CH2:39][CH:7]([S:12][C:14]2[C@H:15]([CH3:38])[C@@H:16]3[C@@H:33]([C@H:34]([OH:36])[CH3:35])[C:32](=[O:37])[N:17]3[C:18]=2[C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)=[O:20])[CH2:6]1
Reactant: CCN(CC)C(=O)c1ccccc1S(=O)C1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H]([C@@H](C)O)[C@H]2[C@H]1C
Agent: O=C1CC(S)CN1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3CNC(=O)C3)[C@H](C)[C@H]12
Yield: 59 %

Procedure:
Following a procedure similar to that described in Example 27(b), but using 4-nitrobenzyl (1R,5S,6S)-2-(2-diethylcarbamoylphenylsulfinyl)-1-methyl-6-[1(R)-hydroxyethyl]-1-carbapen-2-em-3-carboxylate [prepared as described in Example 27(a)] and 4-mercapto-2-oxopyrrolidine as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as a powder in a yield of 59%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH2:9].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].F[C:21]1[CH:29]=[N:28][CH:27]=[CH:26][C:22]=1[C:23]([OH:25])=[O:24].[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:21]1[CH:29]=[N:28][CH:27]=[CH:26][C:22]=1[C:23]([OH:25])=[O:24]
Reactant: O=C(O)c1ccncc1F
Reactant: Nc1ccc(I)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Temperature: -65 °C
Reaction time: 0.5 h
Yield: 93.8 %

Procedure:
A mixture of 2-fluoro-4-iodo-phenylamine (20.0 g, 84.38 mmol) in anhydrous tetrahydrofuran (80 mL) was cooled to −65° C. under an inert atmosphere, prior to slow addition of 1.0 M lithium bis(trimethylsilyl)amide (255 mL, 255 mmol) at a rate that maintained the internal temperature below −55° C. After final addition, the thick slurry was stirred for 30 minutes and then treated with 3-fluoro-isonicotinic acid (8.0 g, 56.69 mmol). The mixture was stirred at room temperature for 4 days and then poured into aqueous 2.0 N sodium hydroxide (1000 mL) and ethyl acetate (250 mL). The layers were separated and the organics were again extracted with aqueous sodium hydroxide (2×1000 mL). The pH of the combined aqueous fractions was adjusted to 2 with concentrated hydrochloric acid, which effected precipitation of a solid. The material was filtered, washed with water (300 mL) and dried under high vacuum at 40° C. for 18 h to afford the product (19.05 g, 53.19 mmol, 94%) as a yellow solid.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][C:6](=[O:8])[O:5][C:3]1=[O:4].[S:9](=[O:12])(=[O:11])=[O:10]>C(OC)(=O)C(C)=C>[S:9]([C:2]1([CH3:1])[CH2:7][C:6](=[O:8])[O:5][C:3]1=[O:4])([OH:12])(=[O:11])=[O:10]
Reactant: CC1CC(=O)OC1=O
Reactant: O=S(=O)=O
Agent: C=C(C)C(=O)OC
Product: CC1(S(=O)(=O)O)CC(=O)OC1=O
Temperature: 110 °C
Reaction time: 1 h

Procedure:
114 g. of methyl-succinic anhydride and 80 g. of liquid sulfur trioxide are stirred and heated to 110° C. in an apparatus fitted with a condenser adequate to contain the low boiling sulfur trioxide. After 1 hour, the product is cooled to 25° C. and has an equivalent weight of about 65. It is stored as a solution in methyl methacrylate.
Reaction SMILES: Br[CH2:2][CH:3]=[C:4]([CH3:12])[CH2:5][CH2:6][CH:7]=[C:8]([CH3:11])[CH2:9][CH3:10].[OH:13][C:14]1[CH:23]=[CH:22][C:17]2[CH2:18][CH:19]([CH3:21])[O:20][C:16]=2[CH:15]=1>>[CH3:12][C:4]([CH2:5][CH2:6][CH:7]=[C:8]([CH3:11])[CH2:9][CH3:10])=[CH:3][CH2:2][O:13][C:14]1[CH:23]=[CH:22][C:17]2[CH2:18][CH:19]([CH3:21])[O:20][C:16]=2[CH:15]=1
Reactant: CCC(C)=CCCC(C)=CCBr
Reactant: CC1Cc2ccc(O)cc2O1
Product: CCC(C)=CCCC(C)=CCOc1ccc2c(c1)OC(C)C2

Procedure:
1-bromo-3,7-dimethyl-2,6-nonadiene and 6-hydroxy-2-methyl-2,3-dihydrobenzofuran are reacted to form 6-[(3,7-dimethyl-2,6-nonadienyl)- oxy]-2-methyl-2,3-dihydrobenzofuran of boiling point ca. 145° C./0.001 mmHg; nD20 = 1.5286;
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:17]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)=[CH:20][CH:19]=3)[C:16]3[C:11](=[CH:12][C:13]([O:32]C)=[CH:14][CH:15]=3)[O:10][CH2:9]2)=[CH:4][CH:3]=1.Cl.N1C=CC=CC=1.[OH-].[Na+].Cl>O.C(O)C.ClCCl>[OH:32][C:13]1[CH:12]=[C:11]2[C:16]([C@H:17]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][N:27]4[CH2:28][CH2:29][CH2:30][CH2:31]4)=[CH:20][CH:19]=3)[C@H:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH2:9][O:10]2)=[CH:15][CH:14]=1
Reactant: COc1ccc2c(c1)OC[C@@H](c1ccc(F)cc1)[C@H]2c1ccc(OCCN2CCCC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: c1ccncc1
Solvent: ClCCl
Product: Oc1ccc2c(c1)OC[C@@H](c1ccc(F)cc1)[C@H]2c1ccc(OCCN2CCCC2)cc1
Temperature: 152.5 °C

Procedure:
A mixture of (±)-cis-3-(4-fluorophenyl)-7-methoxy-4-(4-(2-pyrrolidinoethoxy)phenyl) -chromane (0.90 g, 2.01 mmol) and anhydrous pyridine hydrochloride (11.60 g, 100 mmol) was heated to 150-155° C. as a melt for 18 hours. The mixture was cooled to room temperature, and the resulting orange coloured wax dissolved in a mixture of water (100 ml), hot ethanol (20 ml) and dichloromethane (150 ml). The aqueous layer was basified to pH 14 by adding 10M sodium hydroxide, then 1M hydrochloric acid was added until pH 8-9. The organic layer was collected and the aqueous layer further extracted with dichloromethane (2×150 ml). The combined organics were washed with saturated sodium chloride, dried over sodium sulfate and evaporated to a dark coloured gum, which was purified by column chromatography on silica gel, with 7% methanol in dichloromethane as eluent, giving the product as a colourless glass. This was dissolved in a minimum of acetone and petroleum ether added to precipitate the product as an amorphous solid, which was vacuum dried.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:33][CH2:34][CH2:35][C:36]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[NH:38][CH:37]=1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C>O.C(=O)(O)[O-].[Na+].CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:33][CH2:34][CH2:35][C:36]5[C:44]6[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=6)[NH:38][CH:37]=5)=[O:28])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCCc1c[nH]c2ccccc12
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)NCCc2c[nH]c3ccccc23)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 18 h
Yield: 52.4 %

Procedure:
A mixture of 0.100 g (0.22 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-22), 0.071 g (0.33 mmole) of tryptamine, 0.102 g (0.27 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, 0.195 mL (1.12 mmole) of diisopropylethyl amine and 2.0 mL of dimethylformamide was stirred for 18 hours. The mixture was diluted with 10 mL of water plus 2 mL of saturated aqueous sodium bicarbonate and then extracted 3 times with 10 mL of ethyl acetate. The combined extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 100:0-60:40) to give 0.068 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-[2-(1H-indol-3-yl)-ethyl]-3-methoxy-benzamide (I-51) as a white solid.
Reaction SMILES: [CH2:1]([CH:3]1[C:8](=[O:9])[CH:7]=[CH:6][CH:5]([OH:10])[O:4]1)[CH3:2].S([O-])([O-])(=O)=O.[Mg+2]>C(O)CCC>[CH2:1]([CH:3]1[C:8](=[O:9])[CH:7]=[CH:6][CH:5]([O:10][CH2:2][CH2:1][CH2:3][CH3:8])[O:4]1)[CH3:2]
Reactant: CCC1OC(O)C=CC1=O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCCCO
Product: CCCCOC1C=CC(=O)C(CC)O1
Yield: 82.2 %

Procedure:
A 14.2 g quantity of 2-ethyl-6-hydroxy-3-oxo-3,6-dihydro-2H-pyran and 74 g of n-butyl alcohol are reacted in the presence of 10 g of magnesium sulfate with refluxing for 24 hours. After the reaction, the mixture is filtered to remove the magnesium sulfate, and the filtrate is concentrated at a reduced pressure to remove the excess n-butyl alcohol. The residue is further distilled at a reduced pressure of 5 mm Hg to give 16.2 g of 2-ethyl-6-n-butoxy-3-oxo-3,6-dihydro-2H-pyran as a yellow liquid fraction at 83° to 88° C in a yield of 82.2%.
Reaction SMILES: [C:1](=[N:9][OH:10])([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.[OH-].[Na+].[S:31]1[CH:35]=[CH:34][CH:33]=[C:32]1[C:36](Cl)=O>O>[C:2]1([C:1]2[N:8]=[C:36]([C:32]3[S:31][CH:35]=[CH:34][CH:33]=3)[O:10][N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1cccs1
Reactant: NC(=NO)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: c1ccc(-c2noc(-c3cccs3)n2)cc1
Temperature: 70 °C
Reaction time: 0.25 h

Procedure:
A solution of benzamide oxime (24.92%) in 2-methyl THF (67.53 g, 124 mmoles) was charged to a 500 mL flask, followed by DI water (20.0 g), 55% aqueous tetrabutylammonium hydroxide (0.94 g), and 50% sodium hydroxide (0.96 g, 12 mmoles). To this mixture was added 2-thiophenecarbonyl chloride (17.77 g, 120 mmoles) and 50% sodium hydroxide (9.60 g, 120 mmoles) simultaneously over 30 minutes while heating to about 70° C. The reaction was complete is less than one hour. The temperature was reduced to 60° C., and the pH of the aqueous phase was neutralized to 7.61, and was drained off to waste. A hot solution of 1.25 g of Morwet D-425 in 100 ml DI water was added to the mixture, and the 2-phase mixture was heated to distill off the 2-methyltetrahydrofuran/water azeotrope (boiling point 71° C.). Additional water (150 ml) was pumped into the reactor flask over about 15 minutes, once the 2-methyltetrahydrofuran began to distill out. While maintaining good agitation, the pot temperature reached 100.5° C. (vapor temperature 97° C.). The slurry was cooled and filtered using a coarse glass frit. The scale was scraped off the agitator and combined with the wet cake; the scale was only about 3% of total product. The combined wet cake was washed with hot DI water (3×50 ml) and suction-dried for 5 minutes to give a 3-phenyl-5-(thiophen-2-yl)-1,2,4-oxadiazole wet cake, 34.80 g. The loss on drying of the wet cake was 20.13%. The assay of the dried 3-phenyl-5-(thiophen-2-yl)-1,2,4-oxadiazole was 96.12%, and the residual chloride was <200 ppm.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1/[N:12]=[CH:13]/[N:14](C)C)#[N:2].N[C:18]1[CH:19]=[C:20]([C:24]#[CH:25])[CH:21]=[CH:22][CH:23]=1>CC(O)=O>[C:24]([C:20]1[CH:19]=[C:18]([NH:2][C:1]2[C:3]3[C:4](=[CH:5][CH:6]=[C:7]([N+:9]([O-:11])=[O:10])[CH:8]=3)[N:12]=[CH:13][N:14]=2)[CH:23]=[CH:22][CH:21]=1)#[CH:25]
Reactant: C#Cc1cccc(N)c1
Reactant: CN(C)/C=N/c1ccc([N+](=O)[O-])cc1C#N
Solvent: CC(=O)O
Product: C#Cc1cccc(Nc2ncnc3ccc([N+](=O)[O-])cc23)c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 92.5 %

Procedure:
A mixture of (E)-N′-(2-cyano-4-nitrophenyl)-N,N-dimethylformamidine (1.00 g, 4.58 mmol) and 3-aminophenylacetylene (0.64 g, 5.49 mmol) in HOAc (15 mL) was stirred at 100° C. for 3 h. The resulting mixture was cooled to room temperature. The precipitate was filtered out, washed with ether, and dried in vacuo to give 1.23 g (93%) of N-(3-ethynylphenyl)-6-nitroquinazolin-4-amine as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9](OC)=[O:10])=[CH:7][N:6]=[CH:5][N:4]=1.[H-].C([Al+]CC(C)C)C(C)C>ClCCl.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:8]([CH:9]=[O:10])=[CH:7][N:6]=[CH:5][N:4]=1
Reactant: COC(=O)c1cncnc1OC
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1ncncc1C=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To an cooled solution (−78° C. internal temp) of 0.3 g of methyl 4-methoxypyrimidine-5-carboxylate in 20 mL of dichloromethane was added 2 mL of 1 M diisobutyl aluminum hydride in toluene. After stirring 10 min the reaction was quenched with 5 mL of water, allowed to warm to room temperature and dried with 5 g of MgSO4. Concentration of the filtrate under reduced pressure gave the product as a resin and was used without further purification: MS (m+1)=171.1 (hydrate).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:24]1[N:25]([CH2:32][C@:33]2([CH3:36])[CH2:35][O:34]2)[CH:26]=[C:27]([N+:29]([O-:31])=[O:30])[N:28]=1>CN(C=O)C>[CH3:35][C@@:33]1([CH2:36][O:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]3)=[CH:4][CH:3]=2)[O:34][C:24]2=[N:28][C:27]([N+:29]([O-:31])=[O:30])=[CH:26][N:25]2[CH2:32]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(O)cc2)CC1
Reactant: C[C@@]1(Cn2cc([N+](=O)[O-])nc2Cl)CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(OC[C@@]3(C)Cn4cc([N+](=O)[O-])nc4O3)cc2)CC1
Temperature: 70 °C
Reaction time: 0.33 h
Yield: 44.2 %

Procedure:
Tert-butyl 4-(4-hydroxyphenyl)piperazine-1-carboxylate (13.5 g, 48.8 mmol) was dissolved in DMF (100 ml). To the solution, sodium hydride (2.15 g, 53.7 mmol) was added at room temperature, and the solution was stirred for 20 minutes at 70° C. To the solution, (R)-2-chloro-1-(2-methyloxiran-2-ylmethyl)-4-nitroimidazole prepared in Example 12 (10.6 g, 48.8 mmol) was added with cooling on ice-bath, and the solution was stirred for further 20 minutes at 80° C. To the reaction mixture, ice-water was added, and the solution was stirred vigorously. The precipitates were filtered off, washed with water and dissolved in methylene chloride. The solution was washed with a saturated saline solution, dried over magnesium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/methanol=100/1) and then crystallized from methylene chloride-ethyl acetate to afford tert-butyl (R)-4-[4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethoxy)phenyl]piperazine-1-carboxylate (9.9 g, yield 44%) as a white powder.
Reaction SMILES: O(CC)CC.[H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[CH:20]([CH:25]([CH3:27])[CH3:26])[C:21](OC)=[O:22].[OH-].[Na+]>O>[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[CH:20]([CH:25]([CH3:27])[CH3:26])[CH2:21][OH:22]
Reactant: COC(=O)C(c1ccc(Cl)cc1Cl)C(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: CC(C)C(CO)c1ccc(Cl)cc1Cl
Reaction time: 8 h
Yield: 93.5 %

Procedure:
To 140 parts of 1,1'-oxybisethane are added 3 parts of lithium aluminium hydride. Then there is added dropwise a solution of 24.5 parts of methyl 2,4-dichloro-α-(1-methylethyl)benzeneacetate in 35 parts of 1,1'-oxybisethane while cooling in a water-bath. Upon completion, stirring is continued overnight at room temperature. There are added dropwise successively 3 parts of a sodium hydroxide solution 50% and 1 part of water, and the whole is stirred for one hour at room temperature. The mixture is filtered over hyflo and the filter-cake is washed with 2,2'-oxybispropane. The filtrate is evaporated, yielding 20.5 parts (93.5%) of 2,4-dichloro-β-(1-methylethyl)benzeneethanol as a residue.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH2:6][CH:7]([C:9](O)=[O:10])[NH2:8])[C:3]2[CH:12]=[CH:13][CH:14]=[CH:15][C:2]1=2.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[S:1]1[CH:5]=[C:4]([CH2:6][CH:7]([NH2:8])[CH2:9][OH:10])[C:3]2[CH:12]=[CH:13][CH:14]=[CH:15][C:2]1=2
Reactant: NC(Cc1csc2ccccc12)C(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NC(CO)Cc1csc2ccccc12
Temperature: 25 °C

Procedure:
A solution of β-(3-benzo[b]thienyl)DL alanine (5.0 g) [P. N. Rao et al, Int. J. Peptide Protein Res, 29, 118, (1987)] in dry tetrahydrofuran (50 ml) was added to an ice cold solution of lithium aluminium hydride in dry tetrahydrofuran (22 ml of a 1M solution). Once addition was complete the mixture was warmed to reflux for one hour, cooled to room temperature and the reaction quenched by the addition of 4N sodium hydroxide (5.0 ml). The reaction mixture was diluted with water (100 ml) extracted with ethyl acetate (2×100 ml), the organic layers were separated, dried (MgSO4), filtered and the solvent removal under reduced pressure to afford the title compound as a colourless oil. 1H NMR (360 MHz, CDCl3) δ2.65 (1H, m, CH2CHCH2OH), 2.99 (2H, m, CH2CH2OH), 3.23 (2H, m, CH2CHCH2OH), 7.44 (2H, m, 2×ArH), 7.61 (1H, s, S-CHC), 7.86 (1H, dd, J=6.0, 1.0 Hz, ArH), 7.97 (1H, dd, J=6.0, 1.0 Hz, ArH). m/z (EI+) 207.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[N:11]=[CH:10][CH:9]=[CH:8][N:7]=1.[CH3:12][N:13]=[C:14]=[O:15]>>[CH3:12][NH:13][C:14]([NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[N:7]=[CH:8][CH:9]=[CH:10][N:11]=1)=[O:15]
Reactant: CN=C=O
Reactant: NCCSCc1ncccn1
Product: CNC(=O)NCCSCc1ncccn1

Procedure:
By the procedure of Example 24, 2-[(2-aminoethyl)thiomethyl]pyrimidine is reacted with methyl isocyanate to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:38]=[CH:37][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]4[CH:23]=[N:22][CH:21]=[CH:20][N:19]=4)=[CH:13][CH:14]=3)[C:9]([S:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[C:8]2[CH2:29][C:30]([CH3:36])([CH3:35])[C:31]([O:33]C)=[O:32])=[CH:4][CH:3]=1.CO.[Li+].[OH-].C(O)(=O)C>C1COCC1.O.C([O-])(=O)C.[NH4+]>[Cl:1][C:2]1[CH:38]=[CH:37][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]4[CH:23]=[N:22][CH:21]=[CH:20][N:19]=4)=[CH:13][CH:14]=3)[C:9]([S:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[C:8]2[CH2:29][C:30]([CH3:36])([CH3:35])[C:31]([OH:33])=[O:32])=[CH:4][CH:3]=1
Reactant: COC(=O)C(C)(C)Cc1c(SC(C)(C)C)c2cc(OCc3cnccn3)ccc2n1Cc1ccc(Cl)cc1
Agent: CC(=O)[O-]
Agent: [Li+]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)Sc1c(CC(C)(C)C(=O)O)n(Cc2ccc(Cl)cc2)c2ccc(OCc3cnccn3)cc12
Temperature: 70 °C

Procedure:
The compound from Step 2 (416 mg) was hydrolysed by dissolving it in THF (4 mL), MeOH (2 mL), and 2N LiOH (1.5 mL). The solution was heated at 70° C. for 5 hours. The mixture was cooled to room temperature, diluted with H2O (50 mL), acidified with glacial acetic acid to pH 5, and diluted with 25% aqueous ammonium acetate (50 mL). The mixture was extracted with ethyl acetate (50 mL), washed with brine (50 mL), dried (MgSO4), and evaporated to dryness to provide the title compound as a white solid; m.p. 173°-175° C.
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C:15](=[O:19])[CH2:16][C:17]#[N:18])[CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.B.CSC.N.CO.C(Cl)Cl.BrC1N=C(C(O)=O)C=CC=1>>[NH2:18][CH2:17][CH2:16][CH:15]([C:11]1[CH:10]=[C:9]([O:8][CH2:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:14]=[CH:13][N:12]=1)[OH:19]
Reactant: N#CCC(=O)c1cc(OCC2CCCCC2)ccn1
Agent: B
Agent: N
Agent: O=C(O)c1cccc(Br)n1
Solvent: ClCCl
Solvent: CO
Solvent: CSC
Product: NCCC(O)c1cc(OCC2CCCCC2)ccn1

Procedure:
Reduction of 3-(4-(cyclohexylmethoxy)pyridin-2-yl)-3-oxopropanenitrile with borane-dimethylsulfide following the method used in Example 2 gave after flash chromatography purification (20%-30% 7N NH3/MeOH—CH2Cl2 gradient) Example 12 as a yellow oil. Yield (0.13 g, 43%); 1H NMR (400 MHz, DMSO-d6) δ 8.22 (d, J=4.5 Hz, 1H), 6.98 (d, J=2.3 Hz, 1H), 6.76 (dd, J=5.9, 2.8 Hz, 1H), 4.62-4.58 (m, 1H), 3.94 (d, J=5.8 Hz, 2H), 2.72-2.58 (m, 2H), 1.88-1.58 (m, 8H), 1.40-1.02 (m, 5H); RP-HPLC tR=5.91 min; ESI-MS m/z 265.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]2[C:17]3[C:12](=[C:13]([C:21]([NH2:23])=[O:22])[CH:14]=[C:15]([N+:18]([O-])=O)[CH:16]=3)[N:11]=[CH:10][N:9]=2)=[CH:4][C:3]=1[C:26]([F:29])([F:28])[F:27]>C(O)(=O)C.[Zn]>[NH2:18][C:15]1[CH:16]=[C:17]2[C:12](=[C:13]([C:21]([NH2:23])=[O:22])[CH:14]=1)[N:11]=[CH:10][N:9]=[C:8]2[NH:7][CH2:6][C:5]1[CH:24]=[CH:25][C:2]([Cl:1])=[C:3]([C:26]([F:28])([F:29])[F:27])[CH:4]=1
Reactant: NC(=O)c1cc([N+](=O)[O-])cc2c(NCc3ccc(Cl)c(C(F)(F)F)c3)ncnc12
Agent: [Zn]
Solvent: CC(=O)O
Product: NC(=O)c1cc(N)cc2c(NCc3ccc(Cl)c(C(F)(F)F)c3)ncnc12
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 68 %

Procedure:
Zinc powder (115 mg, 1.76 mmol, 5.0 equiv.) was added to a suspension of 4-{[4-chloro-3-(trifluoromethyl)benzyl]amino}-6-nitroquinazoline-8-carboxamide (150 mg, 0.35 mmol, 1.0 equiv.) in acetic acid (12 mL). The resulting mixture was stirred at 80° C. for 10 min. The reaction mixture was filtered. The filtrate was concentrated and purified by pre-HPLC to yield the title compound as yellow solid in 68% yield. Mass: M+H+: 396.