Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][C@@H:8]([CH:12]=[N:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[C:21](=[O:30])[NH:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:9]([CH3:11])[CH3:10])([CH3:4])([CH3:3])[CH3:2].COCOC.C[Si](N[Si](C)(C)C)(C)C>O>[C:1]([O:5][C:6](=[O:31])[NH:7][C@@H:8]([C:12]1[N:22]([CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:21](=[O:30])[C:15]2[C:14](=[CH:19][C:18]([Cl:20])=[CH:17][CH:16]=2)[N:13]=1)[CH:9]([CH3:11])[CH3:10])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)[C@H](C=Nc1cc(Cl)ccc1C(=O)NCc1ccccc1)NC(=O)OC(C)(C)C
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: COCOC
Solvent: O
Product: CC(C)[C@@H](NC(=O)OC(C)(C)C)c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Yield: 51 %

Procedure:
A dry 3-necked, round bottomed flask, equipped with a magnetic stirrer, gas bubbler, heating mantle and a water condenser, was charged with 545.73 g (1.19 mol) of (R)-{1-[(2-benzylcarbamoyl-5-chloro-phenylimino)-methyl]-2-methyl-propyl}-carbamic acid tert-butyl ester (a compound of Formula 106, obtained, for example, as described in Example 2.3), 520 mL of dimethoxymethane and 520 mL (2.492 mol) of HMDS. The mixture was heated to reflux for 24 hours and then allowed to cool. The volatiles were removed by rotary evaporation, leaving an oily residue that was then triturated with ethanol (3×125 mL) to remove residual HMDS or ammonia. To the resulting oil was added 400 mL of ethanol, and the mixture was heated until a homogeneous solution had been obtained. At refulx temperature, 60 mL of water was added and the solution was allowed to cool slowly with light stirring, overnight. The resulting white suspension was allowed to settle; an aliquot of the supernatant was removed and treated dropwise with water to confirm completion (no more solid was formed). The solid was filtered, washed (3×200 mL H2O/EtOH (1:4)), and dried in an oven at 50° C. for 48 hours to afford 260.23 g (51% yield) of the enantiomerically pure title compound of Formula 107, (R)-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydro-quinazolin-2-yl)-2-methylpropyl]-carbamic acid tert-butyl ester.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8]([O:10]CC2C=CC(OC)=CC=2)[N:7]=[CH:6][C:5]=1[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH:29][C:30]2[O:34][N:33]=[C:32]([C:35]([CH3:41])([CH3:40])[C:36]([F:39])([F:38])[F:37])[CH:31]=2)=[O:28])=[C:22]([F:42])[CH:21]=1)[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:3][C:4]1[C:5]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH:29][C:30]3[O:34][N:33]=[C:32]([C:35]([CH3:41])([CH3:40])[C:36]([F:38])([F:39])[F:37])[CH:31]=3)=[O:28])=[C:22]([F:42])[CH:21]=2)=[CH:6][NH:7][C:8](=[O:10])[CH:9]=1)[CH3:2]
Reactant: CCOc1cc(OCc2ccc(OC)cc2)ncc1-c1ccc(CC(=O)Nc2cc(C(C)(C)C(F)(F)F)no2)c(F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOc1cc(=O)[nH]cc1-c1ccc(CC(=O)Nc2cc(C(C)(C)C(F)(F)F)no2)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.8 %

Procedure:
To a suspension of 2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(3-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-5-yl)acetamide (1.5 g, 2.55 mmol) in DCM (20 mL) was added TFA (2 mL, 26.9 mmol) dropwise. The mixture was stirred at 25° C. for 2 h. The mixture was then concentrated. To the residue was added H2O (50 mL) dropwise and then neutralized with saturated Na2CO3 solution to adjust pH=7.5. The precipitate was filtered, washed with H2O (50 mL×3) and dried in vacuo. To the solid was added PE/EA (3:1, v/v, 30 mL) and stirred for 0.5 h. The solid was filtered, washed with PE/EA (3:1, v/v, 30 mL×2). The solid was redissolved in DCM/MeOH (20:1, v/v, 50 mL) and then concentrated in vacuo to a minimal amount of solvent (about 10 mL). The solid was filtered, washed with CH3CN (10 mL×2) and dried in vacuo. The residue was redissolved in DCM/MeOH (10:1, v/v, 50 mL) and concentrated in vacuo to give a white solid of 2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(3-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-5-yl)acetamide (440 mg, 0.938 mmol, 36.7% yield): 1H NMR (400 MHz, CD3OD): δ 7.39-7.36 (m, 1H), 7.36-7.30 (m, 1H), 7.25-7.18 (m, 2H), 6.37 (s, 1H), 5.99 (s, 1H), 4.11 (q, J=7.2 Hz, 2H), 3.82 (s, 2H), 1.53 (s, 6H), 1.37 (t, J=6.8 Hz, 3H). ES-LCMS m/z: 468 (M+H); CHN analytical report: average (%): N, 8.717; C, 55.32; H, 4.672.
Reaction SMILES: [C:1]([NH:5][C:6](=[O:32])[CH2:7][N:8]1[CH:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][CH:12]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])[CH2:11][CH:10]([N:28]=[N+]=[N-])[C:9]1=[O:31])([CH3:4])([CH3:3])[CH3:2]>C(O)C.C(Cl)Cl.[Pd]>[C:1]([NH:5][C:6](=[O:32])[CH2:7][N:8]1[CH:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:13][CH:12]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])[CH2:11][CH:10]([NH2:28])[C:9]1=[O:31])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccccc1C1CC(N=[N+]=[N-])C(=O)N(CC(=O)NC(C)(C)C)C(c2ccccc2)C1
Agent: [Pd]
Solvent: CCO
Solvent: ClCCl
Product: Cc1ccccc1C1CC(N)C(=O)N(CC(=O)NC(C)(C)C)C(c2ccccc2)C1
Yield: 94.7 %

Procedure:
A solution of 13.7 grams (31.6 mmol) N-(t-Butyl)-2-oxo-3-azido-5-(2-methylphenyl)-7-phenyl-2,3,4,5,6,7-hexahydroazepin-1-yl ethanoic amide in 120 mL ethanol and 60 mL methylene chloride was hydrogenated at 42 p.s.i. in the presence of 3.9 grams 10% palladium-on-carbon for 36 hours. It was then filtered through celite with ethanol and methylene chloride, evaporated, and chromatographed on silica gel using 15% and 30% methanol in ethyl acetate as eluent to afford 12.2 grams (95%) of a foam.
Reaction SMILES: N[C@@H](CC1C=CC=CC=1)[C@H](O)CN1[C@H](C(NC(C)(C)C)=O)C[C@H]2[C@H](CCCC2)C1.[NH2:30][C@H:31]([C:39]([OH:41])=O)[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C1(=O)[O:47][C:45](=[O:46])C2=CC=CC=C12.C1(C[C@H](N2C(=O)C3=CC=CC=C3C2=O)C(O)=O)C=CC=CC=1.C1(C[C@H](N2C(=O)C3=CC=CC=C3C2=O)C(Cl)=O)C=CC=CC=1.C1(C[C@H](N2C(=O)C3=CC=CC=C3C2=O)C=O)C=CC=CC=1.C(C(O)[C@@H](N1C(=O)C2=CC=CC=C2C1=O)CC1C=CC=CC=1)#N>>[NH2:30][C@@H:31]([CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[CH:39]([OH:41])[C:45]([OH:47])=[O:46]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: O=C1OC(=O)c2ccccc21
Agent: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCCC[C@@H]2CN1C[C@@H](O)[C@@H](N)Cc1ccccc1
Agent: N#CC(O)[C@H](Cc1ccccc1)N1C(=O)c2ccccc2C1=O
Agent: O=C(Cl)[C@H](Cc1ccccc1)N1C(=O)c2ccccc2C1=O
Product: N[C@@H](Cc1ccccc1)C(O)C(=O)O

Procedure:
Process for the production of 2-[3-(S)-amino-2(R)-hydroxy-4-phenylbutyl]-N-tert.-butyl-decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide of the formula ##STR20## characterised in that a) L-phenylalanine of the formula ##STR21## is reacted with phthalic anhydride, b) the resultant 3-phenyl-2(S)-phthalimidopropionic acid of the formula ##STR22## is converted into the corresponding acid chloride, c) the resultant 3-phenyl-2(S)-phthalimidopropionic acid chloride of the formula ##STR23## is reduced, d) the resultant 3-phenyl-2(S)-phthalimidopropan-1-al of the formula ##STR24## is transformed into the 1-cyano-3-phenyl-2(S)-phthalimidopropan-1-ol of the formula ##STR25## e) the resultant nitrile of the formula VI is hydrolysed, f) the unisolated 3(S)-amino-2-hydroxy-4-phenylbutyric acid formed of the formula ##STR26## is reacted with a low alkyl ester or the phenyl or benzyl ester of chloroformic acid,
Reaction SMILES: [CH3:1][N:2]([CH3:25])[CH2:3][CH2:4][CH2:5][C@@:6]([C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][C:16]=1[CH2:23]O)([C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)[OH:7].C([O-])([O-])=O.[K+].[K+].ClC1C=CC(Cl)=CC=1[N+]([O-])=O.O.O.[C:45]([OH:50])(=[O:49])[C:46]([OH:48])=[O:47]>C(O)(C)C.O.CS(C)=O>[CH3:25][N:2]([CH2:3][CH2:4][CH2:5][C@@:6]1([C:8]2[CH:9]=[CH:10][C:11]([F:14])=[CH:12][CH:13]=2)[O:7][CH2:23][C:16]2[CH:17]=[C:18]([C:19]#[N:20])[CH:21]=[CH:22][C:15]1=2)[CH3:1].[C:46]([OH:48])([C:45]([OH:50])=[O:49])=[O:47].[CH3:1][N:2]([CH3:25])[CH2:3][CH2:4][CH2:5][C@:6]1([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[C:15]2[C:16](=[CH:17][C:18]([C:19]#[N:20])=[CH:21][CH:22]=2)[CH2:23][O:7]1
Reactant: CN(C)CCC[C@](O)(c1ccc(F)cc1)c1ccc(C#N)cc1CO
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: O=[N+]([O-])c1cc(Cl)ccc1Cl
Solvent: CS(C)=O
Solvent: CC(C)O
Solvent: O
Product: CN(C)CCC[C@@]1(c2ccc(F)cc2)OCc2cc(C#N)ccc21
Temperature: 102.5 °C
Reaction time: 16 h

Procedure:
To a solution of 64 Kg of (S)-(−)-4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxy-1-butyl]-3-(hydroxymethyl)benzonitrile in 300 lit DMSO was added 77.48 Kg of anhydrous K2CO3 and 43.06 Kg of 2,5-dichloronitrobenzene at room temperature and stirred for 16 hours at 100-105° C. To the reaction mixture 3000 ml of water was added at about 30° C. The reaction mixture was extracted with toluene, the toluene layer was washed with water and 5% sodium hydroxide solution and after acid base treatment yielded an oily product. The oil was dissolved in 510 lit of isopropanol at about 30° C. and 20.4 lit water added, stirred for 10 minutes and 20.8 Kg of oxalic acid dihydrate was added and heated to about 70-75° C., stirred, charcolised, cooled and filtered. The filtrate was cooled to 5-10° C. slowly and the resultant solid was filtered, dried at 60° C. and micronised to get the oxalic acid salt of (S)-(+)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofuran carbonitrile.
Reaction SMILES: [CH3:1][N:2]([CH3:25])[CH2:3][CH2:4][CH2:5][C@@:6]([C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][C:16]=1[CH2:23]O)([C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)[OH:7].CC(C)([O-])C.[K+].ClC1C=CC(Cl)=CC=1[N+]([O-])=O.O.O.[C:45]([OH:50])(=[O:49])[C:46]([OH:48])=[O:47]>O1CCCC1.CC(C)=O.O>[CH3:25][N:2]([CH2:3][CH2:4][CH2:5][C@@:6]1([C:8]2[CH:9]=[CH:10][C:11]([F:14])=[CH:12][CH:13]=2)[O:7][CH2:23][C:16]2[CH:17]=[C:18]([C:19]#[N:20])[CH:21]=[CH:22][C:15]1=2)[CH3:1].[C:46]([OH:48])([C:45]([OH:50])=[O:49])=[O:47].[CH3:1][N:2]([CH3:25])[CH2:3][CH2:4][CH2:5][C@:6]1([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[C:15]2[C:16](=[CH:17][C:18]([C:19]#[N:20])=[CH:21][CH:22]=2)[CH2:23][O:7]1
Reactant: CN(C)CCC[C@](O)(c1ccc(F)cc1)c1ccc(C#N)cc1CO
Agent: CC(C)(C)[O-]
Agent: O=C(O)C(=O)O
Agent: O=[N+]([O-])c1cc(Cl)ccc1Cl
Solvent: C1CCOC1
Solvent: CC(C)=O
Solvent: O
Product: CN(C)CCC[C@@]1(c2ccc(F)cc2)OCc2cc(C#N)ccc21
Reaction time: 0.5 h

Procedure:
To a solution of 6 gm of (S)-(−)-4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxy-1-butyl]-3-(hydroxymethyl)benzonitrile in 60 ml tetrahydrofuran (THF) was added 4.33 gm of potassium tertiary butoxide at 0-10° C. and stirred for 30 minutes. A solution of 4.04 gm of 2,5-dichloronitrobenzene in 30 ml THF at 0-10° C. was added to it and stirred for 10-15 hours at room temperature, followed by addition of 250 ml of water. The reaction mixture was extracted with toluene, the toluene layer was washed with water and 5% sodium hydroxide solution and after acid base treatment yielded an oily product. The oil was dissolved in 16 ml of acetone at 30° C. and 1.75 gm of oxalic acid dihydrate in 8 ml acetone was added to it, stirred, cooled, filtered and dried at 60° C. to get the oxalic acid salt of (S)-(+)-1-[3-(dimethylamino) propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofuran carbonitrile.
Reaction SMILES: C([Li:5])CCC.[CH3:6][C:7]1([CH3:15])[CH2:12][CH2:11][CH2:10][C:9]([CH3:14])([CH3:13])[NH:8]1.C1(S(N2C3C(=CN=CC=3)C=C2)(=O)=O)C=CC=CC=1.C1(S(N2C3C(=CN=CC=3)C=C2[Li])(=O)=O)C=CC=CC=1>O1CCCC1.[Mn](Cl)(Cl)=O>[Li:5][N:8]1[C:9]([CH3:14])([CH3:13])[CH2:10][CH2:11][CH2:12][C:7]1([CH3:15])[CH3:6]
Reactant: [Li]CCCC
Reactant: CC1(C)CCCC(C)(C)N1
Agent: O=[Mn](Cl)Cl
Agent: O=S(=O)(c1ccccc1)n1ccc2cnccc21
Agent: [Li]c1cc2cnccc2n1S(=O)(=O)c1ccccc1
Solvent: C1CCOC1
Product: [Li]N1C(C)(C)CCCC1(C)C
Temperature: -70 °C
Yield: 100 %

Procedure:
A solution of 0.15 mole of lithium 2,2,6,6-tetramethylpiperidide is prepared by the addition of 0.15 mole of n-butyllithium to 0.15 mole of 2,2,6,6-tetramethylpiperidine in 120 ml of tetrahydrofuran at a temperature lower than -20° C. This solution is then added over a period of a few minutes to 0.1 mole of 1-benzenesulfonyl 5-aza indole cooled to -70° C. while maintaining this temperature throughout the addition. 0.15 mole of anhydrous manganous chloride is then added to the solution of 1-benzenesulfonyl 2-lithio 5-aza indole. The temperature of the medium is then brought from -65° C. to -25° C. in order to bring the exchange reaction to completion and obtain a solution of the desired manganous derivative which is used as such.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][CH:3]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[C:23]([O:30][CH3:31])(=[O:29])[CH2:24][C:25]([O:27][CH3:28])=[O:26].P(C(C)(C)C)(C(C)(C)C)C(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[C:9]([O:8][C:6]([C:5]1[CH:13]=[CH:14][C:2]([CH:24]([C:23]([O:30][CH3:31])=[O:29])[C:25]([O:27][CH3:28])=[O:26])=[CH:3][CH:4]=1)=[O:7])([CH3:12])([CH3:11])[CH3:10]
Reactant: COC(=O)CC(=O)OC
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COC(=O)C(C(=O)OC)c1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 85 °C
Reaction time: 48 h

Procedure:
To a mixture of tert-butyl 4-bromobenzoate (10.07 g, 39.2 mmol), K3PO4 (20.19 g, 95 mmol), and dimethyl malonate (4.50 mL, 39.2 mmol) was added toluene (69 mL), Pd2(dba)3 (975 mg, 1.08 mmol), and P(tert-Bu)3 (12.8 mL, 10% wt. in hexanes, 4.3 mmol). The reaction mixture was degassed and heated to 85° C. After 2 d, the reaction mixture was diluted with ethyl acetate, washed with water (1×), brine (1×), dried over MgSO4, filtered, and concentrated. Purification by flash column chromatography on silica gel (5% to 20% ethyl acetate in hexanes) gave dimethyl [4-(tert-butoxycarbonyl)phenyl]malonate as a low melting white solid: 1H NMR (600 MHz, CDCl3) δ 7.98 (d, J=8.5 Hz, 2H), 7.45 (d, J=8.2 Hz, 2H), 4.70 (s, 1H), 3.76 (s, 6H), 1.58 (s, 91-1); ESIMS calcd 331.1 (M++Na), found 331.1 (M++Na). General Procedure for the Amidation of Dimethyl [4-(tert-butoxycarbonyl)phenyl]malonate
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)[Cl:2].[O:6]([C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CC(O)C>[O:6]([C:13]1[CH:14]=[CH:15][C:16]([N:17]([CH2:4][CH:3]([OH:5])[CH2:1][Cl:2])[CH2:4][CH:3]([OH:5])[CH2:1][Cl:2])=[CH:18][CH:19]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: ClCC1CO1
Reactant: Nc1ccc(Oc2ccccc2)cc1
Solvent: CC(C)O
Product: OC(CCl)CN(CC(O)CCl)c1ccc(Oc2ccccc2)cc1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
To a four-necked flask equipped with a thermometer, a cooling tube, and a stirrer were charged with 610.6 g (6.6 mol) of epichlorohydrin and 509.3 g of 2-propanol, and then the inside of the four-necked flask was purged with nitrogen. The temperature was raised to 60° C. and 203.7 g (1.1 mol) of a powder of 4-phenoxyaniline was added over three hours. Moreover, the temperature was raised to 80° C. and the reaction was continued at 80° C. for 18 hours under stirring to produce 4-phenoxy-N,N-bis(2-hydroxy-3-chloropropyl)aniline.
Reaction SMILES: [C:1]1([CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][OH:8])[CH:2]=1.C(N(CC)CC)C.[C:18]([Si:22]([CH3:25])([CH3:24])Cl)([CH3:21])([CH3:20])[CH3:19].N>ClCCl>[Si:22]([O:8][CH2:7][C:3]1[CH:2]=[C:1]([CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:25])[CH3:24]
Reactant: OCc1cccc(CO)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCc1cccc(CO)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 45.4 %

Procedure:
To 1,3-benzenedimethanol (5.10 g, 36.91 mmol) in dichloromethane (70 ml) was added at 0° C. triethylamine (7.47 g, 73.82 mmol), 4-dimethyl-aminopyridine (451 mg, 3.61 mmol) and t-butyldimethylchlorosilane (5.56 g, 36.91 mmol) successively, and the mixture was stirred for 20 hours at room temperature. Thereto was added a saturated ammonia solution and the mixture was extracted with ethyl acetate and separated by a separating funnel. The organic layer was washed with water and saturated brine, dried over magnesium sulfate and filtered. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography to give the subject compound (4.23 g, 45%).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]([CH3:14])([N+:11]([O-:13])=[O:12])[CH3:10])(=O)=O.[I-:15].[Na+].O>CC(C)=O>[CH3:10][C:9]([N+:11]([O-:13])=[O:12])([CH3:14])[CH2:8][CH2:7][CH2:6][I:15]
Reactant: [I-]
Reactant: CC(C)(CCCOS(C)(=O)=O)[N+](=O)[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)(CCCI)[N+](=O)[O-]
Reaction time: 8 h
Yield: 99.6 %

Procedure:
4-Methyl-4-nitropentanol methanesulfonate (3.38 g, 15 mmol) was dissolved in acetone (50 ml) and sodium iodide (8.7 g, 58 mmol) was added. The mixture was stirred overnight. Water (20 ml) was added and acetone was evaporated by concentration under reduced pressure. The residue was extracted with ethyl acetate (50 ml). The extract was washed with 5% aqueous sodium thiosulfate solution (20 ml) and saturated brine (20 ml), and ethyl acetate was evaporated by concentration under reduced pressure to give the objective compound (3.84 g, yield 99.6%).
Reaction SMILES: Cl[CH2:2][C:3]1([CH3:7])[CH2:6][O:5][CH2:4]1.[N-:8]=[N+:9]=[N-:10].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[N:8]([CH2:2][C:3]1([CH3:7])[CH2:6][O:5][CH2:4]1)=[N+:9]=[N-:10]
Reactant: [N-]=[N+]=[N-]
Reactant: CC1(CCl)COC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Product: CC1(CN=[N+]=[N-])COC1
Temperature: 25 °C
Yield: 92.7 %

Procedure:
A mixture of 3-chloromethyl-3-methyloxetane (10.1 g, 83.5 mmol), tetra-n-butylammonium bromide (0.308 g, 0.96 mmol), sodium azide (6.5 g, 100 mmol) and water (27 mL) was heated at about 96° C. to about 103° C. for 4.5 h, after which time gas chromatographic analysis of the mixture indicated that the reaction had reached completion. The mixture was cooled to ambient temperature, and extracted with methylene chloride (25 mL). The organic extract was passed through a column containing aluminum oxide (10 g), and the column was rinsed with additional methylene chloride. The solvent was evaporated to give 9.84 g (93% yield) of 3-azidomethyl-3methyloxetane (>99.5% purity by glc and NMR analysis). NMR: 1H NMR: δ1.32 (s, 3H), 3.52 (s, 2H), 4.25 & 4.35 (AB, J=6.0 Hz, 4H); 13C NMR: δ21.44, 58.33, 40.03, 79.76; glc Rt= 3.19 min.
Reaction SMILES: [C:1]1([NH:7][C:8]2[O:9][C:10]3[CH:16]=[C:15]([CH2:17][C:18]([O:20]C)=[O:19])[CH:14]=[CH:13][C:11]=3[N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].C(O)(=O)C>CS(C)=O.O1CCCC1.O>[C:1]1([NH:7][C:8]2[O:9][C:10]3[CH:16]=[C:15]([CH2:17][C:18]([OH:20])=[O:19])[CH:14]=[CH:13][C:11]=3[N:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)Cc1ccc2nc(Nc3ccccc3)oc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: O=C(O)Cc1ccc2nc(Nc3ccccc3)oc2c1
Reaction time: 2 h
Yield: 90.2 %

Procedure:
To methyl 2-phenylaminobenzoxazole-6-acetate (0.28 g) in a mixture of dimethyl sulphoxide (1 ml) and tetrahydrofuran (1 ml) was added 2M sodium hydroxide (1 ml). The mixture was stirred for 2 hrs. then acidified with acetic acid and diluted with water and the precipitate filtered and washed with water and dried to give 2-phenylaminobenzoxazole-6-acetic acid (0.24 g) as a white solid.
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1[C:8]([CH3:16])=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=[O:11].[I-].[Na+].[OH-].[Na+].[CH2:21](O)[CH:22](O)[CH2:23]O>O.CS(C)=O.CO>[CH3:16][C:8]1[C:9]([C:10]([OH:12])=[O:11])=[CH:13][CH:14]=[C:15]2[C:7]=1[N:6]=[CH:23][CH:22]=[CH:21]2
Reactant: Cc1c(N)cccc1C(=O)O
Reactant: OCC(O)CO
Agent: O=S(=O)(O)O
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: CO
Product: Cc1c(C(=O)O)ccc2cccnc12
Temperature: 150 °C

Procedure:
To a solution of concentrated sulfuric acid (21.74 ml) in water (16 ml), was added 3-amino-2-methylbenzoic acid (5 g; supplier Acros), 1,2,3-propanetriol (2.437 ml) and sodium iodide (0.104 g). The reaction mixture was heated to reflux for 2 hours at 150° C. Further 1,2,3-propanetriol (2.437 ml) was added and reaction mixture was refluxed for another two hours. The pH of the reaction mixture was adjusted to pH 3 by adding sodium hydroxide (12.5 M, 32.6 ml) then the mixture was filtered and the solid discarded. The aqueous phase was extracted with ethyl acetate and then the organic solvent was removed under vacuum to give crude product. This was dissolved in 1:1 DMSO & MeOH and purified by reverse phase chromatography and relevant fractions were combined and concentrated to afford the title compound (750 mg) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-])=O)[CH:3]=1>C1COCC1.[Pt]>[Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:6])=[CH:7][CH:8]=1
Reactant: Nc1ccc(Br)cc1[N+](=O)[O-]
Agent: [Pt]
Solvent: C1CCOC1
Product: Nc1ccc(Br)cc1N
Reaction time: 2 h

Procedure:
4-Bromo-2-nitroaniline (10 g, 46 mmol) in THF (120 mL) was treated with 1% Pt/C (1.0 g) and hydrogenated at room temperature under 40 psi of H2 pressure. After 2 hours, the reaction was filtered and the filtrate concentrated to provide the title compound which was used without further purification in the next step. MS 188 (M+H)+; 1H NMR (400 MHz, CDCl3) δ 6.77–6.81 (m, 2H), 6.54 (d, J=8.4 Hz, 1H), 3.28 (br, 4H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]2=[O:17])[CH:2]=1.CC(C)([O-])C.[K+].[CH3:24][N:25]=[C:26]=[S:27]>O1CCCC1>[CH3:24][NH:25][C:26]([C:11]1([C:3]2[CH:2]=[N:1][C:10]3[C:5]([CH:4]=2)=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:16][CH2:15][CH2:14][CH2:13][C:12]1=[O:17])=[S:27]
Reactant: O=C1CCCCC1c1cnc2ccccc2c1
Reactant: CN=C=S
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CNC(=S)C1(c2cnc3ccccc3c2)CCCCC1=O
Yield: 9.4 %

Procedure:
A solution of (±)-2-(quinolin-3-yl)cyclohexanone (0.78 g, 3.5 mmol) in tetrahydrofuran (10 ml) at -5° C. was treated with potassium t-butoxide (0.43 g, 3.9 mmol) in one portion. After 25 minutes at -5° C. the deep red mixture was treated dropwise during 1 minute with a solution of methyl isothiocyanate (0.28 g, 3.9 mmol) in tetrahydrofuran (2 ml). After 4 hours at 0° C. the reaction mixture was partitioned between saturated aqueous ammonium chloride solution (50 ml) and chloroform (50 ml). The aqueous layer was extracted again with chloroform (50 ml). The combined organic extracts were then dried over sodium sulphate and concentrated in vacuo (20° C.; 14 mmHg) to give a crude oil which was purified by flash chromatography over silica gel eluting with ethyl acetate to give (±)-N-methyl-2-oxo-1-(quinolin-3-yl)cyclohexanecarbothioamide (0.1 g, 0.33 mmol), m.p. 235°-236° C.;
Reaction SMILES: [N:1]1[C:10]2[NH:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][CH2:13][NH:14]C(OC(C)(C)C)=O.FC(F)(F)C(O)=O.S(=O)(=O)(O)O>C(OCC)(=O)C.C(Cl)Cl>[N:1]1[C:10]2[NH:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][CH2:13][NH2:14]
Reactant: CC(C)(C)OC(=O)NCCCc1ccc2c(n1)NCCC2
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: NCCCc1ccc2c(n1)NCCC2

Procedure:
The title compound was prepared by treating the Boc derivative 1-5 with either HCI gas in ethyl acetate as described in U.S. Pat. No. 5,952,341 and WO 99/31061, or with trifluoroacetic acid in methylene chloride, or aqueous sulfuric acid; m.p. 66.0-68.5° C.