Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C=C[NH+]=CC=1.[Br:7][Br-]Br.[CH2:10]([O:17][C:18]1[CH:19]=[C:20]([CH:27]=[CH:28][C:29](=[O:31])[CH3:30])[CH:21]=[CH:22][C:23]=1[N+:24]([O-:26])=[O:25])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.B(F)(F)F.CCOCC.C(OCC)(=O)C>O1CCCC1.O>[Br:7][CH2:30][C:29](=[O:31])[CH:28]=[CH:27][C:20]1[CH:21]=[CH:22][C:23]([N+:24]([O-:26])=[O:25])=[C:18]([O:17][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:19]=1
Reactant: CC(=O)C=Cc1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Agent: FB(F)F
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(C=Cc1ccc([N+](=O)[O-])c(OCc2ccccc2)c1)CBr
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 61.4 %

Procedure:
Pyridinium bromide perbromide (82.8 g) was added to a mixture of 1-(3-benzyloxy-4-nitrophenyl)but-1-en-3-one (70.0 g) and boron trifluoride etherate (290 ml) in tetrahydrofuran (1.4 l) under ice-cooling. The mixture was stirred for 2.5 hours at ambient temperature. The reaction mixture was added to a mixture of ethyl acetate and water under stirring. The separated organic layer was washed with saturated aqueous sodium bicarbonate and brine successively. The solution was dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was recrystallized from diisopropyl ether to give 4-bromo-1-(3-benzyloxy-4-nitrophenyl)but-1-en-3-one (54.42 g).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]1([C:13](=[C:29]2[CH2:34][C:33]([CH3:36])([CH3:35])[CH2:32][C:31]([CH3:38])([CH3:37])[CH2:30]2)[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][C:24](OCC)=[O:25])=[CH:16][CH:15]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C1COCC1>[C:7]1([C:13](=[C:29]2[CH2:34][C:33]([CH3:36])([CH3:35])[CH2:32][C:31]([CH3:38])([CH3:37])[CH2:30]2)[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][OH:25])=[CH:16][CH:15]=2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCOC(=O)CCCOc1ccc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccccc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1(C)CC(=C(c2ccccc2)c2ccc(OCCCCO)cc2)CC(C)(C)C1
Reaction time: 0.5 h
Yield: 69.8 %

Procedure:
The LAH reduction procedure described for 15 (example 5) was utilized using 36 (200 mg, 0.46 mmol), LAH (1 M solution in THF, 1.4 mL, 1.38 mmol) in THF (30 mL). The reaction was stirred for 0.5 h. Standard aqueous work-up followed by purification gave 126 mg (70%) of the title product 37 as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.28-7.24 (m, 2H), 7.18-7.14 (m, 3H), 7.07 (d, J=8.4 Hz, 2H), 6.79 (d, J=8.4 Hz, 2H), 3.97 (t, J=6.0 Hz, 2H), 3.71 (br m, 2H), 1.98 (s, 2H), 1.95 (s, 2H), 1.88-1.84 (pentet, J=6.0 Hz, 2H), 1.78-1.70 (pentet, J=5.6 Hz, 2H), 1.28 (s, 2H), 0.93 (s, 6H), 0.92 (s, 6H). LCMS (APCI): m/z 393 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH2:14][C:15]([OH:17])=[O:16])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[CH2:20](O)[CH3:21].C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>O>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH2:14][C:15]([O:17][CH2:20][CH3:21])=[O:16])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: CCO
Reactant: Cn1c(CC(=O)O)ccc1C(=O)c1ccc(Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)Cc1ccc(C(=O)c2ccc(Cl)cc2)n1C

Procedure:
A suspension of 55.4 g. of 5-(p-chlorobenzoyl)-1-methyl-pyrrole-2-acetic acid, 44 ml. of absolute ethanol, 1g. of p-toluenesulfonic acid and 650 ml. of benzene is heated under reflux with azeotropic removal of water for 7 hours. The reaction mixture is filtered, washed with sodium bicarbonate solution, dried over anhyrous magnesium sulfate and the solvent evaporated in vacuo. The crystalline residue is recrystallized twice from cyclohexane to give ethyl 5-(p-chlorobenzoyl)-1-methyl-pyrrole-2-acetate as a yellow solid, m.p. 74°-76°C.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C@H:6]1[O:13][C:14](=[O:16])[CH3:15])(=[O:3])[CH3:2].[C:17]([O:20][C:21]1([C:37](=[O:39])[CH3:38])[CH2:30][C:29]2[C:28](=[O:31])[CH:27]=[CH:26][C:25](=[O:32])[C:24]=2[C:23]2([S:36][CH2:35][CH2:34][S:33]2)[CH2:22]1)(=[O:19])[CH3:18]>>[C:17]([O:20][C:21]1([C:37](=[O:39])[CH3:38])[CH2:30][C:29]2[C:28](=[O:31])[CH:27]3[CH:26]([CH:5]([O:4][C:1](=[O:3])[CH3:2])[C:8]4[C:7]([CH:6]3[O:13][C:14](=[O:16])[CH3:15])=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:25](=[O:32])[C:24]=2[C:23]2([S:36][CH2:35][CH2:34][S:33]2)[CH2:22]1)(=[O:19])[CH3:18]
Reactant: CC(=O)O[C@@H]1c2ccccc2[C@H]1OC(C)=O
Reactant: CC(=O)OC1(C(C)=O)CC2=C(C(=O)C=CC2=O)C2(C1)SCCS2
Product: CC(=O)OC1c2ccccc2C(OC(C)=O)C2C(=O)C3=C(CC(OC(C)=O)(C(C)=O)CC34SCCS4)C(=O)C12
Yield: 78.8 %

Procedure:
A solution of 220 mg (1.0 mmol) of trans-1,2-diacetoxy-1,2-dihydrobenzocyclobutene and 234 mg (0.66 mmol) of rac-3'-acetoxy-3'-acetyl-1',2',3',4',5',8'-hexahydro-5',8'-dioxospiro[1,3-dithiolane-2,1'-naphthalene] [prepared as described in Example 5(A)] in 15 ml of dry xylane was stirred and heated under reflux under an atmosphere of nitrogem for 30 minutes. The pale orange solution was evaporated and the resulting yellow oil was triturated with 15 ml of diethyl ether to yield 298 mg (79%) of rac-3',6',11'-triacetoxy-3'-acetyl-1',2',3',4',5',5a',6',11',11a',12'-decahydro-5',12'-dioxospiro[1,3-dithiolane-2,1'-naphthacene] in the form of a yellow solid of melting point 135°-145° C.
Reaction SMILES: [ClH:1].CC(C)(C)C(O[NH:7][C@@H:8]1[C:14](=[O:15])[NH:13][C:12]2[C:16]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:17][CH:18]=[CH:19][C:11]=2[S:10][CH2:9]1)=O>O1CCOCC1>[ClH:1].[NH2:7][C@@H:8]1[C:14](=[O:15])[NH:13][C:12]2[C:16]([O:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[CH:17][CH:18]=[CH:19][C:11]=2[S:10][CH2:9]1
Reactant: CC(C)(C)C(=O)ON[C@H]1CSc2cccc(Oc3ccccc3)c2NC1=O
Agent: Cl
Solvent: C1COCCO1
Product: N[C@H]1CSc2cccc(Oc3ccccc3)c2NC1=O

Procedure:
3.65 mL of a solution of hydrogen chloride in dioxane (4 M) are placed in a 100 mL round-bottomed flask containing 188 mg of 60 (0.487 mmol). The reaction medium is concentrated to dryness and the residue is taken up in 10 mL of isopropyl ether. After filtering, 100 mg of amine 61 (white solid) are obtained in the form of the hydrochloride.
Reaction SMILES: Br[CH2:2][C@H:3]([O:16][Si:17]([CH2:22][CH3:23])([CH2:20][CH3:21])[CH2:18][CH3:19])[C:4]1[CH:15]=[CH:14][C:7]2[O:8][C:9]([CH3:13])([CH3:12])[O:10][CH2:11][C:6]=2[CH:5]=1.[CH2:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O.C(OCC)C>O1CCOCC1>[CH2:24]([NH:31][CH2:2][C@@H:3]([C:4]1[CH:15]=[CH:14][C:7]2[O:8][C:9]([CH3:13])([CH3:12])[O:10][CH2:11][C:6]=2[CH:5]=1)[O:16][Si:17]([CH2:22][CH3:23])([CH2:20][CH3:21])[CH2:18][CH3:19])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: NCc1ccccc1
Reactant: CC[Si](CC)(CC)O[C@@H](CBr)c1ccc2c(c1)COC(C)(C)O2
Solvent: C1COCCO1
Solvent: O
Solvent: CCOCC
Product: CC[Si](CC)(CC)O[C@@H](CNCc1ccccc1)c1ccc2c(c1)COC(C)(C)O2
Temperature: 105 °C
Reaction time: 8 h

Procedure:
A mixture of {[(1R)-2-Bromo-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethyl]oxy}(triethyl)silane (130 g) and benzylamine (177 ml) in 1,4-dioxane (650 ml) was heated at 105° C. with stirring overnight. The mixture was then cooled to room temperature and water (150 ml) and diethyl ether (1200 ml) added. The layers were separated and the ethereal layer was washed with saturated ammonium chloride solution (3×600 ml), saturated sodium bicarbonate solution (200 ml) and then brine (200 ml). The solution was dried over anhydrous Na2SO4 before being filtered and concentrated under reduced pressure to give the title compound (129.9 g) as an oil, LC RT=5.20 min, δ (CDCl3) 7.22 (5H, m), 7.02 (1H, d, J 8.7 Hz), 6.86 (1H, s), 6.68 (1H, d, J 8.3 Hz), 4.75 (2H, s), 4.69 (1H, m), 3.73 (2H, s), 2.70 (2H, m), 1.46 (6H, s) 0.79 (9H, m), 0.44 (6H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:22])[C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:23]([O:25][CH2:26][CH3:27])=[O:24].C(Cl)(=O)C(Cl)=O.[Cl:34][C:35]1[CH:40]=[CH:39][C:38]([CH2:41][CH2:42][NH2:43])=[CH:37][CH:36]=1.C(N(C(C)C)CC)(C)C>ClCCl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:22])[C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([C:17](=[O:19])[NH:43][CH2:42][CH2:41][C:38]3[CH:39]=[CH:40][C:35]([Cl:34])=[CH:36][CH:37]=3)=[CH:20][CH:21]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)C1CCOc2c1cc(Cl)c(Oc1ccc(C(=O)O)cc1)c2Cl
Reactant: NCCc1ccc(Cl)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CCOc2c1cc(Cl)c(Oc1ccc(C(=O)NCCc3ccc(Cl)cc3)cc1)c2Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 98.2 %

Procedure:
4-(6,8-Dichloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (22.96 g, 55.832 mmol) was dissolved in dichloromethane (200 ml) and DMF (0.2 ml). Oxalyl chloride (8.6 ml, 98.585 mmol) was added slowly over a period of 30 minutes at ambient temperature. The crude mixture was concentrated under reduced pressure. Dry dichloromethane (200 ml) was added and the mixture was cooled in an ice bath. 2-(4-Chlorophenyl)ethylamine (8.5413 ml, 61.415 mmol) and diisopropylethylamine (11.701 ml, 66.999 mmol) were added sequentially to the mixture. The mixture was stirred in an ice bath for 10 minutes and warmed to ambient temperature. The crude mixture was washed with 1N HCl (100 ml), water (2×50 ml), and brine (50 ml), dried over MgSO4, filtered through GF paper, and concentrated to provide 30.1 g of a light brown solid after drying under high vacuum for 2 hours. The crude solid was recrystallized from hot EtOAc-hexanes to provide 26.8 g of the title compound as a light brown solid (87%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:24]([OH:26])=O.Cl.[F:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH2:36][CH2:37][NH:38][CH2:39][CH:40]=2)=[CH:31][CH:30]=1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:24]([N:38]1[CH2:37][CH:36]=[C:35]([C:32]2[CH:33]=[CH:34][C:29]([F:28])=[CH:30][CH:31]=2)[CH2:40][CH2:39]1)=[O:26]
Reactant: CCOC(=O)c1cnn2c(Nc3cc(C)ccc3C)c(C(=O)O)cnc12
Reactant: Fc1ccc(C2=CCNCC2)cc1
Agent: Cl
Product: CCOC(=O)c1cnn2c(Nc3cc(C)ccc3C)c(C(=O)N3CC=C(c4ccc(F)cc4)CC3)cnc12
Yield: 74.7 %

Procedure:
In the same manner as in Example 21, step 5 and using 7-(2,5-dimethylphenylamino)-3-ethoxycarbonylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid (110 mg, 0.31 mmol) obtained in Example 88, step 2 and 4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine hydrochloride (79 mg, 0.37 mmol), the title compound (119 mg, 75%) was obtained.
Reaction SMILES: C([O:8][C:9](=[O:37])[C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17](=[O:36])[CH:18]([C:24]2[CH:33]=[C:32]3[C:27]([C:28]([CH3:35])([CH3:34])[CH2:29][CH2:30][O:31]3)=[CH:26][CH:25]=2)[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:12][CH:11]=1)C1C=CC=CC=1>C([O-])(=O)C.[Pd]>[CH3:34][C:28]1([CH3:35])[C:27]2[C:32](=[CH:33][C:24]([CH:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:17]([O:16][C:13]3[CH:12]=[CH:11][C:10]([C:9]([OH:37])=[O:8])=[CH:15][CH:14]=3)=[O:36])=[CH:25][CH:26]=2)[O:31][CH2:30][CH2:29]1
Reactant: CCCCCC(C(=O)Oc1ccc(C(=O)OCc2ccccc2)cc1)c1ccc2c(c1)OCCC2(C)C
Agent: [Pd]
Agent: CC(=O)[O-]
Product: CCCCCC(C(=O)Oc1ccc(C(=O)O)cc1)c1ccc2c(c1)OCCC2(C)C
Reaction time: 2 h
Yield: 60.1 %

Procedure:
A solution of 4-[2-(4,4-dimethyl-chroman-7-yl)-heptanoyloxy]-benzoic acid benzyl ester (152 mg, 0.3 mmol) in 10 mL of elthyl acetate with 32 mg of 10% palladium on carbon, was subjected to 1 atm. H2. After 2 h, the mixture was filtered through Celite and silica gel, concentrated under vacuum and purified by flash chromatography (gradient elution, 10-50% ethyl acetate/hexane) to afford 74 mg (59%) of 4-[2-(4,4-dimethyl-chroman-7-yl)-heptanoyloxy]-benzoic acid.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3].[C:7]1([CH3:16])[CH:12]=[CH:11][C:10]([C:13](Cl)=[O:14])=[CH:9][CH:8]=1>>[CH3:16][C:7]1[CH:12]=[CH:11][C:10]([C:13]([NH:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3])=[O:14])=[CH:9][CH:8]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: C[C@H](N)C(=O)O
Product: Cc1ccc(C(=O)N[C@@H](C)C(=O)O)cc1

Procedure:
Racemic alanine and p-toluoyl chloride were processed as described in Example 26A to provide the desired product.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C@:8]2([CH2:17][CH2:18][O:19][CH3:20])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[C:5]([F:21])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:29][O:30][C:31]1[CH:52]=[CH:51][C:34]([C:35](Cl)([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=2)=[CH:33][CH:32]=1>ClCCl>[CH3:43][O:42][C:39]1[CH:38]=[CH:37][C:36]([C:35]([NH:16][C:10]2[O:11][CH2:12][C:13]([F:15])([F:14])[C@:8]([C:6]3[C:5]([F:21])=[CH:4][CH:3]=[C:2]([Br:1])[N:7]=3)([CH2:17][CH2:18][O:19][CH3:20])[N:9]=2)([C:34]2[CH:33]=[CH:32][C:31]([O:30][CH3:29])=[CH:52][CH:51]=2)[C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[CH:41][CH:40]=1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: COCC[C@]1(c2nc(Br)ccc2F)N=C(N)OCC1(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCC[C@]1(c2nc(Br)ccc2F)N=C(NC(c2ccccc2)(c2ccc(OC)cc2)c2ccc(OC)cc2)OCC1(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 93 %

Procedure:
To a solution of (R)-4-(6-bromo-3-fluoro-pyridin-2-yl)-5,5-difluoro-4-(2-methoxy-ethyl)-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (200 mg, 0.543 mmol) and triethylamine (110 mg, 1.087 mmol) in dichloromethane (5.4 ml) was added solid 4,4′-dimethoxytrityl chloride (202 mg, 0.598 mmol) under argon atmosphere. The green solution was stirred at rt for 16 hrs and was then evaporated in vacuo. The crude product was taken up with ethyl acetate and washed with aqueous citric acid, aqueous sodium bicarbonate solution, water and brine. The organic phase was dried over sodium sulfate, filtered and evaporated. The crude product (380 mg) was chromatographed over silica gel (Redisep column 12 g, cyclohexane/ethyl acetate 8:2) to give the title compound as a colourless foam. 339 mg (93% yield).
Reaction SMILES: C(O)(=O)C.C1COCC1.[C:10]1([S:16][O:17][C:18](=[O:30])[CH2:19][CH:20]([O:22][Si](C(C)(C)C)(C)C)[CH3:21])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>O>[C:10]1([S:16][O:17][C:18](=[O:30])[CH2:19][CH:20]([OH:22])[CH3:21])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CC(CC(=O)OSc1ccccc1)O[Si](C)(C)C(C)(C)C
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(O)CC(=O)OSc1ccccc1
Temperature: 50 °C
Reaction time: 24 h
Yield: 90.1 %

Procedure:
There was added 50 ml of a mixture of acetic acid, THF and water (3:1:1) to 3.26 g (10.4 mml) of (-)-3-t-butyldimethylsilyloxybutyric acid phenylthioester and the mixture was stirred at 50° C. for 24 hours. The obtained reaction mixture was concentrated and distilled at 128° to 130° C. under a pressure of 0.8 mmHg to give 1.91 g of (-)-3-hydroxybutyric acid phenylthioester.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[C:21]2[CH:22]=[CH:23][S:24][C:20]=2[C:19]([N+:25]([O-])=O)=[CH:18][CH:17]=1>C1COCC1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[C:21]2[CH:22]=[CH:23][S:24][C:20]=2[C:19]([NH2:25])=[CH:18][CH:17]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc([N+](=O)[O-])c2sccc12
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(N)c2sccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
50 g (1.052 mol) of 5-methyl-4-[2-(7-nitro-benzothiophene-4-yloxy)-ethyl]-2-phenyl-oxazole were solved in 1 l of THF at 20 to 25° C. 75 ml Lewatit M 600 (OH−form) (Bayer AG) were washed with about 100 ml THF, added to the 5-methyl-4-[2-(7-nitro-benzothiophene-4-yloxy)-ethyl]-2-phenyl-oxazole solution and stirred at room temperature for 1 hour. Then the Lewatit M 600 material was filtered with suction and washed with 100 ml THF. 12.5 g of Raney nickel were added to the combined THF solutions followed by hydrogenation of the 5-methyl-4-[2-(7-nitro-benzothiophene-4-yloxy)-ethyl]-2-phenyl-oxazole at standard pressure. The temperature of the reaction mixture should not exceed 35 to 40° C. Hydrogen pressure was increased to 6 bar within 6 hours. After hydrogenation the reaction mixture was stirred for 1 hour. Then the catalyst was filtered with suction, the THF was distilled off, 180 ml ethanol was added and the residue was boiled out for 30 minutes. The reaction mixture was stirred at 0° C. for 1 hour. The precipitate was filtered with suction and the residue was washed with 25 ml ethanol and dried for 24 hours at 50° C. (vacuum).
Reaction SMILES: [Na+].[CH2:2]([N:9]1[C:21]2[CH2:20][CH2:19][CH2:18][CH:17]([C:22](=[O:24])[NH2:23])[C:16]=2[C:15]2[C:10]1=[CH:11][C:12]([O:30][CH3:31])=[CH:13][C:14]=2[O:25][CH2:26][C:27]([O-:29])=[O:28])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>[Pd].CCOCCOCCO>[CH2:2]([N:9]1[C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([C:22](=[O:24])[NH2:23])[C:16]=2[C:15]2[C:10]1=[CH:11][C:12]([O:30][CH3:31])=[CH:13][C:14]=2[O:25][CH2:26][C:27]([OH:29])=[O:28])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COc1cc(OCC(=O)[O-])c2c3c(n(Cc4ccccc4)c2c1)CCCC3C(N)=O
Agent: [Pd]
Agent: [Na+]
Solvent: CCOCCOCCO
Product: COc1cc(OCC(=O)O)c2c3c(C(N)=O)cccc3n(Cc3ccccc3)c2c1

Procedure:
A mixture of 430 mg. of the product from Example 3 Part D, 2.0 gm. of 5% Pd/C, and 20 mL of carbitol was heated to reflux and refluxed for 21 hours, cooled, and filtered. The filtrate was diluted with water, acidified with hydrochloric acid, and extracted well with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate and evaporated in vacuo. The residue was triturated with dichloromethane and filtered to remove solid tetrahydrocarbazole. The filtrate was evaporated in vacuo to give the title product, 125 mg, 31%.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:30]/[O:31][CH3:32])/[C:27]([OH:29])=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([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.O[N:34]1[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[N:36]=[N:35]1.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:30]/[O:31][CH3:32])/[C:27]([O:29][N:34]2[C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=3[N:36]=[N:35]2)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: On1nnc2ccccc21
Reactant: CO/N=C(\C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: CO/N=C(\C(=O)On1nnc2ccccc21)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 3 h
Yield: 92.8 %

Procedure:
To a solution of 2-(2-tritylaminothiazol-4-yl)-(Z)-2-methoxyiminoacetic acid (2.22 g, 5 mmol) and 1-hydroxybenzotriazole (0.74 g, 5.5 mmol) in tetrahydrofuran (22 ml) was added N,N'-dicyclohexylcarbodiimide (1.14 g, 5.5 mmol) at 5°-10° C. and the mixture was stirred at the same temperature for 3 hours. Precipitated N,N'-dicyclohexylurea was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was dissolved in chloroform (20 ml) and insoluble material was removed by filtration. The chloroform was evaporated and the residue was treated with a small quantity of ether to give colorless needles of 1-benzotriazolyl 2-(2-tritylaminothiazol-4-yl)-(Z)-2-methoxyiminoacetate (2.60 g, 93%), mp 178°-179° C. (decomposition).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:12])[CH2:9][C:10]#[N:11])[CH:5]=[CH:6][CH:7]=1.Cl>C1COCC1>[NH2:11][CH2:10][CH2:9][CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)[OH:12]
Reactant: N#CCC(O)c1cccc(Br)c1
Agent: Cl
Solvent: C1CCOC1
Product: NCCC(O)c1cccc(Br)c1
Temperature: 25 °C

Procedure:
To a solution of 3-(3-bromophenyl)-3-hydroxypropanenitrile (23) (117.5 g, 519.8 mmol) in anhydrous THF (300 mL) under argon borane-methylsulfide (68 mL, 675.7 mmol) was slowly added over 30 min via a dropping funnel. The reaction mixture was boiled under reflux for 2.5 hr and cooled to room temperature. HCl solution (1.25M in EtOH, 350 mL) was slowly added for 30 min and the mixture was concentrated under reduced pressure. Water (400 mL) was added and the pH of the mixture was then adjusted to 12 with aqueous NaOH (50% wt). The product was extracted with CH2Cl2 (500 mL), the extract was dried over anhydrous Na2SO4 and concentrated under reduced pressure to give hydroxyamine 24 as a colorless oil. Yield (104 g, 87%). 1H NMR (400 MHz, DMSO-d6) δ 7.49 (m, 1H), 7.37 (dt, J=7.2, 1.6 Hz, 1H), 7.23-7.31 (m, 2H), 4.66 (t, J=6.8 Hz, 1H), 2.61 (m, 2H), 1.61 (q, J=6.8 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:16][C:17]2[CH:18]=[CH:19][C:20]([CH2:27][CH2:28][C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)=[C:21]([CH:26]=2)[C:22]([O:24]C)=[O:23])[CH2:9][N:10]2[CH:14]=[CH:13][N:12]=[C:11]2[CH3:15])=[CH:4][CH:3]=1.[OH-].[Na+]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:16][C:17]2[CH:18]=[CH:19][C:20]([CH2:27][CH2:28][C:29]3[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=3)=[C:21]([CH:26]=2)[C:22]([OH:24])=[O:23])[CH2:9][N:10]2[CH:14]=[CH:13][N:12]=[C:11]2[CH3:15])=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(OC(Cn2ccnc2C)c2ccc(F)cc2)ccc1CCc1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Product: Cc1nccn1CC(Oc1ccc(CCc2ccc(F)cc2)c(C(=O)O)c1)c1ccc(F)cc1
Yield: 45.2 %

Procedure:
Methyl 5-[1-(4-fluorophenyl)-2-(2-methylimidazol-1-yl)ethoxy]-2-(4-fluorophenethyl)benzoate (4.2 g, ˜8.8 mmol) was hydrolysed with aqueous sodium hydroxide solution under the usual conditions to give 5-[1-(4-fluorophenyl)-2-(2-methylimidazol-1-yl)ethoxy]-2-(4-fluorophenethyl)benzoic acid (1.84 g, ˜45% ) as a colourless gum.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[N:7][C:6]=2[CH:10]=1.[Br:11]N1C(=O)CCC1=O.O>C(Cl)(Cl)Cl>[Br:11][CH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[N:7][C:6]=2[CH:10]=1
Reactant: Cc1ccc2ocnc2c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Solvent: O
Product: BrCc1ccc2ocnc2c1
Temperature: 25 °C

Procedure:
A solution of 5-methylbenzoxazole (0.5 g) in chloroform (20 ml) containing N-bromosuccinimide (0.18 g) and azoisobutyronitrile (0.05 g) was refluxed for 2 hours. After allowing to cool to room temperature the reaction mixture was treated with water (30 ml). The organic phase was separated and the aqueous phase extracted with dichloromethane (30 ml). The combined organic phases were washed with brine (30 ml), dried over magnesium sulphate and evaporated. The residue was triturated with pentane giving the title compound (0.36 g) as an off-white solid, m.p. 90-93° C.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][CH2:9][C:10]1[C:11]([C:15]2[N:19]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[C:22]([Cl:27])[CH:21]=3)C(=O)[O:17][N:16]=2)=[N:12][O:13][N:14]=1.[S:29](N)([NH2:32])(=[O:31])=[O:30].[OH-].[Na+]>N1C=CC=CC=1.O>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:32][S:29]([NH:8][CH2:9][C:10]1[C:11]([C:15](=[N:16][OH:17])[NH:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[C:22]([Cl:27])[CH:21]=2)=[N:12][O:13][N:14]=1)(=[O:31])=[O:30]
Reactant: NCc1nonc1-c1noc(=O)n1-c1ccc(F)c(Cl)c1
Reactant: NS(N)(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: NS(=O)(=O)NCc1nonc1C(=NO)Nc1ccc(F)c(Cl)c1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 50.7 %

Procedure:
3-[4-(Aminomethyl)-1,2,5-oxadiazol-3-yl]-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one trifluoroacetate (30 mg, 0.07 mmol) and sulfamide (20 mg, 0.2 mmol) was dissolved in pyridine (1.0 mL) and heated at 120° C. for 3 min in a microwave. A solution of sodium hydroxide in water (0.5 mL, 1 N) was added and the solution was stirred for 30 minutes. Acidification with acetic acid and purification by preparative LCMS gave the desired product (17 mg, 50%). MF═C10H10ClFN6O4S; LCMS calculated for C10H11ClFN6O4S(M+H)+: m/z=364.9. 1H NMR (400 MHz, CD3OD): δ 7.02 (m, 2H), 6.76 (m, 1H), 4.50 (s, 2H).