Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[N:6]=[C:5]([C:20]([NH2:22])=[O:21])[CH:4]=1.O.[F:24][C:25]([F:29])([F:28])[CH:26]=[O:27].[CH:30]1C=CC=CC=1>>[CH3:30][O:27][CH:26]([NH:22][C:20]([C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:18])([F:19])[F:17])[CH:11]=2)[N:6]=1)=[O:21])[C:25]([F:29])([F:28])[F:24]
Reactant: c1ccccc1
Reactant: COc1cc(Oc2cccc(C(F)(F)F)c2)nc(C(N)=O)c1
Reactant: O=CC(F)(F)F
Solvent: O
Product: COc1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)NC(OC)C(F)(F)F)c1

Procedure:
4-methoxy-6-{3-(trifluoromethyl)phenoxy}-2-pyridine carboxamide was dissolved in benzene and mixed with 0.36 g (0.0026×1.2 mol) of trifluoroacetaldehyde hydrate, followed by treating the obtained solution under reflux for about 5 hours. The reaction solution was concentrated and then distributed in ethyl acetate-saturated sodium bicarbonate water, followed by washing with saturated brine. The organic phase of the obtained solution was dried with anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography (eluting solution: ethyl acetate/hexane), thereby obtaining an aimed product.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([F:13])=[CH:10][CH:11]=2)[CH2:6][CH:5]1[C:14]([NH2:16])=O)(=[O:3])[CH3:2].C(N(CC)CC)C.ClC(Cl)(Cl)C(Cl)=O>C(Cl)Cl>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([F:13])=[CH:10][CH:11]=2)[CH2:6][CH:5]1[C:14]#[N:16])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(F)cc2CC1C(N)=O
Agent: O=C(Cl)C(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1c2ccc(F)cc2CC1C#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 19.3 %

Procedure:
To a suspension of intermediate (18) (0.0076 mole) in DCM (30 ml), cooled in an ice bath under argon, was added triethylamine (0.0228 mole) followed by trichloroacetyl chloride (0.0115 mole). The mixture was allowed to warm to room temperature and stir for 2 hours. The mixture was washed with water, 2N HCl, and saturated NaHCO3. The organic layer was dried and concentrated. The concentrate was triturated in ether and purified on silica gel column, eluting with 50% ethyl acetate in hexane. The desired fractions were combined and concentrated. The residue was triturated in ether and the solid collected by filtration and allowed to dry, yielding 0.30 g of 1-acetyl-5-fluoro-2,3-dihydro-1H-indole-2-carbonitrile (intermediate 19, mp. 93–95° C.)
Reaction SMILES: C([O:5][C:6]([NH:8][C:9]([CH3:14])([CH2:12][OH:13])[CH2:10]O)=O)(C)(C)C.N1C=CC=CC=1.S(Cl)([Cl:24])(=O)=O>C(Cl)Cl.C(OCC)C>[CH3:14][C:9]1([CH2:10][Cl:24])[CH2:12][O:13][C:6](=[O:5])[NH:8]1
Reactant: O=S(=O)(Cl)Cl
Reactant: CC(CO)(CO)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC1(CCl)COC(=O)N1
Temperature: 25 °C
Yield: 28.3 %

Procedure:
A solution of 2-(tert-butoxycarbonylamino)-2-methyl-1,3-propanediol (2.28 g, 11.1 mmol) in CH2Cl2 (100 ml) and pyridine (2.0 ml, 25 mmol) was cooled to 0° C. and sulfuryl chloride (1.0 ml, 12 mmol) in CH2Cl2 (20 ml) was added dropwise over 15 min. The solution was warmed to RT over 4 h, diluted with diethyl ether (300 ml), washed with 3× 100 ml 5% NaHSO4, 3× 100 ml sat. NaHCO3, 1× 100 ml sat. NaCl, dried on MgSO4, and evaporated. The crude material was purified by flash chromatography (30-100% EtOAc in hexanes) to afford the title compound as a clear oil (470 mg, 3.14 mmol, 28.3%). 1H NMR (CDCl3, 400 MHz) δ 1.49 (s, 3H), 3.55 (s, 2H), 4.12 (d, 1H, J=9.2 Hz), 4.33 (d, 1H, J=8.8 Hz), 5.9 (br s, 1H). APCI/ESI calculated for C5H8ClNO2: 149.02. Found: 150 (MH+).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[C:12]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:12]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N+:19]=2[O-:9])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: c1ccc(-c2ccccn2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: [O-][n+]1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 79.5 %

Procedure:
3-chloroperbenzoic acid (19 g) was added portionwise to an ice-cold solution of 2-phenylpyridine (10 g) in DCM (30 ml). The mixture was allowed to warm to RT and was stirred at RT for 4 h. 100 ml of a NaHCO3 solution were added to the reaction mixture and the phases were separated. The aq. phase was further extracted with DCM and the combined org. phases were washed with an aq. NaHSO3 (40%) solution and evaporated off. Recrystallisation (EA) afforded 8.77 g of the desired compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:13]=[C:12]([CH2:14][N:15]3[CH:19]=[CH:18][N:17]=[C:16]3[NH:20][CH3:21])[N:11]=[CH:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[C:22](O)(=[O:24])C>C=O>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([CH2:22][OH:24])=[C:12]([CH2:14][N:15]3[CH:19]=[CH:18][N:17]=[C:16]3[NH:20][CH3:21])[N:11]=[CH:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(=O)O
Reactant: CNc1nccn1Cc1cn(-c2ccc(Cl)c(Cl)c2)cn1
Agent: C=O
Product: CNc1nccn1Cc1ncn(-c2ccc(Cl)c(Cl)c2)c1CO
Product: Cl

Procedure:
A solution of {1-[1-(3,4-dichloro-phenyl)-1H-imidazol-4-ylmethyl]-1H-imidazol-2-yl}-methyl-amine (0.60 g, 1.7 mmol) in acetic acid (7 ml) and aqueous formaldehyde (2 ml of a 37% solution) was stirred at 20° C. for 96 h. The reaction mixture was evaporated to dryness and chromatographed [silica, elution with gradient CH2Cl2 to 50% (CH2Cl2/MeOH/aq. NH4OH=90:10:1)] to obtain the free base of the title compound. It was crystallized as the off-white hydrochloride salt (0.030 g, 5%). Mp.>180° C. dec. (MeOH/Et2O), MS: m/e=352 (M+H+).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([S:9]([N:12]2[C:17]3[CH:18]=[C:19]([C:22]([NH:24][C:25]4[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=4)=[O:23])[CH:20]=[CH:21][C:16]=3[O:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.F[C:37](F)(F)[C:38]1C=C(S(Cl)(=O)=O)C=CC=1>>[CH2:37]([O:30][C:29](=[O:31])[C:28]1[CH:32]=[CH:33][C:25]([NH:24][C:22]([C:19]2[CH:20]=[CH:21][C:16]3[O:15][CH2:14][CH2:13][N:12]([S:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:34])([F:1])[F:35])[CH:4]=4)(=[O:10])=[O:11])[C:17]=3[CH:18]=2)=[O:23])=[CH:26][CH:27]=1)[CH3:38]
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Reactant: O=C(O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cccc(C(F)(F)F)c2)CCO3)cc1
Product: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cccc(C(F)(F)F)c2)CCO3)cc1

Procedure:
4-{[4-(3-Trifluoromethyl-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoic acid, MS (ISP): m/e=505.1 (M−H), was prepared as described for example 14, steps 1 to 8. Step 7 was performed using 3-trifluoromethyl-benzenesulfonyl chloride and yielded 4-{[4-(3-trifluoromethyl-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoic acid ethyl ester, which was hydrolyzed in step 8.
Reaction SMILES: Br[CH:2]=[C:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.[OH:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>C1COCC1>[OH:16][C:17]1[CH:22]=[C:21]([CH:20]=[CH:19][CH:18]=1)[CH:2]=[C:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1
Reactant: OB(O)c1cccc(O)c1
Reactant: CC(C)(C)OC(=O)N1CCC(=CBr)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(=Cc2cccc(O)c2)CC1
Temperature: 50 °C
Yield: 66.1 %

Procedure:
To a solution of tert-butyl 4-(bromomethylene)piperidine-1-carboxylate (38 g, 0.1376 mol) in dry THF (380 mL) was added 3-hydroxyphenyl boronic acid (22.77 g, 0.165 mol), potassium phosphate (88.2 g, 0.415 mol) and water (7.6 mL). The mixture was degassed with argon. 1,1′-Bis(diphenylphosphino)ferrocene palladium(II) dichloride dichloromethane complex (11.23 g, 0.01376 mol) was added and the mixture was degassed again. The reaction was heated at 50° C. for 1.5 h and then allowed to cool to RT. Water was added and the mixture was extracted with ethyl acetate (3×). The total organic extract was washed with brine, dried over sodium sulfate and evaporated to dryness. The residue was purified by silica gel chromatography using 100-200 mesh silica gel (8% ethyl acetate in hexane) to give the title compound (26.3 g, 66%). 1H NMR (500 MHz, CDCl3): δ 7.16 (t, J=7.5 Hz, 1H), 6.74 (d, J=7.5 Hz, 1H), 6.68 (d, J=9 Hz, 1H), 6.68 (s, 1H), 6.30 (s, 1H), 5.37 (bs, 1H), 3.49 (m, 2H), 3.40 (m, 2H), 2.46 (m, 2H), 2.31 (m, 2H), 1.48 (s, 9H); 13C NMR (125 MHz, CDCl3): δ 156.09, 155.09, 138.87, 138.15, 129.31, 124.58, 120.98, 115.74, 113.54, 80.10, 45.45, 44.57, 36.08, 29.23, 28.50.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:4]([F:13])[C:3]=1[OH:14].[F:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]=[C:23]=S)=[C:18]([CH3:25])[CH:17]=1>CO>[F:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]2[O:14][C:3]3[C:4]([F:13])=[C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:7][C:2]=3[N:1]=2)=[C:18]([CH3:25])[CH:17]=1
Reactant: Cc1cc(F)ccc1N=C=S
Reactant: COC(=O)Cc1ccc(N)c(O)c1F
Solvent: CO
Product: COC(=O)Cc1ccc2nc(Nc3ccc(F)cc3C)oc2c1F
Temperature: 25 °C
Reaction time: 120 h
Yield: 79.1 %

Procedure:
In methanol (30 ml) was dissolved methyl (4-amino-2-fluoro-3-hydroxyphenyl)acetate (1.0 g, 5.02 mmol). To the resulting solution was added 4-fluoro-2-methylphenyl isothiocyanate (0.74 ml, 5.23 mmol). After the mixture was stirred at room temperature for 5 days, mercuric oxide (yellow) (1.14 g, 4.36 mmol) was added thereto. The mixture was stirred at 70° C. for 6 hours. After cooling to room temperature, the reaction mixture was filtered through Celite and washed with methanol. The filtrate was distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from chloroform/ethyl acetate (30/1) eluate fractions, methyl (2-(4-fluoro-2-methylphenylamino)-7-fluoro-6-benzoxazolyl)acetate (1.32 g, 91%) was obtained as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5](O)=[CH:4][CH:3]=1.[C:12](=O)([O-])[O-].[K+].[K+].S([O:23][CH3:24])(OC)(=O)=O>CC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH3:24])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:12])=[O:8]
Reactant: COS(=O)(=O)OC
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1cc(Cl)ccc1O
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cc(Cl)ccc1OC
Yield: 99.3 %

Procedure:
A mixture of 5-chlorosalicylic acid (20.0 g, 0.116 mol), potassium carbonate (40.3 g, 0.290 mol), and dimethyl sulfate (36.5 g, 0.290 mol) in acetone (300 mL) was heated at reflux for 18 hours. The mixture was cooled, concentrated, diluted with H2O, and extracted with ethyl acetate (3×150 mL). The extracts were washed with H2O and saturated NaCl, dried (MgSO4), and concentrated to give 23.10 g (99%) of product as a brown oil.
Reaction SMILES: C(N[C:6](=[O:11])[C:7]([CH3:10])([CH3:9])[CH3:8])(C)(C)C.[CH3:12][CH:13]([CH:15]([NH2:19])[CH:16]([CH3:18])[CH3:17])[CH3:14].C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C>>[CH3:12][CH:13]([CH:15]([NH:19][C:6](=[O:11])[C:7]([CH3:10])([CH3:9])[CH3:8])[CH:16]([CH3:18])[CH3:17])[CH3:14]
Reactant: CC(C)(C)NC(=O)C(C)(C)C
Reactant: CC(C)C(N)C(C)C
Agent: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Product: CC(C)C(NC(=O)C(C)(C)C)C(C)C
Yield: 98 %

Procedure:
In a fashion similar to the preparation of LtBu,tBuH, treatment of 2,4-dimethylpentan-3-amine (14.0 mL, 100 mmol) and triethylamine (14.9 mL, 105 mmol) with pivaloyl chloride (8.9 mL, 100 mmol) afforded LtBu,CHiPr2H as white crystalline solid (19.53 g, 98%) upon sublimation at 65° C./0.05 Torr: mp 107-109° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].C1CCN2C(=NCCC2)CC1.CCCCCC.[C:30](OCC)(=[O:32])C>CO.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1>[CH3:12][S:9]([NH:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[O:32][CH3:30])(=[O:11])=[O:10]
Reactant: CCOC(C)=O
Reactant: CS(=O)(=O)Nc1ccccc1Br
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: CO
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCCCCC
Product: COc1ccccc1NS(C)(=O)=O
Yield: 82 %

Procedure:
2.50 g of 2-bromo-1-methanesulfonylaminobenzene was added to a solution containing 1.52 g of DBU, 85 g of cupric chloride dihydrate, and 90 mg of 1,10-phenanthroline in 40 ml of methanol, and the mixture was heated under reflux for 5 hours. After the temperature was brought to room temperature, the reaction mixture was treated in a usual manner, and crystallization was effected from n-hexane/ethyl acetate, to produce 1.64 g (yield: 82%) of the desired compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[CH2:7][CH2:8][C:9]1(C(OCC)=O)[S:13][C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]([F:24])([F:23])[F:22])=[N:11][C:10]1=[O:25])([CH3:4])([CH3:3])[CH3:2].C1COCC1.O[Li].O.Cl>O.CO>[O:25]=[C:10]1[CH:9]([CH2:8][CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:31])[S:13][C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]([F:24])([F:22])[F:23])=[N:11]1
Reactant: CCOC(=O)C1(CCC(=O)OC(C)(C)C)SC(Nc2ccccc2C(F)(F)F)=NC1=O
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)CCC1SC(Nc2ccccc2C(F)(F)F)=NC1=O
Reaction time: 3 h

Procedure:
To a mixture of ethyl 5-(3-tert-butoxy-3-oxopropyl)-4-oxo-2-(2-(trifluoromethyl)phenylamino)-4,5-dihydrothiazole-5-carboxylate (88.7 mg, 0.19 mmol), THF (1 mL), MeOH (0.3 mL), and water (0.3 mL) was added LiOH.H2O (Aldrich, 20 mg, 0.47 mmol) at room temperature. After 3 h, 1N HCl (0.7 mL) was added to the reaction mixture at 0° C. The mixture was extracted with EtOAc, and the organic phase was dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography. MS: 389 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH:6]([C:7]([O-:9])=[O:8])[N:5]2[C:10](=[O:23])[C@@H:11]([NH:12][C:13](=[O:22])[CH2:14][O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C@H:4]2[S:3]1.[K+].O(CC(O)=O)C1C=CC=CC=1.[C:37]1([C:43]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)=[N+]=[N-])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>O.ClCCl>[CH3:1][C:2]1([CH3:24])[CH:6]([C:7]([O:9][CH:43]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)=[O:8])[N:5]2[C:10](=[O:23])[C@@H:11]([NH:12][C:13](=[O:22])[CH2:14][O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C@H:4]2[S:3]1
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)COc3ccccc3)C(=O)N2C1C(=O)[O-]
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Agent: O=C(O)COc1ccccc1
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CC1(C)S[C@@H]2[C@H](NC(=O)COc3ccccc3)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1
Reaction time: 0.17 h
Yield: 85.7 %

Procedure:
To a solution of potassium (5R,6R)-2,2-dimethyl-6-phenoxyacetamidopenam-3-carboxylate (10 g, 25.7 mM) and phenoxyacetic acid (2 g, 13.1 mM) in water (100 ml) was added a solution of diphenyldiazomethane (5.2 g, 27 mM) in dichloromethane (100 ml). The pH was adjusted to 4.0 and the mixture stirred for 10 minutes. After separation, the solvent was washed with water (100 ml), 5% w/v sodium bicarbonate solution (100 ml) and water (100 ml). The solvent was removed in vacuo to give the title compound (11.4 g).
Reaction SMILES: C[O:2][C:3](=[O:40])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:14]=[C:13]([N:15](S(C3C=CC=CC=3)(=O)=O)[S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)(=[O:18])=[O:17])[N:12]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:11]=2)=[CH:6][CH:5]=1.O.[OH-].[Li+]>CO>[C:19]1([S:16]([NH:15][C:13]2[N:12]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:11]=[C:10]([C:7]3[CH:6]=[CH:5][C:4]([C:3]([OH:40])=[O:2])=[CH:9][CH:8]=3)[CH:14]=2)(=[O:17])=[O:18])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)c1ccc(-c2cc(N(S(=O)(=O)c3ccccc3)S(=O)(=O)c3ccccc3)n(-c3ccccc3)n2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(-c2cc(NS(=O)(=O)c3ccccc3)n(-c3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
A mixture of 4-{5-[bis(Benzenesulfonyl)amino]-1-phenyl-1H-pyrazole-3-yl}-benzoic acid methyl ester (1.0 g, 1.74 mmol) and lithium hydroxide monohydrate (1.0 g, 23.8 mmol) in methanol (20 ml) was stirred at room temperature for 2.5 days. The solvent was evaporated in vacuo, and the residue was dissolved in water (20 ml). The solution was neutralized with concentrated hydrochloric acid to give a white precipitate. The solid was collected by filtration, washed with water and dried in vacuo to yield 4-(5-benzenesulfonylamino-1-phenyl-1H-pyrazole-3-yl)-benzoic acid as a solid.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH:9]1([C:14]([OH:16])=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10]1.[C:17]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:20])[CH:18]=[CH2:19].Cl>C1COCC1>[C:22]([O:21][C:17](=[O:20])[CH2:18][CH2:19][C:9]1([C:14]([OH:16])=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10]1)([CH3:25])([CH3:24])[CH3:23]
Reactant: O=C(O)C1CCCC1
Reactant: C=CC(=O)OC(C)(C)C
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCC1(C(=O)O)CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.9 %

Procedure:
To a 50 ml round-bottomed flask under nitrogen was added lithium diisopropylamide (10.95 mL, 21.90 mmol). The solution was cooled to −20° using a controlled dry ice/acetonitrile bath. Cyclopentanecarboxylic acid (1.187 mL, 10.95 mmol) in dry THF (10 mL) was added over 5 minutes, keeping the temperature at −20° C. The mixture was warmed to room temperature, stirred for one hour, then cooled to −78° C. Tert-butyl acrylate (1.685 mL, 10.95 mmol) in dry THF (10 mL) was added dropwise over 5 min, keeping the temperature at −70° C. After 2 hours at −70° C., the mixture was quickly warmed to 0° C., acidified with 5N HCl, and extracted with hexane. The hexane extract was washed with water and saturated sodium bicarbonate, water, and dried over MgSO4, and then recrystallized from hexanes. Recovered 1-(3-tert-butoxy-3-oxopropyl)cyclopentanecarboxylic acid (1.8 g, 7.43 mmol, 67.8% yield).
Reaction SMILES: [CH:1]([N:4]([C:8]1[CH:13]=[CH:12][C:11]2[O:14][CH2:15][O:16][C:10]=2[CH:9]=1)[C:5]([NH2:7])=[O:6])([CH3:3])[CH3:2].[N:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[C:19]([CH:27]=O)[CH:18]=1>>[CH:1]([N:4]1[C:8]2[C:13](=[CH:12][C:11]3[O:14][CH2:15][O:16][C:10]=3[CH:9]=2)[CH:27]([C:19]2[CH:18]=[N:17][C:26]3[C:21]([CH:20]=2)=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:7][C:5]1=[O:6])([CH3:3])[CH3:2]
Reactant: O=Cc1cnc2ccccc2c1
Reactant: CC(C)N(C(N)=O)c1ccc2c(c1)OCO2
Product: CC(C)N1C(=O)NC(c2cnc3ccccc3c2)c2cc3c(cc21)OCO3
Yield: 14 %

Procedure:
This compound was synthesized from N-isopropyl-N-[3,4-(methylenedioxy)-phenyl]urea (308 mg) and 3-quinolinecarboxaldehyde (243 mg) by the procedure described in example 10 in 14% yield, mp: 202-205° C. 1H NMR (CDCl3): 8.89 (d, J=2.0, 1H), 8.11 (d, J=7.6, 1H), 8.05 (s, 1H), 7.80 (d, J=7.6, 1H), 7.74 (t, J=7.6, 1H), 7.58 (t, J=7.6, 1H), 6.72 (s, 1H), 6.41 (s, 1H), 5.94 (s, 1H), 5.92 (s, 1H), 5.52 (d, J=1.9, 1H), 5.25 (s, 1H), 4.42 (m, 1H), 1.57 (d, J=7.0, 3H), 1.56 (d, J=7.0, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:41]2[C:42]([CH2:51][O:52][Si](C(C)C)(C(C)C)C(C)C)=[N:43][N:44]([CH2:46][CH2:47][N:48]([CH3:50])[CH3:49])[CH:45]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1C[O:84]CC1>>[CH:51]([OH:52])=[O:84].[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:41]2[C:42]([CH2:51][OH:52])=[N:43][N:44]([CH2:46][CH2:47][N:48]([CH3:50])[CH3:49])[CH:45]=2)[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C1CCOC1
Reactant: CC(C)[Si](OCc1nn(CCN(C)C)cc1-n1nc(C(C)(C)C)cc1NC(=O)N[C@H]1CC[C@@H](Oc2ccc3nnc(N4CCCC[C@@H]4C)n3c2)c2ccccc21)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cn(CCN(C)C)nc4CO)c4ccccc43)cn12
Product: O=CO
Temperature: 50 °C
Yield: 32 %

Procedure:
A solution of Intermediate 74k (76 mg, 0.088 mmol) in THF (0.44 mL) was treated with tetrabutylammonium fluoride (1M in THF, 0.44 mL, 0.44 mmol) and the mixture was heated to 50° C. for 5 h. The mixture was evaporated in vacuo and the residue was partitioned between DCM and a saturated aqueous sodium bicarbonate solution. The layers were separated and the aqueous layer was then extracted with DCM (2×). The combined organic layers were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by FCC, using 0-9% [2M NH3 in MeOH] in DCM. Further purification by HPLC in 3 portions (Method 6, 30-60% MeCN in H2O, 0.1% HCO2H over 25 min) gave a colourless glass that was triturated with ether. The solid was collected by filtration, washed with ether and dried at 50° C. in vacuo to give the title compound (20 mg, 32%). LCMS (Method 5): Rt 3.47 min, m/z 710.5 [MH+]. 1H NMR (400 MHz, d6-DMSO): 0.91 (3H, d, J=6.3 Hz), 1.25 (9H, s), 1.44-1.57 (2H, m), 1.61-1.74 (2H, m), 1.74-1.92 (3H, m), 1.92-2.02 (1H, m), 2.01-2.16 (2H, m), 2.18 (6H, s), 2.68 (2H, t, J=6.8 Hz), 2.87-2.95 (1H, m), 3.16 (1H, dt, J=12.0, 4.1 Hz, partially obscured by water), 3.27-3.36 (1H, m, obscured by water), 4.16 (2H, t, J=7.0 Hz), 4.31 (2H, s), 4.80-4.88 (1H, m), 4.92-5.11 (0.3H, br s), 5.53 (1H, t, J=4.3 Hz), 6.30 (1H, s), 7.14-7.22 (2H, m), 7.25-7.40 (4H, m), 7.64 (1H, d, J=10.0 Hz), 7.70 (1H, d, J=1.6 Hz), 8.00 (1H, s), 8.07 (1H, s), 8.19 (1H, s).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]([OH:15])[C:10](=[CH:13][CH:14]=2)[CH:11]=[O:12])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH2:16]([Mg]Br)[CH3:17]>>[OH:15][C:9]1[CH:8]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[CH:14]=[CH:13][C:10]=1[C:11](=[O:12])[CH2:16][CH3:17]
Reactant: CC[Mg]Br
Reactant: O=Cc1ccc(N2CCOCC2)cc1O
Product: CCC(=O)c1ccc(N2CCOCC2)cc1O

Procedure:
Following the procedure for preparing Example 34, 4-(4-morpholinyl)salicylaldehyde (1.0 g, 5 mmol) and ethylmagnesium bromide (1.0 M solution in tetrahydrofuran, 11 mL, 11 mmol) were converted to the product (208 mg, 18%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5](=[S:8])[NH:6][CH:7]=1.C(N(CC)CC)C.Br[C:17]1[S:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=1.[OH-].[Na+]>ClCCl.O>[N+:22]([C:19]1[S:18][C:17]([S:8][C:5]2[N:6]=[CH:7][C:2]([Cl:1])=[CH:3][N:4]=2)=[CH:21][CH:20]=1)([O-:24])=[O:23]
Reactant: O=[N+]([O-])c1ccc(Br)s1
Reactant: S=c1ncc(Cl)c[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=[N+]([O-])c1ccc(Sc2ncc(Cl)cn2)s1
Temperature: 25 °C
Reaction time: 48 h
Yield: 63 %

Procedure:
A mixture of 5-chloropyrimidine-2-thione (7.5 mmol), triethylamine (9 mmol) and 2-bromo-5-nitrothiophene (9 mmol) in dichloromethane (50 ml) was stirred at room temperature for 2 days. The resultant solution was then diluted with dichloromethane (50 ml), the solution shaken with 1 M NaOH (2×10 ml) and subsequently with water (10 ml), the dried (MgSO4) solution evaporated and the solid residue recrystallized from pet. ether; yield 63%, m.p. 141°-143° C. 1H NMR (CDCl3): δ7.16 and 7.83 (H-31, H-41), 8.53 (H-4, H-6).