Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:10])=[C:6]([CH2:8][OH:9])[CH:7]=1.N1C=CN=C1.[Si:16](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:10])=[C:6]([CH:7]=1)[CH2:8][O:9][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: OCc1cc(Br)ccc1Cl
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1cc(Br)ccc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (5-bromo-2-chlorophenyl)methanol from the previous step (1 eq.) in DMF (0.25 M) was added imidazole (1.2 eq.) and tert-butyldimethylsilyl chloride (1.1 eq.). The resulting solution was stirred at RT for 3 h. The reaction mixture was quenched with sat. aq. NH4Cl and extracted with ether. The combined organic extracts were washed further with aq. 10% HCl, sat. aq. NaHCO3, and brine. Concentration of the organic extracts in vacuo afforded an orange oil. Purification of the crude product thus obtained by way of flash chromatography (SiO2, 9:1 (v/v) Hex:EtOAc) afforded the title compound as a light yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:9]([CH3:23])[NH:8][C:7]=1[NH2:24])=[O:5])[CH3:2].CO[CH:27](OC)[N:28]([CH3:30])[CH3:29]>CCOCC>[CH2:1]([O:3][C:4]([C:6]1[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:9]([CH3:23])[NH:8][C:7]=1[N:24]=[CH:27][N:28]([CH3:30])[CH3:29])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(C)NC(N)=C(C(=O)OCC)C1c1ccccc1
Reactant: COC(OC)N(C)C
Solvent: CCOCC
Product: CCOC(=O)C1=C(C)NC(N=CN(C)C)=C(C(=O)OCC)C1c1ccccc1
Reaction time: 1 h

Procedure:
15 g (45 mmols) of 2-amino-4-phenyl-6-methyl-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester were warmed to 100° C. together with 10 g (84 mmols) of dimethylformamide dimethyl acetal and the mixture was stirred for about 60 minutes at this temperature. The reaction mass solidified whilst cooling and was suspended in a little ether, filtered off and recrystallised from ethanol. Melting point: 131° C. Yield: 13.7 g (79%)
Reaction SMILES: [CH3:1][C:2]([CH3:34])([CH3:33])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([C:13]34[C:28]([F:30])([F:29])[CH:14]3[CH:15]3[CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH:16]3[CH2:27]4)=[CH:10][CH:11]=2)[N:6]([CH3:31])[C:5]1=[O:32].FC(F)(F)C(O)=O>ClCCl>[F:30][C:28]1([F:29])[C:13]2([C:9]3[N:8]=[C:7]4[N:6]([CH3:31])[C:5](=[O:32])[N:4]([CH2:3][C:2]([CH3:34])([CH3:1])[CH3:33])[C:12]4=[CH:11][CH:10]=3)[CH2:27][CH:16]3[CH:15]([CH:14]12)[CH2:19][NH:18][CH2:17]3
Reactant: Cn1c(=O)n(CC(C)(C)C)c2ccc(C34CC5CN(C(=O)OC(C)(C)C)CC5C3C4(F)F)nc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1c(=O)n(CC(C)(C)C)c2ccc(C34CC5CNCC5C3C4(F)F)nc21
Reaction time: 18 h

Procedure:
tert-butyl 4a-[1-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo-[4,5-b]pyridin-5-yl]-4,4-difluorooctahydro-2H-cyclopropa[3,4]cyclopenta[1,2-c]pyrrole-2-carboxylate (30-2, 100 mg, 0.21 mmol) was added to a mixture of dichloromethane (2.0 mL) and trifluoroacetic acid (0.5 mL) at room temperature. After stirring for 18 h, the solvent was removed in vacuo. The resulting residue was then diluted with ethyl acetate (100 mL) and washed sequentially with saturated sodium bicarbonate (2×50 mL), water (1×50 mL) and brine (1×50 mL). The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo to give 1-[(2,2-Difluorocyclopropyl)methyl]-5-(1,2,3,3a,4,6a-hexahydrocyclopenta-[c]pyrrol-5-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (30-3) as a white solid. This material was carried on without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=3)[CH:9]=2)[C:4]=1[C:21](O)=[O:22].[C:24]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]>CCOCC>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=3)[CH:9]=2)[C:4]=1[C:21]([N:34]1[CH2:33][CH2:32][N:31]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:36][CH2:35]1)=[O:22]
Reactant: COc1cccc(-c2ccc3c(C(=O)O)c(OC)ccc3c2)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCOCC
Product: COc1cccc(-c2ccc3c(C(=O)N4CCN(C(=O)OC(C)(C)C)CC4)c(OC)ccc3c2)c1

Procedure:
The compound was prepared by reaction of 2-methoxy-6-(3-methoxyphenyl)-1-naphthoic acid (300 mg, 0.97 mmol, 1 eq) with Boc-piperazine (1 eq) according to method D. Characterization of the compound was not effected. The raw product was directly employed for ether cleavage.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=1.[CH3:9][NH2:10]>C1COCC1>[Cl:8][C:7]1[C:2]([NH:10][CH3:9])=[N:3][CH:4]=[CH:5][N:6]=1
Reactant: CN
Reactant: Clc1nccnc1Cl
Solvent: C1CCOC1
Product: CNc1nccnc1Cl
Yield: 43.4 %

Procedure:
2,3-dichloropyrazine (15 g, 101 mmol), methanamine (9.48 g, 101 mmol), and 100 mL of THF were stirred at room temperature for 24 h. The solvent was evaporated. The residue was dissolved in dichloromethane and washed with NaOH solution. The organic layer was separated and dried over MgSO4. After evaporating solvent, the residue was purified by column using dichloromethane as solvent to give 3-chloro-N-methylpyrazin-2-amine (6.3 g, 43.6% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[O:8][C:6](=[O:7])[C:5]2=[CH:11][C:12]=1[Cl:13].[NH3:14]>C1COCC1>[C:9]([C:4]1[CH:3]=[C:2]([Cl:1])[C:12]([Cl:13])=[CH:11][C:5]=1[C:6]([OH:8])=[O:7])(=[O:10])[NH2:14]
Reactant: N
Reactant: O=C1OC(=O)c2cc(Cl)c(Cl)cc21
Solvent: C1CCOC1
Product: NC(=O)c1cc(Cl)c(Cl)cc1C(=O)O
Yield: 80 %

Procedure:
4,5-Dichlorophthalic acid, anhydride (20.0 g, 92.2 mmol) was dissolved in dry THF (400 mL) and cooled in an ice bath. Ammonia gas was then passed through this solution for 10 minutes to afford a precipitate. The THF was removed and water (400 mL) was added. This aqueous solution was brought to acidic pH with 10% aqueous HCl whereupon a precipitate appeared. This solid was collected, washed with water and dried in vacuo to provide the product (17.3 g, 80%) as a tan solid, m.p. 197°-201° C.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH2:8].[CH:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[BH4-].[Na+]>CO.ClCCl>[CH2:9]([NH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH2:8])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=Cc1ccccc1
Reactant: N[C@@H]1CCCC[C@H]1N
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: N[C@@H]1CCCC[C@H]1NCc1ccccc1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
60.0 g (525.4 mmol) of (±)-trans-1,2-diaminocyclohexane is dissolved in 750 ml of absolute methanol and cooled to 0° C. At this temperature, the drop-by-drop addition of 10.5 g (99 mmol) of benzaldehyde, dissolved in 100 ml of absolute methanol, is carried out. After a reaction time of 2 hours at 0° C., the addition in portions of a total of 3.74 g (99 mmol) of sodium borohydride is carried out. After 12 hours at 25° C., the reaction solution is suctioned off on diatomaceous earth, and the solvent is drawn off in a vacuum. The remaining oily residue is taken up in 500 ml of dichloromethane and washed three times with 100 ml of water each. After the organic phase is dried on sodium sulfate, the solvent is drawn off in a vacuum. The oily residue that is thus obtained is chromatographed on silica gel (eluant: methanol/aqueous ammonia solution 20:1).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.C([O:14][CH:15]=[C:16]([C:22](OCC)=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18])C>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH2:20]([O:19][C:17]([CH:16]1[C:15](=[O:14])[C:7]2[C:5](=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=[C:2]([F:1])[CH:8]=2)[N:6]=[CH:22]1)=[O:18])[CH3:21]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1ccc(F)cc1[N+](=O)[O-]
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)C1C=Nc2c(cc(F)cc2[N+](=O)[O-])C1=O
Yield: 45 %

Procedure:
Using an analogous procedure to that described in Example 2, in the section relating to the preparation of starting materials, 4-fluoro-2-nitroaniline and diethyl ethoxymethylenemalonate were reacted, and then refluxed in diphenyl ether to give 3-ethoxycarbonyl-6-fluoro-8-nitro-4-oxo-3,4-dihydroquinoline in 45% yield, mp 278-280° C.
Reaction SMILES: N[C:2]1[N:7]=[C:6](N)[C:5]([NH2:9])=[C:4]([NH2:10])[N:3]=1.[OH:11][CH:12](O)[C:13](=O)[CH3:14]>>[OH:11][CH2:12][C:13]1[N:9]=[C:5]2[C:4](=[N:10][CH:14]=1)[N:3]=[CH:2][N:7]=[CH:6]2
Reactant: Nc1nc(N)c(N)c(N)n1
Reactant: CC(=O)C(O)O
Product: OCc1cnc2ncncc2n1

Procedure:
Condensation of 2,4,5,6-tetraaminopyrimidine with dihydroxyacetone gave 6-hydroxymethylpteridine 1. Compound 1 was treated with bromine and triphenyl phosphine in dimethylacetamide to give the corresponding 6-bromomethylpteridine which was coupled in situ with 4-aminobenzoic acid to afford pteroylbenzoic acid 2. Purity of the crude product was about 85% as analyzed by HPLC. Due to the low solubility of this compound in most solvents, purification by recrystallization proved to be impractical. The corresponding sodium salt, however, was soluble in hot water and crystallized upon cooling. Although compound 2 decomposes in hot aqueous hydroxide, treatment of the crude product with dilute sodium bicarbonate gave the sodium salt without observable decomposition. Recrystallization of the salt from dilute aqueous bicarbonate raised product purity to 93% or above. The purified salt was then converted back to acid 2 by treatment with aqueous acetic acid.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:22])[CH2:7][C@@H:8]1[CH2:13][CH2:12][C@@H:11]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][O:9]1>CO.O>[C:18]([O:17][C:15]([NH:14][C@H:11]1[CH2:10][O:9][C@H:8]([CH2:7][C:6]([OH:22])=[O:5])[CH2:13][CH2:12]1)=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: COC(=O)C[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)CO1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](CC(=O)O)OC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.2 %

Procedure:
Lithium hydroxide monohydrate (61 mg, 1.46 mmol, 2.0 eq) is added at room temperature to a stirred solution of (2S,5R)-(5-tert-butoxycarbonylamino-tetrahydro-pyran-2-yl)-acetic acid methyl ester (200 mg, 0.73 mmol, 1.0 eq) in methanol (10 mL) and water (5 mL) and the resulting mixture is stirred at room temperature for 2 hours. Then solvents are evaporated, the residue is acidified to pH 2 with 2.0 M hydrochloric acid aqueous solution and the resulting aqueous layer is extracted with ethyl acetate (3×20 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to afford (2S,5R)-(5-tert-butoxycarbonylamino-tetrahydro-pyran-2-yl)-acetic acid as a colorless oil (150 mg, 79% yield).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([NH2:7])=[N:4][N:3]=1.[C:8]1([CH:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:15](Cl)=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[CH3:1][C:2]1[O:6][C:5]([NH:7][C:15](=[O:16])[CH:14]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:4][N:3]=1
Reactant: Cc1nnc(N)o1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Product: Cc1nnc(NC(=O)C(c2ccccc2)c2ccccc2)o1

Procedure:
The title compound, white solid, m.p. 160-161° C. and MS: m/e=293.1 (M+) was prepared in accordance with the general method of example 44a from 5-methyl[1,3,4]oxadiazol-2-ylamine and 2,2-diphenylacetic acid chloride.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([C:17]([OH:19])=O)[CH:16]=2)[CH:4]=1)[CH3:2].[NH:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[C:21]1[CH2:29][CH2:30][NH2:31]>>[NH:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[C:21]1[CH2:29][CH2:30][NH:31][C:17]([C:15]1[CH:16]=[C:11]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=2[CH3:10])[CH:12]=[N:13][CH:14]=1)=[O:19]
Reactant: NCCc1nc2ccccc2[nH]1
Reactant: CCc1cc(-c2cncc(C(=O)O)c2)c(C)[nH]c1=O
Product: CCc1cc(-c2cncc(C(=O)NCCc3nc4ccccc4[nH]3)c2)c(C)[nH]c1=O

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5′-ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[3,3′]bipyridinyl-5-carboxylic acid and 2-(1H-benzoimidazol-2-yl)-ethyl-amine to afford the title compound. MS: m/e=402 (M+H).
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([NH:9]C(=O)OC(C)(C)C)[CH:6]=[CH:5][CH:4]=1)#[N:2].C(O)(C(F)(F)F)=O>ClCCl>[NH2:9][C:7]1[N:8]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(C#N)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cccc(N)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 106.7 %

Procedure:
To a round bottom flask charged with tert-butyl (6-cyanopyridin-2-yl)carbamate (0.5383 g, 2.455 mmol) in dichloromethane (9.82 ml) was added TFA (2.455 ml). The reaction mixture was stirred at rt 4 h. Excess TFA was removed in vacuo. The crude residue was taken up in methanol and free based using 2 parallel Phenomenex 5 g SCX columns. The columns were flushed with three column volumes methanol and three column volumes 3.5 N ammonia/methanol. The ammonia layers were concentrated in vacuo to provide 6-aminopicolinonitrile (0.312 g).
Reaction SMILES: Cl.[NH2:2][CH:3]1[C:24](=[O:25])[N:5]2[C:6]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)=[O:13])=[C:7]([CH2:10][Cl:11])[CH2:8][S:9][C@H:4]12.[C:26](OCC)(=[O:28])C.[OH-].[Na+]>O>[Cl:11][CH2:10][C:7]1[CH2:8][S:9][C@@H:4]2[CH:3]([NH:2][CH:26]=[O:28])[C:24](=[O:25])[N:5]2[C:6]=1[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)=[O:13]
Reactant: COc1ccc(COC(=O)C2=C(CCl)CS[C@@H]3C(N)C(=O)N23)cc1
Reactant: CCOC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(COC(=O)C2=C(CCl)CS[C@@H]3C(NC=O)C(=O)N23)cc1
Reaction time: 2 h
Yield: 99 %

Procedure:
To 15 g (37 mM) of p-methoxybenzyl 7-amino-3-chloromethyl-3-cephem-4-carboxylate hydrochloride, 500 ml of ethyl acetate and 100 ml of water were added. Under cooling with ice, the mixture was adjusted to pH 7.5 with a 1N sodium hydroxide aqueous solution and dissolved. The organic layer was separated, washed with a saturated sodium chloride aqueous solution, and then concentrated under reduced pressure. The oily residue was dissolved in 150 ml of methylene chloride. To this solution, a mixed anhydride solution prepared from 4.8 ml (127 mM) of 99% formic acid and 12 ml (127 mM) of acetic anhydride, was dropwise added under cooling with ice, and the mixture was stirred for 2 hours. The reaction solution was concentrated under reduced pressure. To the residue, 300 ml of ethyl acetate, 300 ml of tetrahydrofuran and 100 ml of water were added, and the mixture was adjusted to pH 7.5 with a 1N sodium hydroxide aqueous solution. The organic layer was separated, and washed with a saturated sodium chloride aqueous solution. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 14.5 g (yield: 99%) of p-methoxybenzyl 3-chloromethyl-7-formamido-3-cephem-4-carboxylate.
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:25])[C@@H:8]([NH2:24])[CH2:9][NH:10][C:11]([C:13]1[S:14][C:15]([CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:16][CH:17]=1)=[O:12])([CH3:5])([CH3:4])[CH3:3].C(N(CC)CC)C.[C:33]([C:37]1[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[CH:39][CH:38]=1)([CH3:36])([CH3:35])[CH3:34]>ClCCl>[C:2]([O:6][C:7](=[O:25])[C@@H:8]([NH:24][S:43]([C:40]1[CH:41]=[CH:42][C:37]([C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:38][CH:39]=1)(=[O:45])=[O:44])[CH2:9][NH:10][C:11]([C:13]1[S:14][C:15]([CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:16][CH:17]=1)=[O:12])([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)CCc1ccc(C(=O)NC[C@H](N)C(=O)OC(C)(C)C)s1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CCc1ccc(C(=O)NC[C@H](NS(=O)(=O)c2ccc(C(C)(C)C)cc2)C(=O)OC(C)(C)C)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.6 %

Procedure:
A solution of 0.395 g (1 mmol) of (2S)-2-amino-3-((5-(2-methoxycarbonylethyl)-thiophene-2-carbonyl)-amino)-propionic acid tert-butyl ester hydrochloride (example 15, step a) and triethylamine (0.15 ml, 1.1 mmol) in dichloromethane (10 ml) was cooled to 0° C. in an ice bath and a solution of 0.255 g (1.1 mmol) of 4-tert-butylphenylsulfonyl chloride in dichloromethane (5 ml) was added. Then the reaction mixture was stirred at room temperature overnight. After removal of the solvent in vacuo the residue was absorbed onto silica gel and cromatographed with ethyl acetate/cyclohexane (1/1) to yield 0.285 g (52%) of the title compound as a white amorphous solid.
Reaction SMILES: [I-].[CH2:2]([N+:6]1[C:10]([CH3:11])=[C:9]([CH3:12])[S:8][C:7]=1[CH3:13])[CH2:3][CH2:4][CH3:5].[F:14][C:15]1[CH:16]=[CH:17][C:18]([CH3:24])=[C:19]([CH:23]=1)[C:20](Cl)=[O:21]>CN(C1C=CN=CC=1)C>[CH2:2]([N:6]1[C:10]([CH3:11])=[C:9]([CH3:12])[S:8]/[C:7]/1=[CH:13]\[C:20]([C:19]1[CH:23]=[C:15]([F:14])[CH:16]=[CH:17][C:18]=1[CH3:24])=[O:21])[CH2:3][CH2:4][CH3:5]
Reactant: Cc1ccc(F)cc1C(=O)Cl
Reactant: CCCC[n+]1c(C)sc(C)c1C
Agent: CN(C)c1ccncc1
Agent: [I-]
Product: CCCCN1C(C)=C(C)S/C1=C\C(=O)c1cc(F)ccc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial 3-butyl-2,4,5-trimethylthiazol-3-ium iodide (48 mg in 0.5 mL DMA, 0.16 mmol, 1 equiv.) was added, followed by TEA (38 mg in 0.5 mL DMA, 0.37 mmol, 2.4 equiv.) and the solution went black. DMAP (2 mg in 0.5 mL DMA, 0.016 mmol, 0.1 equiv) was added next, followed by 5-fluoro-2-methylbenzoyl chloride (0.9 mL of 0.2M in DMA, 1.2 equiv). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.91 (t, 3 H) 1.30-1.41 (m, 2 H) 1.55-1.68 (m, 2 H) 2.20 (s, 3 H) 2.22 (s, 3 H) 2.33 (s, 3 H) 3.96-4.04 (m, 2 H) 6.09 (s, 1 H) 7.08-7.14 (m, 1 H) 7.19-7.27 (m, 2 H); MS (ESI) m/z 320 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:6][N:7]2[C:12](=[O:13])[C:11]([CH2:14]OS(C)(=O)=O)=[CH:10][C:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([F:28])[CH:21]=3)=[N:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[N:29]1([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[C:38]([O:37][C:35]([N:29]1[CH2:34][CH2:33][N:32]([CH2:14][C:11]2[C:12](=[O:13])[N:7]([CH2:6][CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[N:8]=[C:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([F:28])[CH:21]=3)[CH:10]=2)[CH2:31][CH2:30]1)=[O:36])([CH3:41])([CH3:40])[CH3:39]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CC3CCCC3)n2)cc1F
Product: COc1ccc(-c2cc(CN3CCN(C(=O)OC(C)(C)C)CC3)c(=O)n(CC3CCCC3)n2)cc1F
Yield: 78.8 %

Procedure:
Following the procedure of Example 1(10), 2-cyclopentylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and tert-butyl 1-piperazinecarboxylate were reacted to yield the title compound as a yellow oil (yield: 78.8%).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[CH3:10][O-:11].[Na+]>O1CCCC1>[Br:1][C:2]1[C:3]([O:11][CH3:10])=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1
Reactant: C[O-]
Reactant: Cc1ccc(Br)c(Cl)n1
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1nc(C)ccc1Br
Temperature: 25 °C
Yield: 46.1 %

Procedure:
To a cooled (0° C.) solution of 3-bromo-2-chloro-6-methylpyridine (300 mg, 1.45 mmol) in tetrahydrofuran (20 mL), add sodium methoxide (1.57 g, 29 mmol), slowly with stirring. Allow the mixture to warm to ambient temperature and stir overnight. Add additional sodium methoxide (500 mg) and stir at 100° C. overnight. Quench with water (20 mL), extract three times with ethyl acetate (30 mL). Combine the organics and wash with water then brine, and dry over sodium sulphate. Filter and concentrate to give the title product as a yellow solid (135 mg, 46%). 1HNMR (MeOH-d4): δ 7.72 (d, 1H), 6.70 (d, 1H), 3.93 (s, 3H), 2.38 (s, 3H).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10](F)[CH:11]=2)[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2].[NH:19]1[CH2:24][CH2:23][S:22][CH2:21][CH2:20]1.C(#N)C>CN(C)C=O>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10]([N:19]3[CH2:24][CH2:23][S:22][CH2:21][CH2:20]3)[CH:11]=2)[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)cc21
Reactant: C1CSCCN1
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCSCC3)cc21
Temperature: 25 °C
Yield: 65.8 %

Procedure:
A solution of 1.35 g (5.33 mmol) of 1-ethyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 1.34 ml (13.3 mmol) of thiomorpholine, 40 ml of acetonitrile, and 20 ml of N,N-dimethylformamide was heated under reflux for 21 hours. The reaction mixture was cooled to room temperature and the solid was collected by filtration, washed with water and acetonitrile, and dried to give 1.18 g of 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(4-thiomorpholinyl)-3-quinolinecarboxylic acid, mp 254°-6°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[CH:18]1([N:24]=[C:25]=[O:26])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>>[CH:18]1([NH:24][C:25]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3[CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[O:26])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: O=C=NC1CCCCC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)NC4CCCCC4)cc23)CC1
Yield: 86.6 %

Procedure:
Beginning with 15.0 mg (0.0655 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 16.37 mg (0.131 mMol) cyclohexyl isocyanate, 20.1 mg (87%) of the title compound were recovered.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:10]=1[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[F:19])=[O:12].CS(C)=[O:27]>>[Cl:24][C:21]1[CH:22]=[CH:23][C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[CH:2]=[O:27])=[C:10]([C:11](=[O:12])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])[CH:20]=1
Reactant: CS(C)=O
Reactant: O=C(c1ccccc1F)c1cc(Cl)ccc1-c1ccccc1CBr
Product: O=Cc1ccccc1-c1ccc(Cl)cc1C(=O)c1ccccc1F

Procedure:
The starting material is prepared as follows: The solution of 3.2 g of 2-(o-bromomethylphenyl)-5-chloro-2'-fluorobenzophenone in 40 ml of freshly distilled dimethylsulfoxide is heated for 30 minutes in an oil bath at 178°. After cooling, the solution is partitioned between diethyl ether and water, the ethereal layer washed again with water and saturated aqueous sodium chloride, and evaporated. The residue is taken up in 40 ml of methylene chloride and the solution treated with 2.6 g of pyridinium chlorochromate for 2 hours at 25°. The mixture is diluted with 100 ml of diethyl ether, filtered through a bed of infusorial earth and the filtrate evaporated, to yield the 2-[4-chloro-2-(2-fluorobenzoyl)-phenyl]-benzaldehyde.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:16](=[O:18])[CH3:17])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.Br[CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23]>CS(C)=O>[CH3:23][C:22]([CH3:24])=[CH:21][CH2:20][O:1][C:2]1[C:3]([C:16](=[O:18])[CH3:17])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:12])([CH3:13])[C:10]=2[CH:11]=1
Reactant: CC(C)=CCBr
Reactant: CC(=O)c1cc2c(cc1O)C(C)(C)CCC2(C)C
Solvent: CS(C)=O
Product: CC(=O)c1cc2c(cc1OCC=C(C)C)C(C)(C)CCC2(C)C
Yield: 126.1 %

Procedure:
1-(3-Hydroxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalen-2-yl)-ethanone (0.125 g, 0.507 mmol) in DMSO (1 mL) was alkylated with 4-bromo-2-methyl-2-butene (0.106 g, 0.710 mmol, 0.082 mL) as described in Example 21. Aqueous workup gave 1-[3-(3-methylbut-2-enyloxy)-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalen-2-yl]ethanone 0.201 g (100% crude) as a clear yellow crystalline solid: 1H-NMR (400 MHz, CDCl3) δ 7.72 (s, 1H, Ar-H), 6.83 (s, 1H, Ar-H), 5,48 (m, 1H, olefinic), 4.59 (d, J=6.6 Hz, 2H, OCH2), 2.60 (s, 3H, CH3), 1.79 (s, 3H, CH3), 1.76 (s, 3H, CH3), 1.67 (appp d, J=2.7 Hz, 4H, 2CH2), 1.28 (s, 6H, 2CH3), 1.26 (s, 6H, 2CH3).