Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][NH2:2].[C:3]([C:5]1[C:10](=S)[NH:9][C:8]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[C:7]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:6]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N+:31]([O-:33])=[O:32])#[N:4]>C(O)C>[NH2:4][C:3]1[C:5]2[C:10](=[N:9][C:8]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)=[C:7]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:6]=2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N+:31]([O-:33])=[O:32])[NH:2][N:1]=1
Reactant: NN
Reactant: CCOC(=O)c1c(-c2ccc(OC)cc2)[nH]c(=S)c(C#N)c1-c1ccccc1[N+](=O)[O-]
Solvent: CCO
Product: CCOC(=O)c1c(-c2ccc(OC)cc2)nc2[nH]nc(N)c2c1-c1ccccc1[N+](=O)[O-]
Reaction time: 5 h
Yield: 74 %

Procedure:
0.5 ml of hydrazine is added to a solution of 0.21 g (0.46 mmol) of ethyl 5-cyano-2-(4-methoxyphenyl)-4-(2-nitrophenyl)-6-thioxo-1,6-dihydropyridine-3-carboxylate dissolved in 2 ml of ethanol. The reaction medium is carried at 90° C. for 5 hours. The precipitate obtained is filtered and then recrystallized in a methanol/diethyl ether mixture to yield 0.20 g (74%) of ethyl 3-amino-6-(4-methoxyphenyl)-4-(2-nitrophenyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate in the form of a yellow solid.
Reaction SMILES: [C:1](Cl)([C:3](Cl)=O)=[O:2].CN(C=O)C.[F:12][C:13]1[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[C:18]2[C:14]=1C=[CH:16][NH:17]2.CCOC(C)=O>C(Cl)Cl>[F:12][C:13]1[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[C:18]2[C:14]=1[C:3]([CH:1]=[O:2])=[CH:16][NH:17]2
Reactant: N#Cc1ccc(F)c2cc[nH]c12
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: N#Cc1ccc(F)c2c(C=O)c[nH]c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.1 %

Procedure:
To a solution of (COCl)2 (16.0 g) in DCM (200 mL) at 0° C. was added a solution of DMF (6 mL) in DCM (50 mL) dropwise. Half an hour later, a solution of 4-fluoro-1H-indole-7-carbonitrile (D41) (11.0 g) in DCM (60 mL) was added. The reaction was allowed to warm to RT to form a yellow precipitate. After 6 h the solvent was removed by evaporation. Then THF (100 mL) and 2M aqueous NaOH (100 L) were added to the residue obtained above. After being stirred for about 1 hour, EtOAc (1 L) was added. The organic phase was separated and the aqueous phase was extracted with EtOAc. The combined organic solution was dried over anhydrous sodium sulfate. The dried solution was concentrated to afford 4-fluoro-3-formyl-1H-indole-7-carbonitrile (D42) as a yellow solid (11.0 g).
Reaction SMILES: [C:1]([C:6]1[C:15](=O)[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH3:18])[CH:13]=2)[NH:8][CH:7]=1)(=[O:5])[CH2:2][CH2:3][CH3:4].N.P(Cl)(Cl)([Cl:22])=O>>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[Cl:22])=[CH:13][C:12]([O:17][CH3:18])=[CH:11][CH:10]=2)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCC(=O)c1c[nH]c2ccc(OC)cc2c1=O
Agent: N
Product: CCCC(=O)c1cnc2ccc(OC)cc2c1Cl
Yield: 62 %

Procedure:
3-Butyryl-6-methoxy-4(1H)-quinolone (20 g) was heated under reflux in phosphorus oxychloride for 1 hour. The mixture was cooled, poured onto ice and carefully neutralized with ammonia solution. The mixture was extracted with dichloromethane and the combined extracts washed with sodium hydrogen carbonate solution (×2) and brine. The organic solution was dried, filtered and evaporated to give 3-butyryl-4-chloro-6-methoxy-quinoline (13.3 g, 62%) as an oil which crystallized from ether/petrol; m.p. 73°-75°.
Reaction SMILES: [C:1]1([C@H:7]([NH:21][O:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)[CH2:8][N:9]2[CH2:13][CH2:12][C@H:11]([O:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)[CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:29][C:30]1[CH:31]=[C:32]([CH2:37][C:38](O)=[O:39])[CH:33]=[CH:34][C:35]=1[Cl:36]>>[Cl:29][C:30]1[CH:31]=[C:32]([CH2:37][C:38]([N:21]([O:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)[C@@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][N:9]2[CH2:13][CH2:12][C@H:11]([O:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)[CH2:10]2)=[O:39])[CH:33]=[CH:34][C:35]=1[Cl:36]
Reactant: c1ccc([C@@H](CN2CC[C@H](OC3CCCCO3)C2)NOC2CCCCO2)cc1
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Product: O=C(Cc1ccc(Cl)c(Cl)c1)N(OC1CCCCO1)[C@H](CN1CC[C@H](OC2CCCCO2)C1)c1ccccc1
Yield: 69.8 %

Procedure:
This was prepared from 1-(S)-Phenyl-N-tetrahydropyranyloxy-2-(3-(S)-tetrahydropyranyloxypyrrolidin-1-yl)ethylamine and 3,4-dichlorophenylacetic acid in 69.8% yield as a clear brown viscous oil according to a procedure similar to that described in Example 1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4]C(F)=[C:6]([CH:9]=1)C#N.[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH2:18])=[CH:15][CH:14]=1.C([N:23]([CH2:26][CH3:27])CC)C>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:27]([C:26]#[N:23])=[C:6]([NH:18][CH2:17][C:16]2[CH:19]=[CH:20][C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)[CH:9]=1
Reactant: CCN(CC)CC
Reactant: N#Cc1cc(Br)ccc1F
Reactant: COc1ccc(CN)cc1
Solvent: CS(C)=O
Product: COc1ccc(CNc2cc(Br)ccc2C#N)cc1
Yield: 81 %

Procedure:
A solution of 5-bromo-2-fluorobenzonitrile (3 g), 4-methoxybenzylamine (2.2 g), and triethyl amine (3 ml) in DMSO (5 ml) was heated at 120° C. for 5 h. The solution was partitioned between water and ethyl acetate. The combined organic extract was washed with brine, dried over Na2SO4 and concentrated. The residue was chromatographed to give the desired product (2.6 g, 81%) HPLC (6 minute gradient) tR=4.33 min; MS m/z 315.09, 317.08 (M+H]+
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.FC(F)(F)C(O)=O.[CH:32]([C:35]1[S:36][CH:37]=[C:38]([C:40]([N:42]2[CH2:66][C:46]3([CH2:49][N:48]([CH2:50][CH2:51][C:52]4[CH:53]=[C:54]([CH:63]=[CH:64][CH:65]=4)[CH2:55][CH2:56][O:57][CH2:58][CH2:59][C:60](O)=[O:61])[CH2:47]3)[O:45][CH2:44][CH2:43]2)=[O:41])[N:39]=1)([CH3:34])[CH3:33].[CH3:67][O:68][CH:69]([O:78][CH3:79])[CH2:70][NH:71][CH:72]1[CH2:77][CH2:76][CH2:75][CH2:74][CH2:73]1.C(N(CC)CC)C>CN(C=O)C>[CH:72]1([N:71]([CH2:70][CH:69]([O:78][CH3:79])[O:68][CH3:67])[C:60](=[O:61])[CH2:59][CH2:58][O:57][CH2:56][CH2:55][C:54]2[CH:63]=[CH:64][CH:65]=[C:52]([CH2:51][CH2:50][N:48]3[CH2:47][C:46]4([CH2:66][N:42]([C:40]([C:38]5[N:39]=[C:35]([CH:32]([CH3:33])[CH3:34])[S:36][CH:37]=5)=[O:41])[CH2:43][CH2:44][O:45]4)[CH2:49]3)[CH:53]=2)[CH2:77][CH2:76][CH2:75][CH2:74][CH2:73]1
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CN(CCc4cccc(CCOCCC(=O)O)c4)C3)C2)cs1
Reactant: COC(CNC1CCCCC1)OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(CN(C(=O)CCOCCc1cccc(CCN2CC3(C2)CN(C(=O)c2csc(C(C)C)n2)CCO3)c1)C1CCCCC1)OC
Temperature: 20 °C
Reaction time: 3 h

Procedure:
HATU (0.201 g) was added in one portion to a stirred solution at 0° C. of 3-(3-(2-(8-(2-isopropylthiazole-4-carbonyl)-5-oxa-2,8-diazaspiro[3.5]nonan-2-yl)ethyl)phenethoxy)propanoic acid trifluoroacetate salt (0.25 g) (example 176 step h), N-(2,2-dimethoxyethyl)cyclohexanamine (0.076 g) (WO2008075025) and triethylamine (0.283 ml) in DMF (4 mL) at 0° C. The mixture was stirred at 20° C. for 3 hours and then partitioned between ethyl acetate and brine, the organic layer was washed with brine (×2), dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure to afford the subtitled compound. Yield 0.270 g.
Reaction SMILES: [CH2:1]1[O:4][CH:2]1[CH3:3].[C:5]([O:8][CH3:9])(=[O:7])[CH3:6]>>[CH3:1][O:4][CH2:2][CH2:3][CH2:9][O:8][C:5](=[O:7])[CH3:6]
Reactant: CC1CO1
Reactant: COC(C)=O
Product: COCCCOC(C)=O

Procedure:
In a preferred reaction propylene oxide is reacted with methyl acetate to produce methoxypropylacetate.
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:63])[C@@H:24](NC(=O)/C(/C4N=C(NC(OC(C)(C)C)=O)SC=4)=N\OC(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C@H:21]3[S:20](=O)[CH2:19][C:18]=2SC(SC2N=CNN=2)C)=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)Cl.C(=O)([O-])O.[Na+].C(OCC)(=O)C>CN(C)C=O>[C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:63])[CH2:24][C@H:21]3[S:20][CH2:19][CH:18]=2)=[O:16])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(SC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)/C(=N\OC(c3ccccc3)(c3ccccc3)c3ccccc3)c3csc(NC(=O)OC(C)(C)C)n3)[C@H]2S(=O)C1)Sc1nc[nH]n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClP(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(OC(c1ccccc1)c1ccccc1)C1=CCS[C@@H]2CC(=O)N12
Reaction time: 0.33 h
Yield: 267.7 %

Procedure:
To a solution of 7β-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-trityloxyiminoacetylamino]-3-(1-methyl-1,2,4-triazol-3-ylthiomethylthio)-3-cephem-4-carboxylic acid diphenylmethyl ester 1-oxide (1.78 g: 1.69 mMol.) in dimethylformamide (15 ml) at -20° C. is added phosphorus trichloride (0.42 ml: 4.18 mMol.), and the mixture is stirred at the same temperature for 20 minutes. The reaction mixture is poured into two layers of cold aqueous sodium hydrogen carbonate and ethyl acetate. The organic layer is taken, washed with water and brine, dried over sodium sulfate, and concentrated. The residue is purified by silica gel chromatography (toluene: ethyl acetate=2:1) to give 7β-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-trityloxyiminoacetamido]-3-(]-methyl-1,2,4-triazol-3-ylthiomethylthio)-3-cephem-4-carboxylic acid diphenylmethyl ester (1.59 g) as brown foam. Yield: 91%.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]([CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](=[O:28])(=[O:27])[NH2:26])=[CH:21][CH:20]=1)[CH2:9][C:10]([O:12]C(C)(C)C)=[O:11]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]([CH2:17][CH2:18][C:19]1[CH:20]=[CH:21][C:22]([S:25](=[O:28])(=[O:27])[NH2:26])=[CH:23][CH:24]=1)[CH2:9][C:10]([OH:12])=[O:11]
Reactant: CC(C)(C)OC(=O)CN(CCc1ccc(S(N)(=O)=O)cc1)Cc1ccccn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1ccc(CCN(CC(=O)O)Cc2ccccn2)cc1
Yield: 99.8 %

Procedure:
To a solution of tert-butyl 2-((pyridin-2-ylmethyl)(4-sulfamoyl-phenethyl)amino)acetate (150 mg, 0.37 mmol) in DCM (3.0 mL) and TFA (3.0 mL) was stirred at room temperature for overnight. Solvent was removed under reduced pressure to give 2-((pyridin-2-ylmethyl)(4-sulfamoylphenethyl)amino)acetic acid (129 mg, 100%). 1H NMR (400 MHz, CD3OD) 8.73 (d, J=5.6 Hz, 0.46H), 8.58 (d, J=4.4 Hz, 1H), 8.57 (t, J=8.0 Hz, 0.46H), 8.16 (t, J=7.6 Hz, 1H), 8.01 (d, J=8.4 Hz, 0.54H), 7.96 (t, J=6.8 Hz, 0.54H), 7.79 (d, J=8.4 Hz, 2H), 7.66 (d, J=7.2 Hz, 2H), 7.35 (d, J=8.4 Hz, 2H), 4.51 (s, 2H), 4.06 (s, 2H), 3.36 (t, J=7.6 Hz, 2H), 3.05 (t, J=7.6 Hz, 2H); MS (ESI), 355 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7](Cl)[CH:8]=2)[N:3]=1.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][NH2:18].[CH2:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([NH:30][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:18][CH2:17][C:16]1[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=1[O:14][CH3:13])[CH:11]=[CH:10]2)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COc1ccccc1CN
Reactant: Clc1ccc2nc(Cl)ccc2c1
Reactant: NCc1ccccc1
Product: COc1ccccc1CNc1ccc2cc(NCc3ccccc3)ccc2n1

Procedure:
The title compound, MS: m/e=369.9 (M+H+), was prepared in accordance with the general method of example 1 from 2,6-dichloroquinoline, 2-methoxybenzylamine and benzylamine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4](=[O:14])[CH:5]([Cl:13])[C:6]1[CH:11]=[CH:10][C:9](F)=[CH:8][CH:7]=1.[CH3:16]C1C=C(C=CC=1)C=O.FC1C=CC(C=O)=CC=1>>[CH3:1][O:2][C:3](=[O:15])[C:4](=[O:14])[CH:5]([Cl:13])[C:6]1[CH:11]=[C:10]([CH3:16])[CH:9]=[CH:8][CH:7]=1
Reactant: Cc1cccc(C=O)c1
Reactant: COC(=O)C(=O)C(Cl)c1ccc(F)cc1
Agent: O=Cc1ccc(F)cc1
Product: COC(=O)C(=O)C(Cl)c1cccc(C)c1

Procedure:
This compound was synthesised as 3-chloro-3-(4-fluoro-phenyl)-2-oxo-propionic acid methylester but using 3-methylbenzaldehyde instead 4-fluorobenzaldehyde.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[ClH:12].[F:13][C:14]([F:31])([F:30])[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:22]=[C:23]3[C:27](=[CH:28][CH:29]=2)[NH:26][CH2:25][CH2:24]3)=[CH:17][CH:16]=1.C(N(CC)CC)C>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:26]2[C:27]3[C:23](=[CH:22][C:21]([C:18]4[CH:17]=[CH:16][C:15]([C:14]([F:13])([F:30])[F:31])=[CH:20][CH:19]=4)=[CH:29][CH:28]=3)[CH2:24][CH2:25]2)(=[O:10])=[O:9])=[CH:4][C:3]=1[Cl:12]
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: FC(F)(F)c1ccc(-c2ccc3c(c2)CCN3)cc1
Reactant: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(c1ccc(Br)c(Cl)c1)N1CCc2cc(-c3ccc(C(F)(F)F)cc3)ccc21
Temperature: 25 °C

Procedure:
1.79 g of commercially available 4-bromo-benzenesulfonyl chloride were dissolved in 35 ml dichloromethane. Then 1.85 g 5-(4-trifluoromethyl-phenyl)-2,3-dihydro-1H-indole hydrochloride were added followed by 2.14 ml triethylamine. The mixture was stirred at room temperature for fifteen minutes. Then 100 ml of dichloromethane were added, the mixture washed with 40 ml water and brine and then dried over MgSO4. The solvent was removed in vacuo to obtain 2.48 g crude 1-(4-bromo-3-chloro-benzenesulfonyl)-5-(4-trifluoromethyl-phenyl)-2,3-dihydro-1H-indole. This material was used without further purification.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)O1.C([O-])(=O)C.[K+].Cl[C:32]1[CH:37]=[CH:36][N:35]=[C:34]([NH2:38])[N:33]=1.C(#N)C>C(Cl)Cl.O>[N+:22]([C:19]1[CH:18]=[CH:17][C:16]([O:15][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:32]2[CH:37]=[CH:36][N:35]=[C:34]([NH2:38])[N:33]=2)=[CH:21][CH:20]=1)([O-:24])=[O:23]
Reactant: CC1(C)OB(c2ccccc2Oc2ccc([N+](=O)[O-])cc2)OC1(C)C
Reactant: Nc1nccc(Cl)n1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: ClCCl
Product: Nc1nccc(-c2ccccc2Oc2ccc([N+](=O)[O-])cc2)n1
Temperature: 85 °C

Procedure:
The compound of step 1 (0.034 g, 0.054 mmol), potassium acetate (0.26 g, 2.7 mmol), 4,4,5,5-tetramethyl-2-(2-(4-nitrophenoxy)phenyl)-1,3,2-dioxaborolane (0.460 g, 1.3 mmol), and 4-chloropyrimidin-2-amine (0.17 g, 1.3 mmol) were combined in a sealed tube under nitrogen, to which 7 mL ACN and water (0.73 ml, 40 mmol) were added. The reaction was sealed and heated to 85° C. overnight. The reaction was diluted with DCM and water, and extracted 2× with DCM. The combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting material was purified by silica gel chromatography (MeOH/DCM) to give 4-(2-(4-nitrophenoxy)phenyl)pyrimidin-2-amine as a white solid MS m/z=309 [M+H]+. Calc'd for C16H12N4O3: 308.3.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][C:5](=[O:7])[CH:4]=[CH:3]1.CN(CC)C.[Si:13](Cl)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].C(OCC)(=O)C>C(Cl)Cl>[CH3:17][C:16]([Si:13]([CH3:15])([CH3:14])[O:7][C@H:5]1[CH2:6][C:2](=[O:1])[CH:3]=[CH:4]1)([CH3:19])[CH3:18]
Reactant: O=C1C=C[C@@H](O)C1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CCN(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@@H]1C=CC(=O)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a 1-L round bottomed flask was charged (4S)-4-Hydroxy-2-cyclopenten-1-one (32) (20 g, 204 mmol, prepared described in Khanapure, S.; Najafi, N.; Manna, S.; Yang, J.; Rokash. J. J. Org. Chem., 1995, 60, 7448) in DCM (200 mL) followed by N,N-dimethylethylamine (47.7 g, 653 mmol), tert-butyldimethylsilyl chloride (46.1 g, 306 mmol) and a catalytic amount of 4-N,N-dimethylaminopyridine (1 g). The mixture was stirred at room temperature for 24 hours. The reaction mixture was poured into ethyl acetate (200 mL) and the organic layer washed with water (200 mL), aqueous HCl (1 N, 2×100 mL), brine (100 mL) and saturated sodium bicarbonate solution (100 mL). The organic layer was dried over magnesium sulfate and concentrated in vacuo to afford the title compound as a crude product (42 g, ˜98% yield).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:15]([O:17][CH3:18])=[O:16].[OH-].[Na+]>C(Cl)(Cl)Cl.O>[C:15]([N:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]1)([O:17][CH3:18])=[O:16]
Reactant: COC(=O)Cl
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: COC(=O)N1CCN(Cc2ccccc2)CC1
Yield: 81.8 %

Procedure:
To a solution of 35.2 g (0.20 mole) of 1-benzylpiperazine in 100 ml of CHCl3 was added dropwise over a period of 30 minutes a solution of 17.0 g (0.18 mole) of methyl chloroformate in 110 ml of CHCl3. The mixture was allowed to reflux during 2.5 hours and was made basic with 16 g of sodium hydroxide in 100 ml of water. The nonaqueous layer was separated, dried over magnesium sulphate and concentrated. The residue was distilled b.p. 108°-10° C. at 0.1-0.2 mmHg to give 34.5 g of 1-carbomethoxy-4-benzylpiperazine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:22])[CH:11]=2)[CH:6]=1.[Cl:24][C:25]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:26]=1[C:27](Cl)=[O:28].C(N(CC)C(C)C)(C)C>ClCCl.O.[Cl-].[Na+].O>[CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([CH:16]2[CH2:17][CH2:18][N:19]([C:27](=[O:28])[C:26]3[CH:30]=[CH:31][C:32]([Cl:34])=[CH:33][C:25]=3[Cl:24])[CH2:20][CH2:21]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:22])[CH:11]=2)[CH:6]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(C2CCNCC2)c1C
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)Cc1cc2ccc(F)cc2c(C2CCN(C(=O)c3ccc(Cl)cc3Cl)CC2)c1C
Reaction time: 15 h
Yield: 64.9 %

Procedure:
To a light brown solution of (6-fluoro-3-methyl-4-piperidin-4-yl-naphthalen-2-yl)-acetic acid methyl ester (which may be prepared as described above; 110 mg, 0.35 mmol) and 2,4-dichlorobenzoyl chloride (110 mg, 0.53 mmol) in dichloromethane (10 mL) was added N,N-diisopropylethylamine (183 μL, 1.05 mmol) at room temperature under a nitrogen atmosphere. The resulting light brown solution was stirred for 15 hours. The reaction mixture was diluted with water and brine and the resulting mixture was extracted into ethyl acetate (2×50 mL). The combined organic extracts were washed with brine solution, dried over MgSO4, filtered, and concentrated to give the crude product. Flash chromatography (40 g ISCO column, eluting with 0-60% ethyl acetate/hexanes) provided {4-[1-(2,4-dichloro-benzoyl)-piperidin-4-yl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (111 mg, 65%) as a white solid. MS cald. for C26H25Cl2FNO3 [(M+H)−] 488, obsd. 488.0.
Reaction SMILES: [C:1]([C:3]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=2[Cl:15])=[C:6]([C:16]2[NH:20][CH:19]=[N:18][N:17]=2)[S:5][C:4]=1[C:21]1[CH:26]=[CH:25][N:24]=[C:23]([NH:27][C:28](=[O:30])[CH3:29])[CH:22]=1)#[N:2].[Br:31]N1C(=O)CCC1=O.C(Cl)(Cl)(Cl)Cl.C(#N)C>>[Br:31][C:19]1[NH:20][C:16]([C:6]2[S:5][C:4]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([NH:27][C:28](=[O:30])[CH3:29])[CH:22]=3)=[C:3]([C:1]#[N:2])[C:7]=2[C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=2[Cl:15])=[N:17][N:18]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)Nc1cc(-c2sc(-c3nnc[nH]3)c(-c3ccc(Cl)cc3Cl)c2C#N)ccn1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC#N
Product: CC(=O)Nc1cc(-c2sc(-c3nnc(Br)[nH]3)c(-c3ccc(Cl)cc3Cl)c2C#N)ccn1
Temperature: 85 °C
Yield: 80.2 %

Procedure:
A suspension of N-(4-(3-cyano-4-(2,4-dichlorophenyl)-5-(4H-1,2,4-triazol-3-yl)thiophen-2-yl)pyridin-2-yl)acetamide (0.0700 g, 0.154 mmol) and N-Bromosuccinimide (33.1 mg, 0.186 mmol) in Carbon tetrachloride (2.5 mL, 26 mmol) was heated to 85° C. in a capped vial for 2.5 hours. To the suspension was added dry Acetonitrile (6.0 mL, 110 mmol) and the mixture was heated at 85° C. (turned into a clear solution) for additional 2 hours. The mixture was cooled to r.t., evaporated in rotavapor. The residue was dry loaded in a silica column and eluted with MeOH/DCM (0/100 to 5/95) to give a solid product (66.0 mg, yield 80.4%). LCMS: (FA) ES+, 533, 535, 537 and ES− 531, 533, 535. 1H NMR (400 MHz, d1-chloroform) δ: 8.65 (s, 1H), 8.42 (d, J=5.02 Hz, 1H), 8.26 (s, 1H), 7.61 (d, J=2.01 Hz, 1H), 7.56 (dd, J=5.27, 1.76 Hz, 1H), 7.43-7.45 (dd, J=8.28, 2.01 Hz, 1H), 7.37-7.39 (d, J=8.28 Hz, 1H), 2.26 (s, 3H).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C(N(CC)CC)C.[OH:14][C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=1)[C:18]([O:20][CH3:21])=O.[CH:25]12[CH2:34][CH:29]3[CH2:30][CH:31]([CH2:33][CH:27]([CH2:28]3)[C:26]1=O)[CH2:32]2>C1COCC1.O>[OH:14][C:15]1[CH:16]=[C:17]([CH2:18][O:20][CH:21]=[C:26]2[CH:27]3[CH2:33][CH:31]4[CH2:30][CH:29]([CH2:34][CH:25]2[CH2:32]4)[CH2:28]3)[CH:22]=[CH:23][CH:24]=1
Reactant: O=C1C2CC3CC(C2)CC1C3
Reactant: COC(=O)c1cccc(O)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Oc1cccc(COC=C2C3CC4CC(C3)CC2C4)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 88.8 %

Procedure:
[(3-Hydroxyphenyl)methoxymethylene]adamantane (1a) was prepared as described in my previous application Ser. No. 224,681, filed July 27, 1988. A 500-mL flask was fitted with a reflux condenser, a 125-mL addition funnel, and nitrogen line. The apparatus was dried by means of a hot air gun and nitrogen purging. Dry THF (40 mL) was added and the flask cooled in an ice bath. TiCl3 (1.5 g, 10 mmol) was added rapidly followed by LAH (0.19 g, 5 mmol) in portions with stirring. The cooling bath was removed and the black mixture was allowed to warm to room temperature. Triethylamine (0.7 mL, 5 mmol) was added to the stirred suspension and refluxed for 15 min. After this period, a solution of methyl 3-hydroxybenzoate (152 mg, 1 mmol) and 2-adamantanone (300 mg, 2 mmol) in 20 mL of dry THF was added dropwise to the refluxing mixture over 15 min. Refluxing was continued for an additional 15 min after which the reaction was cooled to room temperature and diluted with 100 mL of distilled water. The aqueous solution was extracted with 3×50 mL portions of ethyl acetate. The combined organic layer was washed with water, dried over MgSO4, and concentrated. Chromatography over silica with 15% ethyl acetate/hexane gave 240 mg (89%) of 1a as a white solid: mp 133°-4° C.; 1H NMR (CDCl3) δ1.64-1.96 (m, 12H), 2.65 (s, 1H), 3.24 (s, 1H), 3.32 (s, 3H), 5.25 (s, 1H, OH exchange with D2O), 6.70-7.30 (m, 4H); 13C NMR (CDCl3) δ28.45, 30.36, 32.36, 37.30, 39.18, 39.33, 57.82, 114.60, 116.16, 122.19, 129.24, 137.24, 155.62; MS m/e (rel intensity) 271 (20, M+1), 270 (100, M), 253 (7.3), 213 (35.1 ), 121 (41.7), 93 (9.4); Exact mass: calcd 270.1619, found 270.1616. ##STR21##
Reaction SMILES: [O-]CC.[Na+].[CH2:5]([O:7][C:8]([N:10]1[CH2:16][CH2:15][C:14]2[CH:17]=[C:18]([CH:20]=O)[S:19][C:13]=2[CH2:12][CH2:11]1)=[O:9])[CH3:6].[N:22]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[N+:23]=[N-:24]>C(O)C>[CH2:5]([O:7][C:8]([N:10]1[CH2:16][CH2:15][C:14]2[CH:17]=[C:18]([CH:20]=[C:25]([N:22]=[N+:23]=[N-:24])[C:26]([O:28][CH2:29][CH3:30])=[O:27])[S:19][C:13]=2[CH2:12][CH2:11]1)=[O:9])[CH3:6]
Reactant: CCOC(=O)CN=[N+]=[N-]
Reactant: CCOC(=O)N1CCc2cc(C=O)sc2CC1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(=Cc1cc2c(s1)CCN(C(=O)OCC)CC2)N=[N+]=[N-]
Temperature: 0 °C
Yield: 44.8 %

Procedure:
A solution of sodium ethoxide in ethanol (21 wt % in EtOH, 8 ml, 21.4 mmol) was diluted with additional ethanol (˜5 ml) and cooled to 0° C. To this solution was added the product from step (c) (4.50 g, 17.76 mmol) and ethyl azidoacetate (25% wt % in EtOH, 11 ml, 21.4 mmol). The reaction mixture was stirred and allowed to warm to RT over 16 hrs. The reaction mixture was then quenched by pouring into saturated aqueous NH4Cl. The aqueous mixture was extracted with Et2O (3×). The combined Et2O extracts were washed with brine, dried (MgSO4), filtered, and solvent evaporated in vacuo to give an orange oil. The crude oil was purified by flash silica-gel chromatography (gradient elution: 0 to 45% EtOAc in hexanes) to give the subtitled compound as a yellow oil (2.9 g). MS: ESI (positive): 365 (M+H).