Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][CH:9]([O:11][Si](C(C)(C)C)(C)C)[CH2:8][C@H:7]1[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)=[O:5])[CH3:2].N1C=CC=CC=1.[Na]>O1CCCC1>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][CH:9]([OH:11])[CH2:8][C@H:7]1[CH2:19][O:20][C:21]1[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1CC(O[Si](C)(C)C(C)(C)C)C[C@H]1COc1ccc(Cl)cc1
Agent: [Na]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H]1CC(O)C[C@H]1COc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.4 %

Procedure:
To a cold (ice bath) solution of (1R,2R)-4-(tert-Butyl-dimethyl-silanyloxy)-2-(4-chloro-phenoxymethyl)-cyclopentanecarboxylic acid ethyl ester (epimeric mixture, 529 mg) in tetrahydrofuran (20 mL) was slowly added pyridine (8.1 g) and a pyridine-hydrofluoric acid complex (70% HF w/w, 9.07 g). The mixture was stirred 3 h at room temperature then solid sodium hydrogenocarbonate an aqueous saturated solution of sodium hydrogenocarbonate were added to adjust the pH to 7. The mixture was extracted with dichloromethane and the combined organic layers were washed with an aqueous saturated solution of sodium hydrogenocarbonate, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel with a gradient of cyclohexane/ethylacetate (6:1 to 1:1 v/v) as eluant to afford the title compound (0.346 g, 90%) as a light yellow oil. MS (EI): 299.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].CCO>CCOC(C)=O.[Pd]>[NH2:11][C:8]1[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)O
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1ccc(N)cc1C(=O)O
Reaction time: 24 h

Procedure:
To a 250 mL round-bottomed flask was added 2-methyl-5-nitrobenzoic acid (5.0 g, 28 mmol) and palladium 10% on carbon (1.5 g, 14 mmol). The mixture was taken up in EtOAc (30 mL) then EtOH (70 mL) was added. The mixture was purged with H2 then allowed to stir at 1 atm. H2 for 24 h. LCMS indicated about 10% conversion to product. About 0.5 g 10% Pd/C and ˜30 mL MeOH was added to the reaction. The reaction was purged with H2 and let to stir at 1 atm H2 for 20 h. They reaction was monitored for complete conversion by LCMS. The mixture was passed through a pad of celite, washing with MeOH and concentrated to afford 5-amino-2-methylbenzoic acid as an off-white solid MS m/z found 152.1 (ESI, neg. ion).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][S:9]([C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[N:28]=[C:29]([NH2:32])[S:30][CH:31]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][S:9]([C:12]2[CH:13]=[CH:14][C:15]([C:16]([NH:32][C:29]3[S:30][CH:31]=[C:27]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=4)[N:28]=3)=[O:18])=[CH:19][CH:20]=2)(=[O:10])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(S(=O)(=O)Nc2cccc(Cl)c2)cc1
Reactant: Nc1nc(-c2ccccn2)cs1
Product: O=C(Nc1nc(-c2ccccn2)cs1)c1ccc(S(=O)(=O)Nc2cccc(Cl)c2)cc1

Procedure:
4-(N-(3-chlorophenyl)sulfamoyl)benzoic acid (11) (106 mg, 0.34 mmol) was treated with 4-(pyridin-2-yl)thiazol-2-amine (50 mg, 0.28 mmol) using method C. The residue was purified using flash chromatography eluting with 50-100% EtOAc in hexanes. The resulting solid was triturated with diethyl ether to give 4-(N-(3-chlorophenyl)sulfamoyl)-N-(4-(pyridin-2-yl)thiazol-2-yl)benzamide as a yellow solid. Yield: 49 mg (37%). 1H-NMR: 10.77 (s, 1H), 8.63-8.61 (m, 1H), 8.25 (d, J=8.5 Hz, 2H), 8.00 (d, J=8.0 Hz, 1H), 7.95-7.88 (m, 4H), 7.35 (ddd, J=7.5, 5.0, 1.0 Hz, 1H), 7.30 (t, J=8.0 Hz, 1H), 7.15 (t, J=2 Hz, 1H), 7.13-7.08 (m, 2H), 3.32 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](I)[CH:3]=1.N1CCCCC1.[CH3:15][C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[C:17]=1[CH:24]1[C:32](=[O:33])[CH:31]2[CH:26]([CH:27]3[O:34][CH:30]2[CH:29]=[CH:28]3)[C:25]1=[O:35].C(O)=O>CN(C)C=O.ClCCl.O>[F:1][C:2]1[CH:3]=[C:4]([CH:29]2[CH2:28][CH:27]3[O:34][CH:30]2[CH:31]2[CH:26]3[C:25](=[O:35])[CH:24]([C:17]3[C:18]([CH3:23])=[CH:19][C:20]([CH3:22])=[CH:21][C:16]=3[CH3:15])[C:32]2=[O:33])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(C)c(C2C(=O)C3C4C=CC(O4)C3C2=O)c(C)c1
Reactant: Fc1cccc(I)c1
Solvent: ClCCl
Solvent: C1CCNCC1
Solvent: O
Product: Cc1cc(C)c(C2C(=O)C3C4CC(c5cccc(F)c5)C(O4)C3C2=O)c(C)c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Bis(triphenylphosphine)palladium diacetate (20 mg, 0.024 mmol), 1-fluoro-3-iodo-benzene (104 mg, 0.47 mmol) and piperidine (0.16 ml, 1.6 mmol) are added to a solution of (1RS,2SR,6RS,7SR)-4-(2,4,6-trimethylphenyl)-10-oxatricyclo[5.2.1.02,6]dec-8-en-3,5-dione (0.20 g, 0.71 mmol) in dry N,N-dimethylformamide (2 ml). Formic acid (0.06 ml, 1.6 mmol) is added and the reaction mixture is heated at 50° C. for 2 hours. The reaction mixture is cooled to room temperature, water (1 ml) and dichloromethane (1 ml) are added, and the mixture is stirred for 1 hour. The two phases are separated, the organic phase collected and the solvent is evaporated. The residue is purified by preparative reverse-phase HPLC to give (1RS,2SR,6RS,7SR,8RS)-8-(3-fluorophenyl)-4-(2,4,6-trimethylphenyl)-10-oxatricyclo-[5.2.1.02,6]decane-3,5-dione.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]1[C:18]([C:19]([F:22])([F:21])[F:20])=[N:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[N:23]1[N:24]=[C:25]([C:28]2[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=2[C:30](O)=[O:31])[NH:26][CH:27]=1>>[N:23]1[N:24]=[C:25]([C:28]2[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=2[C:30]([N:7]2[CH2:6][CH:5]3[CH2:1][N:2]([C:9]4[C:18]([C:19]([F:22])([F:20])[F:21])=[N:17][C:16]5[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=5)[N:10]=4)[CH2:3][CH:4]3[CH2:8]2)=[O:31])[NH:26][CH:27]=1
Reactant: O=C(O)c1ccccc1-c1nnc[nH]1
Reactant: FC(F)(F)c1nc2ccccc2nc1N1CC2CNCC2C1
Product: O=C(c1ccccc1-c1nnc[nH]1)N1CC2CN(c3nc4ccccc4nc3C(F)(F)F)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 30 and 2-(4H-[1,2,4]triazol-3-yl)-benzoic acid. MS (ESI) mass calcd. for C24H20F4N7O, 479.47; m/z found, 480.2 [M+H]+. 1H NMR (CDCl3): 8.12-7.93 (m, 3H), 7.77 (dd, J=8.5, 0.9 Hz, 1H), 7.69 (ddd, J=8.4, 6.8, 1.4 Hz, 1H), 7.52-7.41 (m, 3H), 7.38-7.34 (m, 1H), 4.01-3.79 (m, 3H), 3.78-3.66 (m, 2H), 3.49 (dd, J=23.0, 15.0 Hz, 2H), 3.16-2.88 (m, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[NH:8][C:6](=[O:7])[C:5]2=[CH:11][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][C:21]([O:23][CH3:24])=[O:22]>CC(C)=O>[CH3:24][O:23][C:21](=[O:22])[CH2:20][N:8]1[C:9](=[O:10])[C:4]2[C:5](=[CH:11][CH:12]=[C:2]([Br:1])[CH:3]=2)[C:6]1=[O:7]
Reactant: O=C1NC(=O)c2cc(Br)ccc21
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)CN1C(=O)c2ccc(Br)cc2C1=O
Temperature: 25 °C

Procedure:
50.3 g of 4-bromophthalimide, 92.0 g of potassium carbonate, and 24.5 ml of methyl bromoacetate were added to 888 ml of acetone. The resultant mixture was heated to reflux temperature for 24 h, and then cooled to room temperature. The mixture was filtered through a fine glass frit to remove all solid material, and the solution was then concentrated under vacuum to provide 66 g of the desired product, a white solid; 1H NMR (CDCl3): δ=3.76 (s, 3H), 4.43 (s, 2H), 7.71-7.75 (m, 1H), 7.85-7.90 (dd, 1H), 8.00 (m, 1H).
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[Cl:25][C:26]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:27]=1B(O)O>>[Cl:25][C:26]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:27]=1[C:5]1[C:4]([C:3]([OH:2])=[O:24])=[CH:9][C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Reactant: COc1ccc(B(O)O)c(Cl)c1
Product: COc1ccc(-c2ccc(-c3nc(-c4ccc(Cl)c(Cl)c4)cs3)cc2C(=O)O)c(Cl)c1
Yield: 4.9 %

Procedure:
Using the conditions of General Procedure A for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 111 mg, 0.25 mmol) was reacted with 2-chloro-4-methoxyphenylboronic acid (available from Combi-Blocks Inc.; 93 mg, 0.5 mmol). The resulting ester was hydrolyzed and the acid was purified to give 2′-chloro-4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-4′-methoxy-biphenyl-2-carboxylic acid (6 mg, 5%). 1H NMR (300 MHz, DMSO-d6) δ 13.00 (br s, 1H), 8.46-8.51 (m, 2H), 8.33 (d, J=2.1 Hz, 1H), 8.24 (dd, J=8.1, 1.9 Hz, 1H), 8.09 (dd, J=8.5, 2.1 Hz, 1H), 7.77 (d, J=8.5 Hz, 1H), 7.43 (d, J=8.1 Hz, 1H), 7.27 (d, J=8.5 Hz, 1H), 7.10 (d, J=2.4 Hz, 1H), 6.99 (dd, J=8.5, 2.6 Hz, 1H), 3.83 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[S:10][CH:11]=[C:12]([C:15]([CH3:17])=O)[C:13]=2[OH:14])[CH:5]=[CH:6][C:7]=1[Cl:8].[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[S:29][C:30]([C:33]([NH:35][NH2:36])=[O:34])=[CH:31][CH:32]=2)=[O:27])[CH2:22][CH2:21][CH2:20][CH2:19]1>CS(C)=O>[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[S:29][C:30]([C:33]([NH:35][N:36]=[C:15]([C:12]3[C:13]([OH:14])=[C:9]([C:4]4[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=4)[S:10][CH:11]=3)[CH3:17])=[O:34])=[CH:31][CH:32]=2)=[O:27])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CC(=O)c1csc(-c2ccc(Cl)c(Cl)c2)c1O
Reactant: NNC(=O)c1ccc(C(=O)NCCN2CCCC2)s1
Solvent: CS(C)=O
Product: CC(=NNC(=O)c1ccc(C(=O)NCCN2CCCC2)s1)c1csc(-c2ccc(Cl)c(Cl)c2)c1O
Yield: 29 %

Procedure:
2-(3,4-Dichlorophenyl)-3-hydroxy-4-methylcarbonylthiophene (22 mg, 0.075 mmol) in dimethyl sulfoxide (2.0 mL) was heated with 5-(hydrazinocarbonyl)thiophene-2-carboxylic acid [2-(pyrrolidin-1-yl)ethyl]-amide (21 mg, 0.075 mmol) prepared in Reference Synthetic Example 1 at 100° C. for 24 hours. Evaporation of the solvent followed by recrystallization from chloroform (1 mL)-diethyl ether (2 mL) affored 12 mg of the desired product (yield 29%).
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[C@@H:4]([C:5]#[C:6][C:7]([OH:9])=[O:8])[C@H:3]1[C:10]([O:12][C@H:13]([C:27]#[N:28])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=1)=[O:11].[CH2:30]([O:32][CH:33](O)[CH3:34])[CH3:31].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:1][C:2]1([CH3:29])[C@@H:4]([C:5]#[C:6][C:7](=[O:9])[O:8][CH2:31][CH2:30][O:32][CH2:33][CH3:34])[C@H:3]1[C:10]([O:12][C@H:13]([C:27]#[N:28])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=1)=[O:11]
Reactant: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1C#CC(=O)O
Reactant: CCOC(C)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCOCCOC(=O)C#C[C@H]1[C@@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)C1(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2 g of (S)α-cyano-3-phenoxy-benzyl (1R,cis) 2,2-dimethyl-3-[3-hydroxy-3-oxo-1-propynyl]-cyclopropane-carboxylate, 20 ml of methylene chloride and 0.7 ml of ethoxyethanol cooled to 0 to +5° C. was admixed with a mixture of 1.1 g of dicyclohexylcarbodiimide, 5 ml of methylene chloride and 15 mg of 4-dimethylamino-pyridine and the mixture was stirred for 1 hour at +5° C. and for 2 hours at room temperature and was filtered. The filtrate was evaporated to dryness and the residue was chromatographed over silica gel and eluted with a 3-1 mixture of cyclohexane-ethyl acetate to obtain 1.3 g of (S)α-cyano-3-phenoxy-benzyl (1R,cis) 2,2-dimethyl-3-[3-oxo-3-ethoxyethoxy-1-propynyl]-cyclopropane-carboxylate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:29]=[CH:28][C:11]3[N:12]=[C:13]([C:18]4[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=4)[C:21]([NH:23][OH:24])=[NH:22])[CH2:14][C:15](=[O:17])[NH:16][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].[C:32]1(=O)[O:36][CH2:35][CH2:34][CH2:33]1>CCO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:29]=[CH:28][C:11]3[N:12]=[C:13]([C:18]4[CH:27]=[CH:26][CH:25]=[C:20]([C:21]5[N:22]=[C:32]([CH2:33][CH2:34][CH2:35][OH:36])[O:24][N:23]=5)[CH:19]=4)[CH2:14][C:15](=[O:17])[NH:16][C:10]=3[CH:9]=2)=[CH:6][CH:7]=1
Reactant: N=C(NO)c1cccc(C2=Nc3ccc(-c4ccc(F)cc4)cc3NC(=O)C2)c1
Reactant: O=C1CCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: O=C1CC(c2cccc(-c3noc(CCCO)n3)c2)=Nc2ccc(-c3ccc(F)cc3)cc2N1
Temperature: 23 °C
Reaction time: 0.08 h
Yield: 65.7 %

Procedure:
To a stirred suspension of 3-[7-(4-fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-N-hydroxy-benzamidine (Example 167) (78 mg, 0.2 mmol) in EtOH (3 mL) was added at 23° C. sodium hydride (55% dispersion in oil, 32 mg, 0.8 mmol) and the mixture was stirred at 23° C. for 5 min. Butyrolactone (103 mg, 1.2 mmol) was added and the mixture was heated to 70° C. for 3 h. The reaction mixture was cooled to 23° C. and partitioned between ethyl acetate and H2O. The organic layer was dried over Na2SO4, evaporated in vacuum, and the residue was crystallized from dichloromethane to give the title compound as light yellow solid (60 mg).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Br:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([S:16](Cl)(=[O:18])=[O:17])[CH:10]=[CH:9]2.[C:20]1([O:26][CH3:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl>C(Cl)Cl.O>[Br:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([S:16]([C:23]1[CH:24]=[CH:25][C:20]([O:26][CH3:27])=[CH:21][CH:22]=1)(=[O:18])=[O:17])[CH:10]=[CH:9]2
Reactant: COc1ccccc1
Reactant: O=S(=O)(Cl)c1ccc2cc(Br)ccc2c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: COc1ccc(S(=O)(=O)c2ccc3cc(Br)ccc3c2)cc1
Temperature: 4 °C
Yield: 23.1 %

Procedure:
Aluminium chloride (3.33 g) was added portionwise over 30 minutes to a stirred mixture of 6-bromonaphth-2-ylsulphonyl chloride (6.11 g) and anisole (3.33 g) in dry methylene chloride (35 ml). The resultant mixture was stirred for 24 hours. Methylene chloride (75 ml) was added. the mixture cooled to 4° C. and water (100 ml) added cautiously. The mixture was acidified with 2M hydrochloric acid, separated and the aqueous phase extracted with methylene chloride (30 ml). The combined organic phases were washed with water, dried (MgSO4) and evaporated. Recrystallisation of the residue from an ethyl acetate/ethanol mixture gave 4-(6-bromonaphth-2-ylsulphonyl)anisole (1.74 g), m.p. 180-181° C.;
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[OH:7].[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1>N1C=CC=CC=1>[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14]([O:7][CH:3]2[CH2:4][CH2:5][CH2:6][CH:2]2[CH3:1])(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: CC1CCCC1O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC2CCCC2C)cc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 92.8 %

Procedure:
A three-necked flask (500 cc) equipped with a mechanical stirrer was charged with 2-methylcyclopentyl alcohol (21.19, 0.210 mol) and p-toluenesulfonyl chloride (48.3 g, 0.252 mol), followed by the addition of pyridine (170 ml) under ice cooling to form a solution. The solution was stirred for 10 h as it was warmed gradually to room temperature. After completion of the reaction, the reaction mixture was poured into ice water and stirred thoroughly. Following extraction with ether (200 mL×3), the organic layers were washed with 2N HCl, water and saturated brine and dried with anhydrous magnesium sulfate. After the desiccant was removed, the solvent was distilled off under vacuum to give 2-methylcyclopentyl p-toluenesulfonate as a colorless clear oil (49.7 9; yield=92.8%). 1H-NMR(CDCl3,TMS,ppm): δ0.85(3H,d,J=7.5Hz), 1.41-2.10(TH,m), 2.43(3H,s), 4.42 and 4.80(total 1H, each m), 7.33(2H,d,J=9.0Hz), 7.80(2H,d,J=9.0Hz).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]([OH:10])[CH3:9])=[CH:6][C:5]([C:11]#[N:12])=[CH:4][C:3]=1[NH:13][C:14]1[N:19]=[C:18]([NH:20][CH:21]2[CH2:23][CH2:22]2)[C:17]2=[N:24][CH:25]=[C:26]([C:27]#[N:28])[N:16]2[N:15]=1.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C1COCC1>[CH3:29][S:30]([O:10][CH:8]([C:7]1[CH:6]=[C:5]([C:11]#[N:12])[CH:4]=[C:3]([NH:13][C:14]2[N:19]=[C:18]([NH:20][CH:21]3[CH2:22][CH2:23]3)[C:17]3=[N:24][CH:25]=[C:26]([C:27]#[N:28])[N:16]3[N:15]=2)[C:2]=1[Cl:1])[CH3:9])(=[O:32])=[O:31]
Reactant: CC(O)c1cc(C#N)cc(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c1Cl
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Product: CC(OS(C)(=O)=O)c1cc(C#N)cc(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c1Cl
Yield: 101.2 %

Procedure:
A solution of 2-((2-chloro-5-cyano-3-(1-hydroxyethyl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Example 677) (56 mg, 0.14 mmol) in THF (4 mL) was cooled in an ice bath and methanesulfonyl chloride (28 μL, 0.36 mmol) was added. The bath was removed and quenched after 5 min with a little water. This was extracted with EtOAc and the organic extracts were washed with brine and dried with sodium sulfate. The solvent was removed to leave 1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)ethyl methanesulfonate (67 mg) as a white solid that was used as such.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5]([C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[C:9]([OH:14])[CH:8]=1)[CH3:6])[CH3:2].C1C=CC(O[C:23](Cl)=[S:24])=CC=1.C1CCN2C(=NCCC2)CC1.O>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:15])[CH:5]([C:7]1[CH:12]=[CH:11][C:10]2[NH:13][C:23](=[S:24])[O:14][C:9]=2[CH:8]=1)[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)c1ccc(N)c(O)c1
Reactant: S=C(Cl)Oc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C)c1ccc2[nH]c(=S)oc2c1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Solution of 2-(4-Amino-3-hydroxy-phenyl)-propionic acid ethyl ester (570 mg) in DMF (5 mL) was added phenyl chlorothionoformate (563 mg in DMF), and DBU (829 mg, in DMF) at room temperature. The reaction mixture was stirred for 14 h at room temperature and water was added to this mixture. The resulting mixture was extracted with ethyl ether. The combined organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting residue was chromatographed on silica gel (n-Hex:EtOAc=10:1 to 4:1) to afford the product as yellow oil. (90 mg, 13.2%)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=[C:8]2[CH2:17][CH:16]([CH3:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=O)=[CH:3][CH:2]=1.[NH2:20][NH2:21].C(Cl)(Cl)Cl>C(O)C>[CH3:18][CH:16]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]2=[N:20][NH:21][CH:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[CH:8]2[CH2:17]1
Reactant: CC1CC(=Cc2ccncc2)C(=O)c2ccccc21
Reactant: NN
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CC1CC2C(=NNC2c2ccncc2)c2ccccc21

Procedure:
To a mixture of 25 grams of 2-(4-pyridylmethylene)-3,4-dihydro-4-methyl-1 (2H)-naphthalenone and 5 grams of hydrazine in 150 ml of ethanol is added sufficient chlorform to dissolve all the reactants. The solution is refluxed overnight under anhydrous conditions. After cooling, the reaction mixture is filtered and the solvent removed by evaporation to yield 5-methyl-3-(4-pyridyl)-3,3a,4,5-tetrahydro-2H-naphtho[1,2-c]Pyrazole. This is chromatographed on silica using benzene as the eluant to yield 4,5-dihydro-5-methyl-3l -(4-pyridyl)-2H-naphtho[1,2c]pyrazole.
Reaction SMILES: C([O:5][C:6]([C:8]1[N:13]2[C:14](=[O:73])[C@@H:15]([NH:16][C:17](=[O:72])/[C:18](/[C:47]3[N:48]=[C:49]([NH:52]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[S:50][CH:51]=3)=[N:19]\[O:20][CH2:21][C:22]3[N:23]=[C:24]([NH:27]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[S:25][CH:26]=3)[C@H:12]2[S:11][CH2:10][C:9]=1[CH2:74][O:75][C:76](=[O:78])[CH3:77])=[O:7])(C)(C)C.[F:79][C:80]([F:85])([F:84])[C:81]([OH:83])=[O:82].C(OC(C)C)(C)C>C1(OC)C=CC=CC=1>[F:79][C:80]([F:85])([F:84])[C:81]([OH:83])=[O:82].[NH2:52][C:49]1[S:50][CH:51]=[C:47](/[C:18](=[N:19]/[O:20][CH2:21][C:22]2[N:23]=[C:24]([NH2:27])[S:25][CH:26]=2)/[C:17]([NH:16][C@@H:15]2[C:14](=[O:73])[N:13]3[C:8]([C:6]([OH:7])=[O:5])=[C:9]([CH2:74][O:75][C:76](=[O:78])[CH3:77])[CH2:10][S:11][C@H:12]23)=[O:72])[N:48]=1
Reactant: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@@H](NC(=O)/C(=N\OCc3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)OC(C)C
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)/C(=N\OCc3csc(N)n3)c3csc(N)n3)[C@H]2SC1

Procedure:
2.3 g of the (6R,7R)-7-[(Z)-2-(2-tritylaminothiazol-4-yl)-2-[(2-tritylaminothiazol-4-yl)methoxyimino]acetamido]-3-(acetoxymethyl)-ceph-3-em-4-carboxylic acid t-butyl ester was suspended in 2.1 ml of anisole, 21 ml of trifluoroacetic acid was added with ice cooling, and reacted at the same temperature for about 3 hours. After the completion of the reaction, the reaction mixture was poured into 200 ml of isopropyl ether with ice cooling, and the supernatant was removed. The residue was washed thoroughly with isopropyl ether, and the precipitates were filtered off to obtain 1.4 g of (6R,7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-[(2-aminothiazol-4-yl)methoxyimino]acetamido]-3-(acetoxymethyl)-ceph-3-em-4-carboxylic acid trifluoroacetate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([CH3:13])[CH:9]=[C:8]2[NH:14][CH:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:16][NH2:17].[CH3:24][C:25]([CH3:27])=O>>[CH:25]([NH:17][CH2:16][CH:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[NH:14][C:8]1[C:7]2[C:12](=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][CH:6]=2)[N:11]=[C:10]([CH3:13])[CH:9]=1)([CH3:27])[CH3:24]
Reactant: CC(C)=O
Reactant: COc1cccc2c(NC(CN)c3ccccc3)cc(C)nc12
Product: COc1cccc2c(NC(CNC(C)C)c3ccccc3)cc(C)nc12

Procedure:
Preparation was made using a similar procedure as described in example 79. Starting materials were N*1*-(8-methoxy-2-methylquinolin-4-yl)-1-phenylethane-1,2-diamine (Example 75) and acetone.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[O:10][CH3:11].[Li]CCCC.Cl[C:18]([O:20][CH2:21][CH3:22])=[O:19]>C1COCC1>[F:1][C:2]1[C:3]([O:10][CH3:11])=[CH:4][CH:5]=[C:6]([O:8][CH3:9])[C:7]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: COc1ccc(OC)c(F)c1
Reactant: CCOC(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1c(OC)ccc(OC)c1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 68.3 %

Procedure:
To a solution of 2-fluoro-1,4-dimethoxybenzene (8.1 g, 52.0 mmol) in anhydrous THF at −78° C., n-BuLi (2.5 M in hexane, 22 mL, 55 mmol) was added dropwise. The resulting mixture was stirred at −78° C. for 1 h, and then ethyl chloroformate (5 mL, 52.1 mmol) was added dropwise. The reaction mixture was stirred at −78° C. for additional 2 h and quenched with water (200 mL). The mixture was extracted with ethyl acetate (2×180 mL). The combined organic layers were washed with brine (200 mL), dried (Na2SO4), and concentrated in vacuo. The residue was purified by silica gel column chromatography (1:5 EtOAc/petroleum ether) to give ethyl 2-fluoro-3,6-dimethoxybenzoate (8.1 g).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][N:7]=[C:6]2O.P(Cl)(Cl)([Cl:18])=O>>[Cl:18][C:6]1[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([C:2]([F:15])([F:14])[F:1])[CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: Oc1ncnc2ccc(C(F)(F)F)cc12
Reactant: O=P(Cl)(Cl)Cl
Product: FC(F)(F)c1ccc2ncnc(Cl)c2c1
Temperature: 25 °C

Procedure:
Preparation D3, Step 3: A suspension of 6-(trifluoromethyl)quinazolin-4-ol (10.41 g, 48.4 mmol) in phosphorous oxychloride (100 mL) was heated at reflux for 3 h, during which time a clear, amber solution was observed. The solution was cooled to room temperature, concentrated in-vacuo, and stripped 3× from 150 mL methylene chloride to remove any remaining phosphorous oxychloride. The residue was partitioned between EtOAc and saturated sodium bicarbonate (1:1, 300 mL), and the mixture was stirred until gas evolution ceased. The layers were separated, the organic phase was washed successively with saturated sodium bicarbonate and brine, the combined aqueous phases were extracted with EtOAc (50 mL), and the combined organic phases were dried over sodium sulfate then concentrated in-vacuo. The residue was purified over silica gel, eluting with 25% EtOAc/Heptane, to yield 8.14 g of 4-chloro-6-(trifluoromethyl)quinazoline as a white solid. MS (ES+)=233, 235 (M+H+).