Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13](C)[N:12]=1)[CH2:9][CH3:10])(OC(C)(C)C)=O.C(=O)([O:22][CH2:23][CH3:24])OCC>C1COCC1>[CH2:9]([NH:8][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH:23]([OH:22])[CH3:24])[N:12]=1)[CH3:10]
Reactant: CCN(C(=O)OC(C)(C)C)c1cccc(C)n1
Reactant: CCOC(=O)OCC
Solvent: C1CCOC1
Product: CCNc1cccc(C(C)O)n1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
Ethyl 2-(N-Boc-N-ethylamino)-6-pyridylacetate LDA (0.018 mol) was prepared in THF (30 mL), cooled to -78° C., and 2-(N-Boc-N-ethylamino)-6-picoline (3.5 g, 15 mmol) was added, forming a deep red solution. After 15 min, diethyl carbonate (2.2 mL, 17.9 mmol) was added, the burgundy-colored solution was stirred at -78° C. for an additional 15 min, then the reaction was quenched with saturated NH4Cl. The mixture was warmed to RT and extracted with EtOAc(3×30 mL). The combined organic layers were washed with brine, dried (MgSO4), and concentrated. Silica gel chromatography (10% EtOAc/hexane) gave the title compound as colorless oil: MS (ES) m/e 309 (M+H)+.
Reaction SMILES: C([NH:9][C:10]([NH:12][C:13]1[CH:27]=[CH:26][C:16]([CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:15][CH:14]=1)=[S:11])(=O)C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>CO.O>[NH2:9][C:10]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[CH:26][CH:27]=1)=[S:11]
Reactant: CC(C)(C)OC(=O)NCc1ccc(NC(=S)NC(=O)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NCc1ccc(NC(N)=S)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 100 %

Procedure:
To a stirred near solution of tert-butyl N-(4-{[(benzoylamino)carbothioyl]amino}benzyl)carbamate (10.4 g, 27.0 mmol) in MeOH (150 ml) was added a solution of K2CO3 (8.5 g, 61.5 mmol) in 15 ml water. The solution was stirred at room temperature for 24 hours and filtered to remove a white precipitate. The filtrate was evaporated in vacuo to yield 100% (7.6 g) of the desired product as an off-white solid.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[C:4](=[O:10])[NH:5][C:6](=[O:9])[NH:7][CH:8]=1.[CH3:13][Si:14]([CH3:17])([CH3:16])Cl>C[Si](C)(C)N[Si](C)(C)C>[F:12][C:2]([F:11])([F:1])[C:3]1[C:4]([O:10][Si:14]([CH3:17])([CH3:16])[CH3:13])=[N:5][C:6]([O:9][Si:14]([CH3:17])([CH3:16])[CH3:13])=[N:7][CH:8]=1
Reactant: C[Si](C)(C)Cl
Reactant: O=c1[nH]cc(C(F)(F)F)c(=O)[nH]1
Agent: C[Si](C)(C)N[Si](C)(C)C
Product: C[Si](C)(C)Oc1ncc(C(F)(F)F)c(O[Si](C)(C)C)n1

Procedure:
In 50 ml of hexamethyldisilazane, 6.16 g of 5-trifluoromethyluracil was suspended and then 0.22 ml of trimethylchlorosilane was added to the suspension, followed by heating the resulting mixture to reflux for 5 hours. After the reaction, the excess hexamethyldisilazane was removed by evaporation and the resultant was distilled in vacuum. All of the fractions of distillate obtained at about 60° C. under 1 mmHg were collected. Yield: 10.3 g
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:12]([O:11][C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[F:1])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCc2ccccc2)c(F)c1
Temperature: 25 °C
Yield: 95.4 %

Procedure:
A solution of 2-fluoro-4-nitrophenol (50.0 g, 318 mmol), benzyl bromide (42 mL, 350 mmol) and potassium carbonate (66.0 g, 478 mmol) in DMF (200 mL) was heated to 40° C. overnight. The solution was cooled to room temperature, poured over ice and the resultant solid was filtered. This material was washed with water and dried to give 1-benzyloxy-2-fluoro-4-nitrobenzene (75.0 g, 95%). 1H NMR (400 MHz, d6-DMSO): δ 8.19-8.11 (m, 2H), 7.53-7.37 (m, 6H), 5.36 (s, 2H); 13C NMR (100 MHz, d6-DMSO): δ 152.8, 152.4, 149.9, 140.9, 136.1, 129.3, 129.1, 128.7, 122.0, 115.2, 112.8, 112.6, 71.6; IR (cm−1): 1499, 1346, 1279, 1211, 1142, 1072, 986, 885, 812, 789, 754, 742, 700, 648, 577.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:18]2[O:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:19](=[O:25])[N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])[CH:15]=3)[N:10]([CH:26]3[CH2:31][CH2:30][N:29]([CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH2:28][CH2:27]3)[C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+]>CO>[CH2:32]([N:29]1[CH2:28][CH2:27][CH:26]([N:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[C:5]([C:3]([OH:4])=[O:2])[C:18]=3[O:17][C:16]3[C:11]2=[CH:12][CH:13]=[C:14]([C:19](=[O:25])[N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])[CH:15]=3)[CH2:31][CH2:30]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CCN(CC)C(=O)c1ccc2c(c1)Oc1c(C(=O)OC)cccc1N2C1CCN(Cc2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCN(CC)C(=O)c1ccc2c(c1)Oc1c(C(=O)O)cccc1N2C1CCN(Cc2ccccc2)CC1
Temperature: 50 °C

Procedure:
To a solution of 10-(1-benzylpiperidin-4-yl)-7-diethylcarbamoyl-10H-phenoxazine-4-carboxylic acid methyl ester, 3l (2.92 g, 5.7 mmol) in methanol (10 mL) was added a 1N sodium hydroxide solution (5 mL), and the mixture was heated to 50° C. for 30 min. The mixture was allowed to cool to rt, the solvent was evaporated, and the residue was purified via reverse phase HPLC (eluent: CH3CN in water containing 0.1% TFA), yielding title compound 10-(1-benzylpiperidin-4-yl)-7-diethylcarbamoyl-10H-phenoxazine-4-carboxylic acid, 4l, as a TFA salt. MS m/z (MH+) 500.1
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH:20]1([NH:23][C:24]([C:26]2[S:39][C:29]3=[N:30][C:31](S(C)=O)=[C:32]([Cl:35])[C:33]([CH3:34])=[C:28]3[C:27]=2[NH2:40])=[O:25])[CH2:22][CH2:21]1>C1COCC1>[CH:20]1([NH:23][C:24]([C:26]2[S:39][C:29]3=[N:30][C:31]([O:1][CH2:2][CH2:3][N:4]4[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]4)=[C:32]([Cl:35])[C:33]([CH3:34])=[C:28]3[C:27]=2[NH2:40])=[O:25])[CH2:22][CH2:21]1
Reactant: Cc1c(Cl)c(S(C)=O)nc2sc(C(=O)NC3CC3)c(N)c12
Reactant: OCCN1CCNCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c(Cl)c(OCCN2CCNCC2)nc2sc(C(=O)NC3CC3)c(N)c12
Temperature: 75 °C
Reaction time: 0.25 h
Yield: 59.8 %

Procedure:
To a solution of 1-(2-hydroxyethyl)piperazine (1.061 g, 8.15 mmol) in THF (3 ml) at room temperature is added dropwise a solution of lithium bis(trimethylsilyl)amide (1.0 M in hexanes)(3.50 ml, 3.50 mmol). The reaction mixture is stirred for 15 minutes and then is treated with 3-amino-5-chloro-6-methanesulfinyl-4-methyl-thieno[2,3-b]pyridine-2-carboxylic acid cyclopropylamide (0.345 g, 1.00 mmol). The reaction mixture is heated at 75° C. for 1 hour, cooled to room temperature, and then quenched by the addition of water (15 ml). Ice is added to the reaction mixture and, while stirring, a yellow precipitate is formed. This solid is collected by filtration and placed in the vacuum oven to dry (60° C. for 16 hours). This affords the title compound as a yellow solid (0.245 g, 71%). Mass (m/z): 410.2 (M++1), 408.2 (M+−1).
Reaction SMILES: N[C:2]1[N:6]2[CH:7]=[C:8](SC3C=CC=CC=3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.C(Cl)(Cl)Cl.COC(Cl)=O>C(N(CC)CC)C>[N:4]1[CH:3]=[CH:2][N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=12
Reactant: Nc1cnc2ccc(Sc3ccccc3)cn12
Agent: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: c1ccn2ccnc2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 1.0 g. of 3-amino-6-(phenylthio) imidazo [1,2-a] pyridine in 25 ml. of chloroform containing 0.401 g. of triethyl amine is treated dropwise with 0.378 g. of methylchloroformate. The reaction mixture is stirred for 3 hours at room temperature. The chloroform is removed in vacuo and the residue is triturated with water. The solids are collected by filtration, washed well with water and dried. Recrystallization from dimethylformamide-ethane yields pure 3-(methoxycarbonylamino) 6-phenylthio) imidazo [1,2-a] pyridine m.p. 211°-215° C.
Reaction SMILES: CS(O[CH2:6][CH2:7][C@H:8]1[C:13]2[CH:14]=[CH:15][C:16]([N:18]=[C:19]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:17][C:12]=2[CH2:11][CH2:10][O:9]1)(=O)=O.[F:32][C:33]1[CH:34]=[C:35]2[C:40](=[CH:41][CH:42]=1)[C:39]([N:43]1[CH2:48][CH2:47][NH:46][C@H:45]([CH3:49])[CH2:44]1)=[CH:38][CH:37]=[CH:36]2>>[C:26]1([C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:18][C:16]2[CH:15]=[CH:14][C:13]3[C@H:8]([CH2:7][CH2:6][N:46]4[CH2:47][CH2:48][N:43]([C:39]5[C:40]6[C:35](=[CH:34][C:33]([F:32])=[CH:42][CH:41]=6)[CH:36]=[CH:37][CH:38]=5)[CH2:44][C@H:45]4[CH3:49])[O:9][CH2:10][CH2:11][C:12]=3[CH:17]=2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: C[C@@H]1CN(c2cccc3cc(F)ccc23)CCN1
Reactant: CS(=O)(=O)OCC[C@@H]1OCCc2cc(N=C(c3ccccc3)c3ccccc3)ccc21
Product: C[C@@H]1CN(c2cccc3cc(F)ccc23)CCN1CC[C@@H]1OCCc2cc(N=C(c3ccccc3)c3ccccc3)ccc21

Procedure:
2-{(1S)-6-[(Diphenylmethylene)amino]-3,4-dihydro-1H-2-benzopyran-1-yl}ethyl methanesulfonate was coupled with (3R)-1-(6-fluoro-1-naphthyl)-3-methylpiperazine, as described for Example 1b), to yield (1S)-N-(diphenylmethylene)-1-{2-[(2R)-4-(6-fluoro-1-naphthyl)-2-methylpiperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-amine.
Reaction SMILES: [CH:1]([C:3]1[N:7]([CH3:8])[C:6]([C:9]([O:11][CH3:12])=[O:10])=[CH:5][CH:4]=1)=[O:2].[BH4-].[Na+].[Cl-].[NH4+]>C1COCC1>[OH:2][CH2:1][C:3]1[N:7]([CH3:8])[C:6]([C:9]([O:11][CH3:12])=[O:10])=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc(C=O)n1C
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CO)n1C
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 87.3 %

Procedure:
670 mg of methyl 5-formyl-1-methyl-1H-pyrrole-2-carboxylate was dissolved in 10.0 mL of THF, and 303 mg of sodium borohydride was added thereto at −20° C., followed by stirring at −20° C. for 30 minutes, and then at 0° C. for further 1 hour. To the reaction liquid was added an aqueous saturated ammonium chloride solution, followed by extraction with ethyl acetate. The organic layer was washed with an aqueous saturated sodium hydrogen carbonate solution and brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 592 mg of methyl 5-(hydroxymethyl)-1-methyl-1H-pyrrole-2-carboxylate.
Reaction SMILES: S([O-])(O[CH3:5])(=O)=O.[CH2:7]([N:11]1[C:16](=[O:17])[NH:15][C:14](=[O:18])[O:13][C:12]1=[O:19])[CH2:8][CH2:9][CH3:10].C([N+](CCCC)(CCCC)CC1C=CC=CC=1)CCC>>[CH2:7]([N:11]1[C:16](=[O:17])[N:15]([CH3:5])[C:14](=[O:18])[O:13][C:12]1=[O:19])[CH2:8][CH2:9][CH3:10]
Reactant: CCCCn1c(=O)[nH]c(=O)oc1=O
Reactant: COS(=O)(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)Cc1ccccc1
Product: CCCCn1c(=O)oc(=O)n(C)c1=O
Yield: 81 %

Procedure:
The process described in example 14 is carried out without distillation of the solvent. 72 g of methyl sulfate (0.57 mole) are added to the solution of the salt of tributylbenzylammonium 3-butyl-1,3,5-oxadiazine-2,4,6-trione. The solvent is evaporated after 5 hours of reaction at 25° C. The solid residue is washed with water and with carbon tetrachloride. 88 g of 3-butyl-5-methyl-1,3,5-oxadiazine-2,4,6-trione (yield: 81%) of the formula (II) are obtained.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[C:8]#[N:9].C[Si](C)(C)[N-][Si](C)(C)C.[Na+].[N+](C1C=CC([O:29][C:30]([C:32]2[C:40]3[S:39][C:38]([N:41]4[CH2:46][CH2:45][N:44]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:43][CH2:42]4)=[N:37][C:36]=3[C:35]([O:54][CH3:55])=[CH:34][CH:33]=2)=O)=CC=1)([O-])=O>O1CCCC1>[C:8]([C:3]1[CH:4]=[N:5][N:6]([CH3:7])[C:2]=1[NH:1][C:30]([C:32]1[C:40]2[S:39][C:38]([N:41]3[CH2:46][CH2:45][N:44]([C:47]([O:49][C:50]([CH3:51])([CH3:52])[CH3:53])=[O:48])[CH2:43][CH2:42]3)=[N:37][C:36]=2[C:35]([O:54][CH3:55])=[CH:34][CH:33]=1)=[O:29])#[N:9]
Reactant: Cn1ncc(C#N)c1N
Reactant: COc1ccc(C(=O)Oc2ccc([N+](=O)[O-])cc2)c2sc(N3CCN(C(=O)OC(C)(C)C)CC3)nc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Nc2c(C#N)cnn2C)c2sc(N3CCN(C(=O)OC(C)(C)C)CC3)nc12
Yield: 107.5 %

Procedure:
Starting from 5-amino-1-methyl-1H-pyrazole-4-carbonitrile (119 mg) in dimethyl fonnamide (10 ml), sodium hexamethyldisilazide in tetrahydrofuran (0.97 ml, 1.0 M), 2-(4-tert-butoxycarbonylpiperazin-1-yl)-4-methoxybenzothiazole-7-carboxylic acid 4-nitrophenyl ester (250 mg). Purification by flash chromatography (eluent 5% methanol in dichloromethane) followed by trituration with diethyl ether yielded the title compound as a pale yellow solid (260 mg). TLC Rf 0.48 (ethyl acetate); Mpt 231-232° C.
Reaction SMILES: [Br:1][C:2]1[C:3]2[N:10](CC)[C:9]([C:13]3C(N)=NON=3)=[N:8][C:4]=2[CH:5]=[N:6][CH:7]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+]>C(O)C.O.ClCCl>[Br:1][C:2]1[C:3]([NH:10][CH2:9][CH3:13])=[C:4]([NH2:8])[CH:5]=[N:6][CH:7]=1
Reactant: CCn1c(-c2nonc2N)nc2cncc(Br)c21
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCO
Product: CCNc1c(N)cncc1Br
Temperature: 25 °C

Procedure:
A solution of the product of Step 1 (0.5 g, 2 mmol) in ethanol (8 ml)/water (10 ml) was stirred at 60° C. and sodium dithionite (2.12 g, 12.2 mmol) was added protionwise. After 10 minutes the mixture was cooled to room temperature, and diluted with water and dichloromethane. The organic phase was dried and evaporated in vacuo, the residue was used directly in the next reaction; 1H NMR (DMSO-d6) 7.76 (1H, s), 7.75 (1H, s), 5.0 (2H, br), 4.46 (1H, t, J=9.6 Hz), 3.26 (2H, m), 1.06 (3H, t, J=7.2 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]([CH3:10])[CH3:9])=[CH:6][C:5]([OH:11])=[C:4]([CH3:12])[CH:3]=1.[Cl-].[Mg+2].[Cl-].C(N(CC)CC)C.[CH2:23]=[O:24]>C(#N)C.O>[Cl:1][C:2]1[C:7]([CH:8]([CH3:9])[CH3:10])=[C:6]([C:5]([OH:11])=[C:4]([CH3:12])[CH:3]=1)[CH:23]=[O:24]
Reactant: C=O
Reactant: Cc1cc(Cl)c(C(C)C)cc1O
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: Cc1cc(Cl)c(C(C)C)c(C=O)c1O
Temperature: 0 °C
Reaction time: 1 h
Yield: 31.8 %

Procedure:
The 4-chloro-5-isopropyl-2-methylphenol (5.0 g, 27.08 mmole) and magnesium chloride (3.87 g, 40.61 mmole) were mixed in acetonitrile (150 mL) and the mixture was cooled to 0° C. (ice bath). Triethylamine (10.28 g, 101.55 mmole) followed by para-formaldehyde (5.48 g, 182.79 mmole) were added to above mixture, which was stirred at 0° C. for 1 hour. The mixture was warmed to room temperature and then heated to 90° C. for 1 week. The contents were poured into water (100 mL) and extracted with EtOAc (2×100 mL). The combined extracts were washed with brine (50 mL), dried over MgSO4, filtered and concentrated in vacuo to give an off-white solid which was subject to flash chromatography (silica gel) and eluted with 100% CH2Cl2 to give an off-white solid (1.83 g, 32%): GCMS m/z 212.0 (M+).
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:13][C@H:12]([O:14][C:15]2[C:20]([F:21])=[CH:19][C:18]([S:22]([N:25]([CH2:32][C:33]3[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][C:34]=3[O:41][CH3:42])[C:26]3[CH:31]=[CH:30][N:29]=[CH:28][N:27]=3)(=[O:24])=[O:23])=[C:17]([F:43])[CH:16]=2)[C@@H:11]([C:44]2[N:48]([CH3:49])[N:47]=[CH:46][CH:45]=2)[CH2:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH3:42][O:41][C:34]1[CH:35]=[C:36]([O:39][CH3:40])[CH:37]=[CH:38][C:33]=1[CH2:32][N:25]([C:26]1[CH:31]=[CH:30][N:29]=[CH:28][N:27]=1)[S:22]([C:18]1[CH:19]=[C:20]([F:21])[C:15]([O:14][C@H:12]2[CH2:13][C@H:9]([OH:8])[CH2:10][C@@H:11]2[C:44]2[N:48]([CH3:49])[N:47]=[CH:46][CH:45]=2)=[CH:16][C:17]=1[F:43])(=[O:23])=[O:24]
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(F)c(O[C@H]3C[C@H](O[Si](C)(C)C(C)(C)C)C[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(F)c(O[C@H]3C[C@H](O)C[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Yield: 147.4 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 120c by using the 4-{[(1S*,2R*,4R*)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(2,4-dimethoxybenzyl)-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide (1.39 g, 1.94 mmol) prepared in Example 121b, tetrabutyl ammonium fluoride (1.0 M solution in THF; 5.82 mL, 5.82 mmol) and THF (8.0 mL), to yield the title compound (1.72 g, 99%) as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:12][CH:11]=[N:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Cl[CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[CH:11]=[N:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Brc1cccc(-c2cnc[nH]2)c1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1cncc1-c1cccc(Br)c1
Reaction time: 0.5 h
Yield: 0.1 %

Procedure:
To a stirred solution of 5-(3-bromophenyl)-1H-imidazole (1 g, 4.5 mmol) in anhydrous N,N-dimethylformamide (20 mL) was added sodium hydride (60% in mineral oil, 160 mg, 4.7 mmol) at 0° C., and the mixture was stirred at this temperature for 0.5 h. A solution of (2-(chloromethoxy)ethyl)trimethylsilane (0.9 mL, 5.36 mmol) in N,N-dimethylformamide (5 mL) was added dropwise, and the resulting mixture was stirred at room temperature for 4 h. When the starting material was consumed, the reaction was quenched with water. The mixture was extracted with ethyl acetate, and the combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and evaporated in vacuo. The residue was purified on silica gel column (eluting with 5-10% ethyl acetate in petroleum ether) to give 5-(3-bromophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (1.1 mg, 69.6% yield) as a yellow solid. MS (ESI): m/z 353.0 [M+1]+.
Reaction SMILES: C([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:30]/[O:31]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)/[C:27]([O-:29])=O)[N:25]=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Na+].CS(Cl)(=O)=O.[NH2:57][C@@H:58]1[C:91](=[O:92])[N:60]2[C:61]([C:75]([O:77]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:76])=[C:62](/[CH:65]=[C:66]3/[C:67]([O:73][CH3:74])=[C:68]([CH3:72])[C:69](=[O:71])[O:70]/3)[CH2:63][S:64][C@H:59]12>CN(C=O)C.C(OCC)(=O)C>[NH2:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:30]/[OH:31])/[C:27]([NH:57][C@@H:58]2[C:91](=[O:92])[N:60]3[C:61]([C:75]([OH:77])=[O:76])=[C:62](/[CH:65]=[C:66]4/[C:67]([O:73][CH3:74])=[C:68]([CH3:72])[C:69](=[O:71])[O:70]/4)[CH2:63][S:64][C@H:59]23)=[O:29])[N:25]=1
Reactant: COC1=C(C)C(=O)O/C1=C\C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: O=C([O-])/C(=N\OC(c1ccccc1)(c1ccccc1)c1ccccc1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC1=C(C)C(=O)O/C1=C\C1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)/C(=N\O)c3csc(N)n3)[C@H]2SC1
Temperature: -15 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
Sodium 2-(2-tritylaminothiazol-4-yl)-2-Z-trityloxyiminoacetate (0.759 g), in dry DMF (5 mls) was cooled to ca -50° C. under argon. This solution was treated with methanesulphonyl chloride (0.085 mls) and allowed to warm to -15° C. A solution of diphenylmethyl 7β-amino-3-(Z-2,5-dihydro-4-methoxy-3-methyl-2-oxofuran-5-ylidenemethyl)ceph-3-em-4-carboxylate, (0.46 g) in dry DMF (5 mls) was added, and the solution allowed to reach room temperature over 1 h. The solution was diluted with ethl acetate and washed with water, brine and then dried. After removal of solvent the residue was flash chromatographed on silica gel eluting with 50% ethyl acetate/hexane to give the title compound as a yellow foam, (0.375 g, 36%), νmax 3380, 1770(br), 1725, 1685, 1630, 1505(br), 1440, 1370 and 1345cm-1 ; δH (CDCl3) 2.07 (3H,s), 3.74 and 3.96 (2H,ABq, J18.3Hz, sharpens on D2O shake), 5.08 (1H, m, sharpens to d, J5.0Hz on D2O shake), 6.12 (1H, br.m, sharpens to d, J5.0Hz on D2O shake), 6.43 (1H, br.s, sharpens on D2O shake), 6.74 (1H, s), 6.78 (1H, br.s, exch.), 6.98 (1H, s) and 7.20 to 7.55 (40H, m, arom-H); [mass spectrum: +ve ion (NOBA, Na+) MNa+, 1180].
Reaction SMILES: Cl[C:2]1[N:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:7]([O:6][C:4](=[O:5])[C:3]1[CH:9]=[CH:10][CH:11]=[N:12][C:2]=1[C:18]1[CH:19]=[CH:20][C:15]([C:14]([F:25])([F:24])[F:13])=[CH:16][CH:17]=1)[CH3:8]
Reactant: CCOC(=O)c1cccnc1Cl
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)c1cccnc1-c1ccc(C(F)(F)F)cc1
Yield: 109.7 %

Procedure:
Ethyl 2-chloro-nicotinate (1.86 g, 10.0 mmol) was dissolved in 10 ml of dimethoxyethane. Tetrakis(triphenylphosphine)palladium (347 mg, 0.3 mmol) was added and the reaction vessel purged by alternating vacuum and nitrogen gas three times. A solution of 4-trifluoromethylphenylboronic acid (2.09 g, 11.0 mmol) in 20 ml of dimethoxyethane was added to the reaction mixture followed by 10 ml of a 2M sodium carbonate solution. The reaction mixture was heated at 90 C. for 1.5 h before being cooled and extracted with 150 ml of ether. The organic layer was washed with 50 ml of 2N NaOH, 2×50 ml water, and brine before being dried (magnesium sulfate), filtered and concentrated under vacuum to afford 3.24 g of a brown oil. This material was purified by silica gel chromatography eluting with 5 to 10% ethyl acetate in hexanes to afford 2.34 g of the title compound as a pale yellow oil.
Reaction SMILES: Br[C:2]1[C:3]([F:26])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([CH2:18][C:19]4[N:20]([CH3:24])[N:21]=[CH:22][CH:23]=4)=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:25]=1.[CH3:27][C:28]([OH:32])([CH3:31])[C:29]#[CH:30].C(NC(C)C)(C)C>CN(C=O)C>[F:26][C:3]1[C:2]([C:30]#[C:29][C:28]([OH:32])([CH3:31])[CH3:27])=[CH:25][C:6]2[C:7]3[N:8]([C:12]([CH2:18][C:19]4[N:20]([CH3:24])[N:21]=[CH:22][CH:23]=4)=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=3)[CH2:9][CH2:10][O:11][C:5]=2[CH:4]=1
Reactant: C#CC(C)(C)O
Reactant: Cn1nccc1Cc1c(C(N)=O)nc2n1CCOc1cc(F)c(Br)cc1-2
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: Cn1nccc1Cc1c(C(N)=O)nc2n1CCOc1cc(F)c(C#CC(C)(C)O)cc1-2
Yield: 23 %

Procedure:
9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-3-[(2-methylpyrazol-3-yl)methyl]-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide was prepared similarly according to General Procedure E with slight modification. 10-bromo-9-fluoro-3-[(2-methylpyrazol-3-yl)methyl]-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide was reacted with 3-methyl-1-butyne-3-ol in a solution of DMF (1.3 mL/mmol) and diisopropylamine (2.6 mL/mmol) to afford 2.5 mg (23% yield). M+1=424.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[S:12][C:13]2[C:18]([N:19]=1)=[CH:17][CH:16]=[C:15]([C:20]1([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:22][CH2:21]1)[N:14]=2)[C:5](O)=[O:6].[NH:29]1[CH2:32][CH:31]([C:33]([OH:35])=[O:34])[CH2:30]1>>[F:1][C:2]1[CH:3]=[C:4]([C:5]([N:29]2[CH2:32][CH:31]([C:33]([OH:35])=[O:34])[CH2:30]2)=[O:6])[CH:8]=[CH:9][C:10]=1[C:11]1[S:12][C:13]2[C:18]([N:19]=1)=[CH:17][CH:16]=[C:15]([C:20]1([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:21][CH2:22]1)[N:14]=2
Reactant: O=C(O)C1CNC1
Reactant: O=C(O)c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Product: O=C(O)C1CN(C(=O)c2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)c(F)c2)C1

Procedure:
The title compound was synthesized using the procedure described in Example 105 above, with 3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzoic acid (104 mg, 0.266 mmol) and azetidine-3-carboxylic acid (32 mg, 0.320 mmol). MS (ESI) m/z: Calculated: 473.1; Observed: 474.1 (M++1).