Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:19]=[C:18]([OH:20])[CH:17]=[C:16]2[C:3]=1[C@@:4]1([CH3:26])[C@H:13]([CH2:14][S:15]2(=[O:22])=[O:21])[C@:12]2([CH3:23])[C@H:7]([C:8]([CH3:25])([CH3:24])[CH2:9][CH2:10][CH2:11]2)[CH2:6][CH2:5]1.[CH3:27][Si](C=[N+]=[N-])(C)C>C(Cl)Cl.CO>[OH:1][C:2]1[CH:19]=[C:18]([O:20][CH3:27])[CH:17]=[C:16]2[C:3]=1[C@@:4]1([CH3:26])[C@H:13]([CH2:14][S:15]2(=[O:22])=[O:21])[C@:12]2([CH3:23])[C@H:7]([C:8]([CH3:25])([CH3:24])[CH2:9][CH2:10][CH2:11]2)[CH2:6][CH2:5]1
Reactant: CC1(C)CCC[C@]2(C)[C@H]3CS(=O)(=O)c4cc(O)cc(O)c4[C@]3(C)CC[C@@H]12
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: ClCCl
Solvent: CO
Product: COc1cc(O)c2c(c1)S(=O)(=O)C[C@@H]1[C@@]3(C)CCCC(C)(C)[C@@H]3CC[C@@]21C
Temperature: 25 °C
Reaction time: 18 h
Yield: 59.4 %

Procedure:
To a solution of (1R,10R,11S,16S)-3,5-dihydroxy-1,11,15,15-tetramethyl-8λ6-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-triene-8,8-dione (28) (8.0 g, 21 mmol) in CH2Cl2 (192 mL) and methanol (64 mL), (trimethylsilyl)diazomethane (2 M in diethyl ether, 16.9 mL, 33.8 mmol) was added in 2 mL increments every hour at room temperature under N2. The mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated to dryness and the residue was purified by flash chromatography on silica gel (Hexanes/EtOAc, 2:1) to yield (1R,10R,11S,16S)-3-hydroxy-5-methoxy-1,11,15,15-tetramethyl-8λ6-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-triene-8,8-dione (30) (4.9 g, 58%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]2[NH:6][CH:7]([CH3:10])[CH2:8][O:9][C:4]=2[C:3]=1[F:13].C(O[CH:17]=[C:18]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20])C>>[F:1][C:2]1[CH:12]=[CH:11][C:5]2[N:6]([CH:17]=[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:7]([CH3:10])[CH2:8][O:9][C:4]=2[C:3]=1[F:13]
Reactant: CC1COc2c(ccc(F)c2F)N1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)C(=CN1c2ccc(F)c(F)c2OCC1C)C(=O)OCC
Reaction time: 1.17 h
Yield: 113.9 %

Procedure:
To 1.13 g of (-)-7,8-difluoro-2,3-dihydro-3-methyl-4H-[1,4]benzoxazine was added 1.5 g of diethyl ethoxymethylenemalonate, and the mixture was stirred at 130° to 140° C. for 70 minutes. The reaction mixture was subjected as such to column chromatography using 50 g of silica gel and eluted with chloroform to obtain 2.47 g of diethyl [(-)-7,8-difluoro-3-methyl-2,3-dihydro-4H-[1,4]benzoxazin-4-yl]methylenemalonate. This product was dissolved in 5 ml of acetic anhydride, and 10 ml of a mixture of acetic anhydride and concentrated sulfuric acid (2/1 by volume) with stirring under ice-cooling, followed by stirring at 50° to 60° C. for 40 minutes. To the reaction mixture were added ice and an aqueous solution of sodium bicarbonate, and the reaction product was extracted three times with 150 ml portions of chloroform. The combined extract was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. When a solid began to precipitate, a small amount of diethyl ether was added thereto, and the precipitate was collected by filtration. The precipitate was washed with a small amount of diethyl ether to yield 1.32 g of (-)-ethyl 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylate.
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[S:7][CH2:6][CH2:5][N:4]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH:19]=[C:20]=[CH:21][CH3:22])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[C@H:3]1[C:23]([O:25]C(C)(C)C)=[O:24].FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:30][C:2]1([CH3:1])[S:7][CH2:6][CH2:5][N:4]([S:8]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH:19]=[C:20]=[CH:21][CH3:22])=[CH:15][CH:16]=2)(=[O:9])=[O:10])[C@H:3]1[C:23]([OH:25])=[O:24]
Reactant: CC=C=CCOc1ccc(S(=O)(=O)N2CCSC(C)(C)[C@@H]2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC=C=CCOc1ccc(S(=O)(=O)N2CCSC(C)(C)[C@@H]2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.6 %

Procedure:
To a solution of the product from Example 27 (200 mg, 0.44 mmol) in methylene chloride (4 mL) was added trifluoroacetic acid (1 mL) and the resulting mixture was stirred for 2 h at room temperature. The solvents were removed in vacuo and the residue was purified by silica gel column chromatagraphy to obtain the product (120 mg, 69%) as a white solid.
Reaction SMILES: [CH:1]([O:14][C:15]([C:17]1[N:22]2[C:23](=[O:43])[C@@H:24]([NH:25][C:26](=[O:42])[C:27]([C:32]3[N:33]=[C:34]([NH:37]C(=O)CCl)[S:35][CH:36]=3)=[N:28][O:29][CH2:30][CH3:31])[C@H:21]2[S:20][CH2:19][C:18]=1[CH:44]([S:46][C:47]1[NH:51][N:50]=[N:49][N:48]=1)[CH3:45])=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NC(N)=S>O1CCCC1.C(O)C.[Br-].C([N+](CC)(CC)CC1C=CC=CC=1)C>[CH:1]([O:14][C:15]([C:17]1[N:22]2[C:23](=[O:43])[C@@H:24]([NH:25][C:26](=[O:42])[C:27](=[N:28][O:29][CH2:30][CH3:31])[C:32]3[N:33]=[C:34]([NH2:37])[S:35][CH:36]=3)[C@H:21]2[S:20][CH2:19][C:18]=1[CH:44]([S:46][C:47]1[NH:51][N:50]=[N:49][N:48]=1)[CH3:45])=[O:16])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C(C)Sc3nnn[nH]3)CS[C@H]12)c1csc(NC(=O)CCl)n1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: NC(N)=S
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C(C)Sc3nnn[nH]3)CS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 52.9 %

Procedure:
To a solution of 2.2 g of 7β-{α-ethoxyimino-[2-(chloroacetamido)thiazol-4-yl]acetamido}-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid benzhydryl ester in 20 ml of tetrahydrofuran is added a solution of 550 mg of thiourea in 20 ml of ethanol, followed by addition of 50 mg of triethylbenzylammonium bromide. The mixture is stirred for 20 hours at room temperature and concentrated. The residue is dissolved in a mixture of ethyl acetate and tetrahydrofuran and the solution was washed with aq. sodium bicarbonate solution and then water, followed by drying over anhydrous magnesium sulfate. The dried solution is subjected to distillation of the solvent to give powder which is washed with chloroform and ether and dried. The procedure yields 1.047 g of 7β-[β-ethoxyimino-(2-aminothiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid benzhydryl ester. Yield 52.9%.
Reaction SMILES: CON=C1CN([C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])=[CH:13][CH:12]=2)=[O:10])[C@H](C(OC)=O)C1.FC1C=CC=CC=1C1C=CC(C(O)=O)=CC=1.C(Cl)(=O)C([Cl:47])=O>C1COCC1.CN(C=O)C>[F:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:14]1[CH:15]=[CH:16][C:11]([C:9]([Cl:47])=[O:10])=[CH:12][CH:13]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CON=C1C[C@@H](C(=O)OC)N(C(=O)c2ccc(-c3ccccc3F)cc2)C1
Agent: O=C(O)c1ccc(-c2ccccc2F)cc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(-c2ccccc2F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Method B (e.g. methyl (2S,4EZ)-4-(methoxyimino)-1-[(2′-fluoro[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxylate): To a solution of 2′-fluoro[1,1′-biphenyl]-4-carboxylic acid (69 mg, 0.32 mmol.) in 9 ml THF, were added oxalyl chloride (0.09 mL, 0.99 mmol) and DMF (three drops) under ice cooling. The mixture was stirred for 2 h at rt. The solvent was removed affording the corresponding acyl chloride, 2′-fluoro[1,1′biphenyl]-4-carbonyl chloride. The latter was now dissolved in THF (7 mL) and added slowly on a 0° C. solution containing the free NH-compound from the previous step, e.g. methyl (2S,4EZ)-4-(methoxyimino)-2-pyrrolidinecarboxylate (38 mg, 0.22 mmol), and triethylamine (2eq, 0.44 mmol, 0.06 ml) in THF/DCM 1:1 mixture (12 ml). The reaction mixture was stirred overnight at r.t. Pol-trisamine was added (69 mg, 3.45 mmol/g) in order to scavenge excess of acyl chloride. The mixture was shaken 5 h, filtered and the resulting solution was washed with NH4Cl 20%, brine, and dried over MgSO4. After filtration and evaporation of the solvents, the resulting dark oil (3.26 g) was purified by SPE (SAX sorbent) using neat DCM as eluent. The desired product, e.g. methyl (2S,4EZ)-4-(methoxyimino)-1-[(2′-fluoro[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxylate was obtained as a mixture of two isomers as a white foam in 34% yield (97.3% purity by HPLC).
Reaction SMILES: [NH:1]([CH2:7][CH2:8][CH2:9][C:10]#[N:11])[CH2:2][CH2:3][CH2:4][C:5]#[N:6].C(N(CC)CC)C.[CH2:19]([O:21][P:22](Cl)([O:24][CH2:25][CH3:26])=[O:23])[CH3:20]>ClCCl>[CH2:19]([O:21][P:22]([N:1]([CH2:2][CH2:3][CH2:4][C:5]#[N:6])[CH2:7][CH2:8][CH2:9][C:10]#[N:11])([O:24][CH2:25][CH3:26])=[O:23])[CH3:20]
Reactant: N#CCCCNCCCC#N
Reactant: CCOP(=O)(Cl)OCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOP(=O)(OCC)N(CCCC#N)CCCC#N
Yield: 75 %

Procedure:
3,3′-Iminodipropyl cyanide (50 mmol) was dissolved in dichloromethane (100 ml). To the system was added triethylamine (10 ml), and then dropwise added at room temperature diethoxyphosphoryl chloride (50 mmol) in dicholormethane (60 ml) solution. The mixture was allowed to react at room temperature over night. The resultant was concentrated and performed to column chromatography (eluant: dichloromethane/methanol system) to obtain 9.7 g of a colorless transparent oily substance, yield 75%, MS[M]+=259.2 m/e.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH2:19][CH2:18][C@@H:17]([NH:26][C:27](=[O:40])[CH2:28][C:29]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])([CH3:31])[CH3:30])[C:16]2=[O:41])=[CH:10][CH:9]=1.[CH2:42]([N:44]=[C:45]=[O:46])[CH3:43]>>[CH2:42]([NH:44][C:45]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[CH:10][C:11]([CH2:14][N:15]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH2:19][CH2:18][C@@H:17]([NH:26][C:27](=[O:40])[CH2:28][C:29]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])([CH3:31])[CH3:30])[C:16]2=[O:41])=[CH:12][CH:13]=1)=[O:46])[CH3:43]
Reactant: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3N)cc2)C1=O)NC(=O)OC(C)(C)C
Reactant: CCN=C=O
Product: CCNC(=O)Nc1ccccc1-c1ccc(CN2C(=O)[C@H](NC(=O)CC(C)(C)NC(=O)OC(C)(C)C)CCc3ccccc32)cc1

Procedure:
Prepared from N-[1-[[(2'-amino)[1,1'-biphenyl]-4-yl]-methyl]-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl]-3-t-butoxycarbonylamino-3-methylbutanamide (Example 2, Step B) and ethyl isocyanate by the procedure described in Example 2, Step C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([O:8][CH2:9][CH:10]2[CH2:12][CH2:11]2)=[N:6][CH:7]=1.B([O-])[O-:15]>>[CH:10]1([CH2:9][O:8][C:5]2[N:6]=[CH:7][C:2]([OH:15])=[CH:3][C:4]=2[CH3:13])[CH2:12][CH2:11]1
Reactant: Cc1cc(Br)cnc1OCC1CC1
Reactant: [O-]B[O-]
Product: Cc1cc(O)cnc1OCC1CC1

Procedure:
Following Typical Procedures 4 and 5a, conversion of 5-bromo-2-cyclopropylmethoxy-3-methyl-pyridine to the boronate and oxidation with NaBO3 provided the title compound. MS ESI+: m/z=180 [M+H]+.
Reaction SMILES: [CH2:1]([O:4][NH:5][C:6](=[C:9]1[C:14](=[O:15])[CH2:13][C:12]([CH3:17])([CH3:16])[CH2:11][C:10]1=[O:18])[CH2:7][CH3:8])[CH:2]=[CH2:3].[OH-].[Na+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CC(C)=O.O>[CH2:1]([O:4][N:5]=[C:6]([C:9]1[C:10](=[O:18])[CH2:11][C:12]([CH3:17])([CH3:16])[CH2:13][C:14]=1[O:15][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:7][CH3:8])[CH:2]=[CH2:3]
Reactant: C=CCONC(CC)=C1C(=O)CC(C)(C)CC1=O
Reactant: BrCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: C=CCON=C(CC)C1=C(OCc2ccccc2)CC(C)(C)CC1=O
Temperature: 60 °C
Reaction time: 10 h

Procedure:
To a solution of 2-(1-allyloxyaminopropylidene)-5,5-dimethylcyclohexane-1,3-dione (2.5 g) in acetone (30 ml), sodium hydroxide (0.4 g) in water (2 ml) was added at room temperature and then benzyl bromide (2.0 g) was added. After stirring for 10 hours at 60° C the reaction mixture was poured into ice-water and extracted with chloroform. The extract was washed with one normal sodium hydroxide and dried over magnesium sulfate. The solvent was removed in vacuo and an oily substance which solidified on standing at 0° C was obtained. Recrystallization from the mixture of methanol and water gave the desired product as crystal.
Reaction SMILES: [2H][C:2]1[C:7]([2H])=[C:6]([NH2:9])[C:5]([NH2:10])=[C:4]([2H])[C:3]=1[2H].[Cl:13][C:14]([Cl:20])([Cl:19])[C:15](=N)OC>C(O)(=O)C>[Cl:13][C:14]([Cl:20])([Cl:19])[C:15]1[NH:10][C:5]2[CH:4]=[CH:3][CH:2]=[CH:7][C:6]=2[N:9]=1
Reactant: [2H]c1c([2H])c([2H])c(N)c(N)c1[2H]
Reactant: COC(=N)C(Cl)(Cl)Cl
Solvent: CC(=O)O
Product: ClC(Cl)(Cl)c1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
O-Phenylenediamine (25 g) was dissolved in acetic acid (750 ml), and methyl 2,2,2-trichloroacetimidate (28.5 ml) was added dropwise over 15 min. After stirring at room temperature for 1 hr, the reaction mixture was concentrated to about 150 ml, and poured into water (1500 ml). The precipitated crystals were collected by filtration, washed with water (1000 ml) and suspended in toluene (500 ml). The solvent was evaporated under reduced pressure. The residue was again suspended in toluene (500 ml) and the solvent was evaporated under reduced pressure. The residue was dried under reduced pressure to give the object product (51.8 g).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:7])=[CH:4][CH:3]=1.[N+:15]([O-])([OH:17])=[O:16]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:7])=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16]
Reactant: O=C(O)CCC(=O)c1ccc(Br)cc1
Reactant: O=[N+]([O-])O
Product: O=C(O)CCC(=O)c1ccc(Br)c([N+](=O)[O-])c1
Temperature: -5 °C
Reaction time: 1 h

Procedure:
Under salt-ice cooling, 3-(4-bromobenzoyl)propionic acid (75.0 g, 291.7 mmol) was added to fuming nitric acid (200 mL) in portions at such a rate that the temperature of the reaction solution could be maintained at −5° C. or lower. After stirring at −12° C. to −10° C. for 1 hour, the reaction solution was poured onto ice. The solid which precipitated was collected by filtration, washed with purified water, and thereafter dried under reduced pressure to obtain 3-(4-bromo-3-nitrobenzoyl)propionic acid (91.0 g).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[C:9]([CH:13]=1)[C:10]([OH:12])=O)(=[O:4])=[O:3].Cl.[CH2:21]([S:25]([C:28]1[S:32][C:31]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[N:30][CH:29]=1)(=[O:27])=[O:26])[CH2:22][CH2:23][CH3:24]>>[CH2:21]([S:25]([C:28]1[S:32][C:31]([N:33]2[CH2:38][CH2:37][N:36]([C:10]([C:9]3[CH:13]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=[CH:7][C:8]=3[N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[O:12])[CH2:35][CH2:34]2)=[N:30][CH:29]=1)(=[O:27])=[O:26])[CH2:22][CH2:23][CH3:24]
Reactant: CS(=O)(=O)c1ccc(N2CCOCC2)c(C(=O)O)c1
Reactant: CCCCS(=O)(=O)c1cnc(N2CCNCC2)s1
Agent: Cl
Product: CCCCS(=O)(=O)c1cnc(N2CCN(C(=O)c3cc(S(C)(=O)=O)ccc3N3CCOCC3)CC2)s1
Yield: 60 %

Procedure:
Prepared in analogy to example 1 (b) from 5-Methanesulfonyl-2-morpholin-4-yl-benzoic acid (Example A13) and 1-[5-(butane-1-sulfonyl)-thiazol-2-yl]-piperazine hydrochloride (Example 38(c)). The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) followed by trituration in ether to yield the title compound as a light red crystalline solid (yield 60%). MS (m/e): 557.2 (M+H+, 65%), 574.4 (M+NH4+, 100%).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[N:14]=[CH:15][N:16]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)[CH:17]=1.[Li]CCCC.Cl[C:34]([O:36][CH2:37][CH3:38])=[O:35].O>C1COCC1>[CH2:37]([O:36][C:34]([C:15]1[N:16]([C:18]2[CH:19]=[CH:20][C:21]([C:24]([F:27])([F:25])[F:26])=[CH:22][CH:23]=2)[CH:17]=[C:13]([C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[N:5][O:6][C:2]=2[CH3:1])[N:14]=1)=[O:35])[CH3:38]
Reactant: CCOC(=O)Cl
Reactant: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccc(C(F)(F)F)cc2)cn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1nc(-c2c(-c3ccccc3)noc2C)cn1-c1ccc(C(F)(F)F)cc1
Temperature: -25 °C
Yield: 20.2 %

Procedure:
To a solution of 5-methyl-3-phenyl-4-[1-(4-trifluoromethyl-phenyl)-1H-imidazol-4-yl]-isoxazole (950 mg, 2.6 mmol) in THF (50 mL) at −78° C. was added BuLi (1.6 M in hexane, 2.4 mL, 3.9 mmol) and the resulting mixture allowed to warm up to −25° C. over 20 min and then re-cooled to −78° C. Then ethyl chloroformate (474 mg, 4.4 mmol) was added and the resulting mixture allowed to warm up to −25° C. over 3 h and then warmed up to 0° C. whereupon water was added. The reaction mixture was then extracted with ethyl acetate and the combined organic layers were then washed with a saturated solution of sodium hydrogen carbonate, brine and then dried over sodium sulphate and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 80:20) afforded the title compound (232 mg, 18%) which was obtained as an off-white foam. MS: m/e=442.5 [M+H]+.
Reaction SMILES: [Br-].[F:2][CH:3]([F:34])[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH:10]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[O:9][C:8]2=[O:33].[Cl:35][C:36]1[CH:37]=[N:38][CH:39]=[C:40]([Cl:44])[C:41]=1[CH:42]=O.C(N(CC)CC)C.Cl>C(Cl)Cl>[Cl:35][C:36]1[CH:37]=[N:38][CH:39]=[C:40]([Cl:44])[C:41]=1[CH:42]=[C:10]1[C:11]2[C:7](=[CH:6][C:5]([O:4][CH:3]([F:2])[F:34])=[CH:13][CH:12]=2)[C:8](=[O:33])[O:9]1
Reactant: O=C1OC([P+](c2ccccc2)(c2ccccc2)c2ccccc2)c2ccc(OC(F)F)cc21
Reactant: O=Cc1c(Cl)cncc1Cl
Agent: Cl
Agent: [Br-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1OC(=Cc2c(Cl)cncc2Cl)c2ccc(OC(F)F)cc21
Temperature: 4 °C
Reaction time: 3 h
Yield: 191.5 %

Procedure:
A solution of (5-difluoromethoxy-3-oxo-1,3-dihydro-isobenzofuran-1-yl)-triphenyl-phosphonium bromide (11.4 g, 21 mmoles), prepared as described in example 96, in dry CH2Cl2 (110 ml), under N2, was added with 3,5-dichloro-4-formyl-pyridine (4.06 g, 23.1 mmoles). The mixture was cooled to 4° C. and added with triethylamine (3.8 ml, 27.3 mmoles) while keeping the temperature below 10° C. At the end of the addition the mixture was stirred at room temperature for 3 hours, then cooled and added with 5% HCl. The organic phase was washed with an aqueous NaCl solution, discoloured with charcoal, filtered over celite and dried to give 14.4 g of the title compound (stoichiometric yield; containing 1 equivalent of triphenylphosphine oxide).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[C:13]1[N:31]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[C:16]2=[N:17][CH:18]=[C:19]([CH2:21][NH:22][C:23](=O)C3C=CC=CC=3)[N:20]=[C:15]2[CH:14]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=S)=CC=1>O1CCOCC1.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[C:13]1[N:31]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:38])([CH3:37])[CH3:39])[C:16]2[N:17]=[CH:18][C:19]3[N:20]([CH:23]=[N:22][CH:21]=3)[C:15]=2[CH:14]=1
Reactant: COc1ccc2c(c1)c(-c1cc3nc(CNC(=O)c4ccccc4)cnc3n1COCC[Si](C)(C)C)cn2C
Agent: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1ccc2c(c1)c(-c1cc3c(ncc4cncn43)n1COCC[Si](C)(C)C)cn2C
Temperature: 80 °C
Reaction time: 1 h
Yield: 56.4 %

Procedure:
N-((6-(5-Methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)methyl)benzamide (0.118 g, 0.218 mmol) in 1,4-dioxane (3 mL) was treated with Lawesson's Reagent (0.070 g, 0.17 mmol) and was heated to about 80° C. in an oil bath for about 20 min. The mixture was cooled to ambient temperature and then mercuric acetate (0.073 g, 0.23 mmol) was added. The mixture was stirred for about 60 min at ambient temperature then another portion of mercuric acetate (0.069 g, 0.22 mmol) was added and stirring was continued for about 20 min at ambient temperature. The mixture was diluted with EtOAc (20 mL) and then filtered. The filtrate was concentrated under reduced pressure and the material was purified by silica gel chromatography eluting with EtOAc to give 7-(5-methoxy-1-methyl-1H-indol-3-yl)-6-((2-(trimethylsilyl)ethoxy)methyl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine (0.055 g, 48%): LC/MS (Table 2, Method d) Rt=1.91 min; MS m/z: 524 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[C:4]([F:17])[CH:3]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:21]=1B(O)O>>[F:17][C:4]1[CH:3]=[C:2]([C:21]2[CH:22]=[C:23]([CH3:26])[CH:24]=[CH:25][C:20]=2[O:19][CH3:18])[CH:7]=[CH:6][C:5]=1[S:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:10])=[O:9]
Reactant: COc1ccc(C)cc1B(O)O
Reactant: O=S(=O)(c1ccccc1)c1ccc(Br)cc1F
Product: COc1ccc(C)cc1-c1ccc(S(=O)(=O)c2ccccc2)c(F)c1

Procedure:
The subtitle compound was prepared by the method of example 2 step (ii) using the product of example 2 step (i) and (2-methoxy-5-methylphenyl)boronic acid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[CH2:7][C@H:8]([NH:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[CH:22][C:21]=1[O:29]CC1C=CC=CC=1)(=[O:19])=[O:18])[CH:9]([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].O1CCCC1.C(O)C>[C:1]([O:5][C:6](=[O:37])[CH2:7][C@H:8]([NH:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][C:21]=1[OH:29])(=[O:18])=[O:19])[CH:9]([O:10][CH2:11][CH3:12])[O:13][CH2:14][CH3:15])([CH3:3])([CH3:4])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(OCC)[C@H](CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccc([N+](=O)[O-])cc1OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(OCC)[C@H](CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccc(N)cc1O

Procedure:
(S)-3-(2-Benzyloxy-4-nitro-benzenesulfonylamino)-4,4-diethoxy-butyric acid tert-butyl ester (150 mg, 0.28 mmol) was hydrogenated with 10% Pd/C (50 mg) in 1:1 tetrahydrofuran/ethanol (10 mL) at room temperature under 50 psi hydrogen in a Parr shaker for 3 h. The reaction mixture was filtered over a celite pad, the catalyst was washed with ethanol, the organics were combined and the solvent was removed under reduced pressure to give (S)-3-(4-amino-2-hydroxy-benzenesulfonylamino)-4,4-diethoxy-butyric acid tert-butyl ester, 100 mg, 85%. RP-HPLC (10 to 90% acetonitrile in 0.1 N aqueous ammonium acetate over 10 min at 2 mL/min using a Waters Symmetry C18 150×4.6 mm column) 8.3 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:13][CH3:14])[C:11]=1[F:12])[N:8]=[CH:7][C:6]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:5]2[OH:20].[C:21](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:13][CH3:14])[C:11]=1[F:12])[N:8]([CH3:21])[CH:7]=[C:6]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:5]2=[O:20]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1cnc2c(OC)c(F)c(F)cc2c1O
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(C)c2c(OC)c(F)c(F)cc2c1=O
Reaction time: 17 h
Yield: 94.4 %

Procedure:
1.60 g (0.0057 mole) of ethyl 6,7-difluoro-4-hydroxy-8-methoxyquinoline-3-carboxylate (IX) [prepared as described in step (B3) above] were dissolved in 20 ml of dimethylformamide, and 1.20 g (0.0085 mole) of potassium carbonate and 2.40 g (0.017 mole) of methyl iodide were added to the resulting solution. The mixture was then stirred at 60°-65° C. for 17 hours. At the end of this time, the solvent was distilled off under reduced pressure. The residue was extracted with methylene chloride, and the methylene chloride extract was washed with water, dried and concentrated by evaporation under reduced pressure to give 1.60 g of ethyl 6,7-difluoro-8-methoxy-1-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylate (X, R9' =methyl) as a pale brown powder.