Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([O:9][C:10]2[CH:11]=[C:12]([NH2:17])[C:13]([NH2:16])=[CH:14][CH:15]=2)[CH:6]=[CH:5][N:4]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=S)=[CH:21][C:20]=1[C:28]([F:31])([F:30])[F:29].C(Cl)CCl>CC#N>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]2[NH:16][C:13]3[CH:14]=[CH:15][C:10]([O:9][C:7]4[CH:6]=[CH:5][N:4]=[C:3]([S:2][CH3:1])[N:8]=4)=[CH:11][C:12]=3[N:17]=2)=[CH:21][C:20]=1[C:28]([F:29])([F:30])[F:31]
Reactant: FC(F)(F)c1cc(N=C=S)ccc1Cl
Reactant: CSc1nccc(Oc2ccc(N)c(N)c2)n1
Solvent: CC#N
Solvent: ClCCCl
Product: CSc1nccc(Oc2ccc3[nH]c(Nc4ccc(Cl)c(C(F)(F)F)c4)nc3c2)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-(2-methylsulfanyl-pyrimidin-4-yloxy)-benzene-1,2-diamine (Example 18, Step B, 400 mg, 1.6 mmol, 1.0 eq.) in anhydrous CH3CN (20 mL) was added drop wise a solution of 1-chloro-4-isothiocyanato-2-trifluoromethylbenzene (380 mg, 1.6 mmol, 1.0 eq.) in anhydrous CH3CN (10 mL). The solution was stirred for 16 h at RT. EDC (470 mg, 2.4 mmol, 1.5 eq.) was added and the reaction was heated to 80° C. and stirred for 2 h. The solvent was removed under reduced pressure. The residue was dissolved in CH2Cl2, and the solution was washed with H2O (25 mL), NaHCO3 (aq., 25 mL) and brine (25 mL). The aqueous layers were back extracted with CH2Cl2 and the combined organic layers were dried over MgSO4, filtered and concentrated. The crude was further purified by column chromatography (0-100% EtOAc/hexanes) to yield (4-chloro-3-trifluoromethyl-phenyl)-[5-(2-methylsulfanyl-pyrimidin-4-yloxy)-1H-benzimidazol-2-yl]-amine. MS m/z=452.1 (M+H)+; MW Calc'd for C19H13ClF3N5OS: 451.86.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8][CH2:7]2)([O-:3])=[O:2].Cl.Cl[CH2:17][CH2:18][N:19]([CH3:21])[CH3:20].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:20][N:19]([CH3:21])[CH2:18][CH2:17][N:10]1[C:11]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:13][CH:12]=2)[CH2:7][CH2:8][C:9]1=[O:14]
Reactant: O=C1CCc2cc([N+](=O)[O-])ccc2N1
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CCN1C(=O)CCc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 73 %

Procedure:
A suspension of 6-nitro-3,4-dihydroquinolin-2(1H)-one (1.5 g, 7.80 mmol), 2-chloro-N,N-dimethylethanamine hydrochloride (2.25 g, 15.60 mmol) and potassium carbonate (6.47 g, 46.80 mmol) in 25 mL DMF was stirred at room temperature for 3 days. After this time, the mixture was poured into 20 mL H2O then extracted with 3×150 mL EtOAc. The combined organic fractions were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was subjected to flash chromatography on silica gel using 5% 2M NH3 in MeOH/CH2Cl2 to give a yellow viscous oil (1.5 g, 73.2%). 1H-NMR (CDCl3) δ: 8.14 (dd, J=2.4, 9.0 Hz, 1H), 8.06 (d, J=2.4 Hz, 1H), 7.15 (d, J=9.0 Hz, 1H), 4.09 (t, J=7.5 Hz, 2H), 3.03-2.98 (m, 2H), 2.73-2.68 (m, 2H), 2.51 (t, J=7.5 Hz, 2H), 2.31 (s, 6H).
Reaction SMILES: C[Li].C(NC(C)C)(C)C.[C:10]1([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl[Si:23]([CH3:26])([CH3:25])[CH3:24]>C(OCC)C>[CH2:20]([O:19][C:17]([O:18][Si:23]([CH3:26])([CH3:25])[CH3:24])=[CH:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:21]
Reactant: C[Si](C)(C)Cl
Reactant: CCOC(=O)Cc1ccccc1
Agent: [Li]C
Solvent: CC(C)NC(C)C
Solvent: CCOCC
Product: CCOC(=Cc1ccccc1)O[Si](C)(C)C
Temperature: -78 °C
Reaction time: 8 h
Yield: 65.9 %

Procedure:
Methyllithium in diethyl ether (0.25 mol, 140 ml of 1.8 M solution) was added dropwise to a solution of 27.6 g (0.27 mol) of diisopropylamine in 40 ml of diethyl ether. The reaction mixture was cooled to -78° C. and 26.3 g (0.16 mol) of ethyl phenylacetate were added dropwise. The reaction mixture was warmed to 0° C. and 46 ml (0.36 mol) of chlorotrimethylsilane were added rapidly. The reaction mixture was stirred overnight at 25° C., filtered to remove LiCl, and then distilled under reduced pressure to give 24.91 g (66% yield) of β-ethoxy-β-trimethylsiloxystyrene as a colorless liquid: bp 92° C. (0.7 mm); 1H NMR (CFCl3) δ 0.0 ppm (s, 9H), 0.94 ppm (t,J=7 Hz, 3H), 3.44 and 3.63 ppm (qs, J=7 Hz, 25:75, 2H), 4.17 and 4.36 ppm (ss, 25:75, 1H) and 6.57-7.20 ppm (m, 5H). Anal. Calcd. for C13H20O2Si: C, 66.05; H, 8.53; Found: C, 66.26; H, 8.88.
Reaction SMILES: [OH:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:3][C:4]#[N:5].NCC[C@@H:14]([OH:20])[CH2:15][CH2:16][CH2:17][CH2:18]C.O.[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28]([OH:31])(=[O:30])=[O:29])=[CH:24][CH:23]=1>>[C:22]1([CH3:32])[CH:23]=[CH:24][C:25]([S:28]([OH:31])(=[O:29])=[O:30])=[CH:26][CH:27]=1.[NH2:5][CH2:4][CH2:3][C@@H:2]([O:1][CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18][O:20]1)[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCC[C@H](O)CCN
Reactant: CCCCCC(O)CC#N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CCCCC[C@@H](CCN)OC1CCCCO1

Procedure:
This compound is prepared essentially by the same method as described in Example 1, Step A-2, except that the 3-hydroxycaprylonitrile is replaced by 1-amino-3(S)-octanol and slightly more than one equivalent of p-toluenesulfonic acid. hydrate is used. This method provides the p-toluenesulfonic acid salt of the title compound which is converted to the oily title compound by distribution between dilute sodium hydroxide and ether. The organic phase is washed with saturated aqueous brine, dried over sodium sulfate, and filtered. Evaporation of the filtrate in vacuo leaves the title compound as a residual oil.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([NH:8][C:9]2[NH:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[S:7])=[CH:2]1.BrBr>C(Cl)(Cl)Cl>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[S:7][N:10]3[C:9](=[N:13][C:12]4[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=43)[N:8]=2)=[CH:2]1
Reactant: S=C(Nc1nc2ccccc2[nH]1)c1ccoc1
Agent: BrBr
Solvent: ClC(Cl)Cl
Product: c1ccc2c(c1)nc1nc(-c3ccoc3)sn12
Reaction time: 1 h

Procedure:
To 4.8 g. of 2-(3-furylthiocarbonylamino)-benzimidazole [ (IV), R = 3-furyl] in 200 ml. of chloroform at 20°-30°C. (room temperature) is added 1.1 ml. of bromine. After 1 hour, the reaction mixture is filtered and the residue (the hydrobromide salt) is treated with 500 ml. of chloroform and 50 ml. of aqueous ammonia. The chloroform layer is separated, dried over magnesium sulfate, and concentrated. The product is recrystallized from methanol-chloroform to yield 2-(3-furyl)-1,2,4-thiadiazolo-[2,3-a]-benzimidazole [(I), R = 3-furyl].
Reaction SMILES: C([O:8][CH2:9][CH2:10][O:11][CH2:12][C@@H:13]1[CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][N:14]1[C:23]([C:25]1[CH:30]=[C:29]([C:31](=[O:46])[NH:32][S:33]([C:36]2[CH:45]=[CH:44][C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH:37]=2)(=[O:35])=[O:34])[CH:28]=[CH:27][C:26]=1[N:47]1[C:51]([CH3:52])=[C:50]([Cl:53])[C:49]([C:54]([N:56]([CH2:61][CH2:62][CH2:63][CH3:64])[CH2:57][CH2:58][CH2:59][CH3:60])=[O:55])=[N:48]1)=[O:24])C1C=CC=CC=1.B(Cl)(Cl)Cl>C(Cl)Cl>[CH2:61]([N:56]([CH2:57][CH2:58][CH2:59][CH3:60])[C:54]([C:49]1[C:50]([Cl:53])=[C:51]([CH3:52])[N:47]([C:26]2[CH:27]=[CH:28][C:29]([C:31](=[O:46])[NH:32][S:33]([C:36]3[CH:45]=[CH:44][C:43]4[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=4)[CH:37]=3)(=[O:34])=[O:35])=[CH:30][C:25]=2[C:23]([N:14]2[C@H:13]([CH2:12][O:11][CH2:10][CH2:9][OH:8])[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:24])[N:48]=1)=[O:55])[CH2:62][CH2:63][CH3:64]
Reactant: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4ccccc4c3)cc2C(=O)N2Cc3ccccc3C[C@H]2COCCOCc2ccccc2)c(C)c1Cl
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4ccccc4c3)cc2C(=O)N2Cc3ccccc3C[C@H]2COCCO)c(C)c1Cl
Temperature: -78 °C
Reaction time: 1 h
Yield: 31.5 %

Procedure:
A solution of (S)-1-(2-(3-((2-(benzyloxy)ethoxy)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-(naphthalen-2-ylsulfonylcarbamoyl)phenyl)-N,N-dibutyl-4-chloro-5-methyl-1H-pyrazole-3-carboxamide (Example 117, 35 mg, 0.039 mmol) in CH2Cl2 (1.0 mL) was cooled to −78° C., and boron trichloride (270 μL, 0.27 mmol) was added dropwise via syringe. The resulting solution was stirred at −78° C. for 1 h and then at room temperature overnight. Additional boron trichloride (270 μL, 0.27 mmol) was added, and the reaction mixture was stirred at room temperature for 5 h. After quenching with sat. aq. NH4Cl, the solution was extracted with EtOAc (3×). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by preparative HPLC to give the title compound (10 mg, 31%). 1H NMR (1:1 CD3OD:CDCl3, mixture of amide rotamers) δ 8.65 (s, 1H), 8.40 (s, 0.5H), 8.19-8.11 (m, 1H), 8.09-7.83 (m, 4H), 7.63-7.52 (m, 2.5H), 7.47-7.30 (m, 1H), 7.26-6.98 (m, 3.5H), 6.88 (br s, 0.5H), 5.25 (d, J=18.3 Hz, 0.5H), 4.36-4.07 (m, 3H), 3.75-3.17 (m, 6.5H), 3.12-2.61 (m, 4H), 2.51 (d, J=16.4 Hz, 0.5H), 2.35-2.17 (m, 3.5H), 1.68-0.79 (m, 11.5H), 0.75-0.56 (m, 2.5H); MS(ESI+) m/z 814.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[NH2:10].[CH3:11][N:12]([CH2:16][CH2:17]Cl)[CH2:13][CH2:14]Cl.Cl.C(=O)([O-])[O-].[K+].[K+]>ClC1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[N:10]1[CH2:17][CH2:16][N:12]([CH3:11])[CH2:13][CH2:14]1
Reactant: COc1cccc(C)c1N
Reactant: CN(CCCl)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Clc1ccccc1
Product: COc1cccc(C)c1N1CCN(C)CC1

Procedure:
A mixture of 2-methoxy-6-methylphenylamine (D28) (3.62 g, 26.4 mmol), mechlorethamine hydrochloride (12.7 g, 66 mmol) and potassium carbonate (15 g) in chlorobenzene (90 ml) was refluxed under argon for 20 h. The mixture was cooled and filtered, and the filtrate evaporated under reduced pressure to leave the title compound (D29) as a red oil which slowly crystallised on standing (5.4 g, 93%) MH+=221.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([O:10][C:11]1[CH:15]=[C:14]([N:16]2[C:24]3[CH:23]=[C:22]([CH2:25][OH:26])[N:21]=[CH:20][C:19]=3[N:18]=[CH:17]2)[S:13][C:12]=1[C:27]([NH2:29])=[O:28])[CH3:9].[CH3:30][S:31](Cl)(=[O:33])=[O:32].C(N(CC)CC)C>ClCCl>[CH3:30][S:31]([O:26][CH2:25][C:22]1[N:21]=[CH:20][C:19]2[N:18]=[CH:17][N:16]([C:14]3[S:13][C:12]([C:27](=[O:28])[NH2:29])=[C:11]([O:10][C@@H:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])[CH3:9])[CH:15]=3)[C:24]=2[CH:23]=1)(=[O:33])=[O:32]
Reactant: C[C@@H](Oc1cc(-n2cnc3cnc(CO)cc32)sc1C(N)=O)c1ccccc1F
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H](Oc1cc(-n2cnc3cnc(COS(C)(=O)=O)cc32)sc1C(N)=O)c1ccccc1F

Procedure:
In a similar manner as described for example 49 (step 1), 737 mg of 3-[(1R)-1-(2-fluorophenyl)ethoxy]-5-[6-(hydroxymethyl)-1H-imidazo[4,5-c]pyridin-1-yl]thiophene-2-carboxamide, 409 mg of methanesulfonyl chloride, and 362 mg of triethylamine in 18 ml dichloromethane give (1-{5-carbamoyl-4-[(1R)-1-(2-fluorophenyl)ethoxy]-2-thienyl}-1H-imidazo[4,5-c]pyridin-6-yl)methyl methanesulfonate as crude material that is used for step 2 without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:18]([F:19])=[C:17]([F:20])[CH:16]=[CH:15][C:11]=2[C:12]([OH:14])=[O:13])=[C:5]([F:21])[CH:4]=1)#[CH:2].N1C2C(=CC=CC=2)C=CC=1>C1COCC1.[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[F:19][C:18]1[C:10]([NH:9][C:6]2[CH:7]=[CH:8][C:3]([CH:1]=[CH2:2])=[CH:4][C:5]=2[F:21])=[C:11]([CH:15]=[CH:16][C:17]=1[F:20])[C:12]([OH:14])=[O:13]
Reactant: C#Cc1ccc(Nc2c(C(=O)O)ccc(F)c2F)c(F)c1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: C1CCOC1
Solvent: c1ccc2ncccc2c1
Product: C=Cc1ccc(Nc2c(C(=O)O)ccc(F)c2F)c(F)c1
Reaction time: 0.25 h
Yield: 71.5 %

Procedure:
The product of Example 1, Step C, 2-[(4-ethynyl-2-fluorophenyl)amino]-3,4-difluorobenzoic acid (540 mg, 1.86 mmol) and quinoline (220 mg) were dissolved in THF (50 mL), then Lindlar catalyst (11 mg) added. This mixture was stirred under an atmosphere of hydrogen (60 psi) for 3 periods of 15 minutes and monitored carefully by TLC (50% EtOAc/hexanes as eluant). The reaction mixture was filtered through Celite® which was washed well with EtOAc and the resulting filtrate concentrated (to 100 mL) under reduced pressure. This organic solution was then washed with 1 M HCl (2×100 mL), water (100 mL) and saturated NaCl solution (100 mL), dried (Na2SO4), and the solvent removed under reduced pressure. The resulting crude solid was purified by flash chromatography on silica (10% EtOAc/hexanes as eluant) to afford 3,4-difluoro-2-[(2-fluoro-4-vinylphenyl)amino]benzoic acid as a crystalline yellow solid (390 mg, 72%); m.p. (EtOAc/hexanes) 162-166° C. 1H NMR [400 MHz, (CD3)2SO] δ 13.20 (br s, 1 H), 9.30 (br s, 1 H), 7.52 (ddd, J=8.3, 6.1, 1.8 Hz, 1 H), 7.41 (dd, J=12.8, 1.7 Hz, 1 H), 7.19 (dd, J=8.3, 1.7 Hz, 1 H), 7.08 (dd, J=16.6, 9.3 Hz, 1 H), 7.00 (td, J=8.7, 5.2 Hz, 1 H), 6.67 (dd, J=17.6, 10.9 Hz, 1 H), 5.78 (d, J=17.6 Hz, 1 H), 5.22 (d, J=11.0 Hz, 1 H). Anal. Calcd for C15H10F3NO2: C, 61.4; H, 3.3; N, 4.9. Found C, 61.4; H, 3.4; N, 4.8.
Reaction SMILES: C([Li])(C)(C)C.[CH3:6][CH2:7][CH2:8][CH2:9][CH3:10].BrC1C2[C:15](=[CH:16][CH:17]=[C:18]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])C=2)[N:14]([Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])[CH:13]=1.C(I)C>C1COCC1>[C:32]([Si:29]([CH3:31])([CH3:30])[N:14]1[C:15]2[C:7](=[CH:6][C:18]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])=[CH:17][CH:16]=2)[C:8]([CH2:9][CH3:10])=[CH:13]1)([CH3:35])([CH3:34])[CH3:33]
Reactant: CCCCC
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2c(c1)c(Br)cn2[Si](C)(C)C(C)(C)C
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCI
Product: CCc1cn([Si](C)(C)C(C)(C)C)c2ccc(O[Si](C)(C)C(C)(C)C)cc12
Temperature: -78 °C
Reaction time: 2 h
Yield: 98.3 %

Procedure:
A 1.5 M solution of tert-butyllithium in pentane (3.3 ml, 4.99 mmol) was added dropwise to a solution of 3-bromo-1-(tert-butyl-dimethyl-silanyl)-5-(tert-butyl-dimethyl-silanyloxy)-1H-indole (1 g, 2.3 mmol) in THF (6 ml) at −78° C. under an argon atmosphere. After 15 min ethyl iodide (0.37 ml, 4.5 mmol) was added at −78° C. The reaction mixture was stirred for 30 min at −78° C. and for 2 h at RT. After quenching with saturated aqueous NaHCO3 solution the reaction mixture was partitioned between ether and water. The organic layer was dried over sodium sulfate and concentrated in vacuo to give 880 mg (2.26 mmol, 99%) 1-(tert-butyl-dimethyl-silanyl)-5-(tert-butyl-dimethyl-silanyloxy)-3-ethyl-1H-indole.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[C:14]([O:16][C:17]3[C:22]([CH3:23])=[CH:21][C:20]([N+:24]([O-:26])=[O:25])=[CH:19][C:18]=3[CH3:27])[CH:13]=[CH:12][C:11]=2[O:28]C)=[O:9])=[CH:4][CH:3]=1.B(Cl)(Cl)Cl>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:10]2[CH:15]=[C:14]([O:16][C:17]3[C:22]([CH3:23])=[CH:21][C:20]([N+:24]([O-:26])=[O:25])=[CH:19][C:18]=3[CH3:27])[CH:13]=[CH:12][C:11]=2[OH:28])=[O:9])=[CH:6][CH:7]=1
Reactant: COc1ccc(Oc2c(C)cc([N+](=O)[O-])cc2C)cc1C(=O)c1ccc(F)cc1
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: Cc1cc([N+](=O)[O-])cc(C)c1Oc1ccc(O)c(C(=O)c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 5.12 g (13.0 mmol) of (4-fluorophenyl)[2-methoxy-5-(2,6-dimethyl-4-nitrophenoxy)phenyl]methanone in 100 ml methylene chloride is chilled in an ice bath and 40 ml (40 mmol) of 1.0M boron trichloride in methylene chloride is gradually added. The solution is stirred at room temperature overnight, then pour into 300 ml of ice water and stirred 2 hours. The organic layer is separated, washed with 5% aqueous sodium carbonate, water, dried (CaSO4) and evaporated. The residue is recrystallized from ethanol to give (4-fluorophenyl)[2-hydroxy-5-(2,6-dimethyl-4 nitrophenoxy)phenyl]methanone, m.p. 148°-150°.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:27]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[N:29]([CH3:36])[CH:28]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([N+:15]([O-])=O)[C:12]([N:18]3[CH2:21][CH:20]([N:22]([CH3:24])[CH3:23])[CH2:19]3)=[CH:11][C:10]=2[O:25][CH3:26])=[N:6][CH:7]=1.[NH4+].[Cl-]>C(O)C.O.[Fe]>[Cl:1][C:2]1[C:3]([C:27]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[N:29]([CH3:36])[CH:28]=2)=[N:4][C:5]([NH:8][C:9]2[C:10]([O:25][CH3:26])=[CH:11][C:12]([N:18]3[CH2:19][CH:20]([N:22]([CH3:24])[CH3:23])[CH2:21]3)=[C:13]([NH2:15])[CH:14]=2)=[N:6][CH:7]=1
Reactant: COc1cc(N2CC(N(C)C)C2)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cn(C)c3ccccc23)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COc1cc(N2CC(N(C)C)C2)c(N)cc1Nc1ncc(Cl)c(-c2cn(C)c3ccccc23)n1
Yield: 98.3 %

Procedure:
A mixture of 5-chloro-N-[4-(3-dimethylaminoazetidin-1-yl)-2-methoxy-5-nitrophenyl]-4-(1-methylindol-3-yl)pyrimidin-2-amine (Intermediate 113, 285 mg, 0.56 mmol), iron (188 mg, 3.37 mmol) and NH4Cl (22.51 mg, 0.42 mmol) in ethanol (9 mL) and water (3 mL) was heated at reflux for 2 h. The mixture was then cooled and filtered through diatomaceous earth (Celite™). The filtrate was concentrated in vacuo and the resulting residue was dissolved in CH2Cl2. This solution was washed with brine, dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with 1-20% 7N methanolic ammonia in CH2Cl2 gave the title compound (263 mg, 98%) as a brown dry film; 1H NMR: (CDCl3) 2.21 (6H, s), 3.08-3.18 (1H, m), 3.30 (2H, br s), 3.58 (2H, t), 3.86 (3H, s), 3.88 (3H, s), 3.93 (2H, t), 6.38 (1H, s), 7.2-7.42 (3H, m, partially obscured by chloroform signal), 7.50 (1H, s), 7.99 (1H, s), 8.20 (1H, s), 8.31 (1H, s), 8.63 (1H, d); m/z: ES+ MH+ 478.
Reaction SMILES: [CH2:1]([O:3][N:4]=[C:5]([C:31]1[N:35]=[C:34]([NH2:36])[S:33][N:32]=1)[C:6]([NH:8][CH:9]1[C:29](=[O:30])[N:11]2[C:12]([C:16]([O:18]CC3C=CC([N+]([O-])=O)=CC=3)=[O:17])=[CH:13][CH2:14][S:15][C@H:10]12)=[O:7])[CH3:2]>[Pd].O1CCCC1>[CH2:1]([O:3][N:4]=[C:5]([C:31]1[N:35]=[C:34]([NH2:36])[S:33][N:32]=1)[C:6]([NH:8][CH:9]1[C:29](=[O:30])[N:11]2[C:12]([C:16]([OH:18])=[O:17])=[CH:13][CH2:14][S:15][C@H:10]12)=[O:7])[CH3:2]
Reactant: CCON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12)c1nsc(N)n1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1nsc(N)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 35.6 %

Procedure:
A mixture of 4-nitrobenzyl 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylate (syn isomer) (5.0 g) and 10% palladium on carbon (2.5 g) in 70% aqueous tetrahydrofuran (75 ml) was stirred under hydrogen atmosphere for 3 hours at ambient temperature. The catalyst was removed by filtration and the filtrate was concentrated to third volume. The residue was extracted with ethyl acetate and transferred into an aqueous solution of sodium bicarbonate. The aqueous layer was acidified to pH 3 with 10% hydrochloric acid and extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated to 10 ml under reduced pressure. The resultant precipitates were collected, washed with ethyl acetate and dried to give 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylic acid (syn isomer) (1.33 g), mp. 190° to 195° C. (dec.).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][S:6][CH:7](SCC(OC)=O)[CH:8]([CH3:13])[C:9](OC)=[O:10])=[O:4]>C[O-].[Na+].CO>[OH:10][C:9]1[C:8]([CH3:13])=[CH:7][S:6][C:5]=1[C:3]([O:2][CH3:1])=[O:4]
Reactant: COC(=O)CSC(SCC(=O)OC)C(C)C(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1scc(C)c1O
Temperature: 25 °C

Procedure:
Dithioacetal of (b) above (0.08 mol) was dissolved in 120 ml of 2N sodium methoxide in methanol and stirred over night at room temperature.
Reaction SMILES: [OH-].[Li+].[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[C:20]([CH3:32])=[C:21]4[C:25](=[CH:26][CH:27]=3)[CH2:24][CH:23]([C:28]([O:30]C)=[O:29])[CH2:22]4)[N:15]=2)[CH:7]=[N:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12]>C1COCC1.O>[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[C:20]([CH3:32])=[C:21]4[C:25](=[CH:26][CH:27]=3)[CH2:24][CH:23]([C:28]([OH:30])=[O:29])[CH2:22]4)[N:15]=2)[CH:7]=[N:8][C:9]=1[O:10][CH:11]([CH3:12])[CH3:13]
Reactant: COC(=O)C1Cc2ccc(-c3noc(-c4cnc(OC(C)C)c(Cl)c4)n3)c(C)c2C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(-c2noc(-c3cnc(OC(C)C)c(Cl)c3)n2)ccc2c1CC(C(=O)O)C2
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 92.5 %

Procedure:
Lithium hydroxide (3.3 mg, 0.0795 mmol) was added to a solution of methyl 5-(5-(5-chloro-6-isopropoxypyridin-3-yl)-1,2,4-oxadiazol-3-yl)-4-methylindane-2-carboxylate (17.0 mg, 0.0397 mmol, from Step G) in THF (1.0 mL) and H2O (300 μL) and heated to 50° C. After 30 min, the reaction mixture was concentrated in vacuo and partitioned between EtOAc (5 mL) and 5% citric acid (2 mL). The layers were separated and organic layer was washed with H2O (3×2 mL), brine (1×2 mL) and dried over MgSO4. The mixture was filtered and the filtrated concentrated in vacuo. Purification of the residue by flash chromatography (3% CH3OH/CH2Cl2/1% HCO2H) on SiO2 afforded 15.2 mg of the title compound as a white solid: 1H NMR (500 MHz, CD3OD) δ 1.41 (d, 6H, J=6.2 Hz), 2.51 (s, 3H), 3.19-3.41 (m, 5H), 5.49 (septet, 1H, J=6.2 Hz), 7.17 (d, 1H, J=8.0 Hz), 7.78 (d, 1H, J=7.8 Hz), 8.39 (s, 1H), 8.83 (s, 1H); HPLC A: rt=4.11 min, m/z=414.3 (M+H)+.
Reaction SMILES: [N+](=[CH:3][C:4](=[O:8])[CH2:5][CH2:6][CH3:7])=[N-].O.[C:10]1([S:16]([OH:19])(=[O:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CCOCC>[O:8]=[C:4]([CH2:5][CH2:6][CH3:7])[CH2:3][O:19][S:16]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:18])=[O:17]
Reactant: CCCC(=O)C=[N+]=[N-]
Reactant: O=S(=O)(O)c1ccccc1
Solvent: O
Solvent: CCOCC
Product: CCCC(=O)COS(=O)(=O)c1ccccc1
Yield: 77.2 %

Procedure:
A 1.2 g quantity of 1-diazo-2-pentanone is dissolved in 50 ml of ether, and 2.3 g of benzenesulfonic acid monohydrate is slowly added to the solution at room temperature. The same procedure as in Example 1 is thereafter followed to give 2.0 g of 2-oxopentylbenzene sulfonate in the form of a colorless transparent oil (Compound 6). Yield 77.2%.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9])[CH3:2].[CH3:10][O:11]C(Cl)Cl.Cl>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[CH2:1]([C:3]1[CH:8]=[C:7]([CH:6]=[CH:5][C:4]=1[OH:9])[CH:10]=[O:11])[CH3:2]
Reactant: CCc1ccccc1O
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Solvent: ClCCl
Product: CCc1cc(C=O)ccc1O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
TiCl4 (45.6 g, 238 mmol) was added slowly to a solution of 2-ethylphenol (15 g, 119 mmol) in CH2Cl2 (150 ml) was at 0° C. The mixture was warmed to room temperature and dichloromethyl methyl ether (18.3 ml, 200 mmol) was added (strong HCl evolution). The mixture was stirred for 4 h. at room temperature, subsequently cooled to 0° C. and 1M HCl (119 ml, 119 mmol) was added dropwise. The mixture was stirred for 10 min. and subsequently extracted with diethyl ether. The organic phase was washed with saturated NaHCO3 solution and with NaCl solution, dried, filtered and concentrated. The residue was purified by chromatography (SiO2, CH2Cl2=>CH2Cl2/MeOH 9:1). 3-Ethyl-4-hydroxy-benzaldehyde was obtained as a brown oil (7.97 g, 45%).