Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Br:16])[C:9]=1[S:10](=[O:15])(=[O:14])[N:11]([CH3:13])[CH3:12])[CH2:5]O.S(Cl)([Cl:19])=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Br:16])[C:9]=1[S:10](=[O:15])(=[O:14])[N:11]([CH3:13])[CH3:12])[CH2:5][Cl:19]
Reactant: O=S(Cl)Cl
Reactant: CN(C)S(=O)(=O)c1c(Br)cc(CO)cc1Br
Solvent: ClCCl
Product: CN(C)S(=O)(=O)c1c(Br)cc(CCl)cc1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of OBS02015 (3.93 g, 10.10 mmol) in anhydrous DCM (50 mL) was added thionyl chloride (1.11 mL, 15.15 mmol). The mixture was stirred at room temperature for 2 h and the volatiles removed in vacuo. The residue was re-dissolved and co-evaporated three times with DCM (3×20 mL) to give OBS02018 as a brown oil which solidified on standing (3.93 g, 96%). TLC [SiO2, EtOAc-n-hexane (1:1)] Rf=0.83; 1H-NMR (270 MHz, CDCl3)=3.11 (6H, s), 4.46 (2H, s), 7.59 (2H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:16])[N:10]2[CH2:13][CH:14]=C)=[CH:5][CH:4]=1.I([O-])(=O)(=O)=[O:18].[Na+]>O1CCOCC1.O.[Os](=O)(=O)(=O)=O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:16])[N:10]2[CH2:13][CH:14]=[O:18])=[CH:5][CH:4]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CCn1c(=O)ccc2ccc(OC)cc21
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc2ccc(=O)n(CC=O)c2c1
Reaction time: 8 h
Yield: 71 %

Procedure:
To a stirred solution of 7-(methyloxy)-1-(2-propen-1-yl)-2(1H)-quinolinone (4.14 g, 0.019 mol) in 1,4-dioxane (80 ml) and water (40 ml) under N2 was added sodium periodate (9.5 g; 0.044 mol) and osmium tetroxide (10 ml, 4% aqueous solution) and stirred overnight. The reaction was concentrated and partitioned in 20% MeOH/DCM (300 ml) and water (200 ml). The organic layer was dried over magnesium sulphate, filtered, and concentrated. The product was obtained after column chromatography (neat ethyl acetate) to yield g (71%) of the title compound as a green solid.
Reaction SMILES: C([O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([Cl:20])=[CH:16][C:17]=2[Cl:19])[N:12]=[C:11]([C:21]([O:23][CH2:24][CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])=[O:22])[CH:10]=1)C1C=CC=CC=1.[BrH:30]>C(O)(=O)C>[BrH:30].[Cl:19][C:17]1[CH:16]=[C:15]([Cl:20])[CH:14]=[C:13]2[C:18]=1[C:9](=[O:8])[CH:10]=[C:11]([C:21]([O:23][CH2:24][CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])=[O:22])[NH:12]2
Reactant: CN(C)CCCOC(=O)c1cc(OCc2ccccc2)c2c(Cl)cc(Cl)cc2n1
Agent: Br
Solvent: CC(=O)O
Product: CN(C)CCCOC(=O)c1cc(=O)c2c(Cl)cc(Cl)cc2[nH]1

Procedure:
Treatment of 3-dimethylaminopropyl 4-benzyloxy-5,7-dichloroquinoline-2-carboxylate (0.52 g) with hydrogen bromide in acetic acid (10 ml, 48%) as described in Example 33d gave 3-dimethylaminopropyl 5,7-dichloro-4-oxo-1,4-dihydroquinoline-2-carboxylate hydrobromide (0.27 g), m.p. 228° C. (dec). δ (360 MHz, DMSO-d6) 2.13 (2H, m, CO2CH2CH2), 2.81 (6H, s, (CH3)2) 3.25 (2H, t, CH2N), 4.42 (2H, t, CO2CH2), 6.72 (1H, s, 3-H), 7.45 (1H, d, 6-H), 8.01 (1H, d, 8-H), 9.43 (1H, bs, NH) and 12.04 (1H, bs, NH). (Found: C, 41.60; H, 4.34; N, 6.04%. C15H16Cl2N2O2. HBr.0.4H2O requires C, 41.77; H, 4.16; N, 6.49%).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:9]([C:10]#[N:11])=[CH:8][N:7]=[C:6]([Cl:12])[N:5]=1.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=1[N:21]=[C:22]=[O:23].Cl>C(OCC)(=O)C.CN(C)C=O>[Cl:12][C:6]1[N:5]=[C:4]2[NH:3][C:22](=[O:23])[N:21]([C:15]3[C:14]([Cl:13])=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:20])[C:10](=[NH:11])[C:9]2=[CH:8][N:7]=1
Reactant: O=C=Nc1c(Cl)cccc1Cl
Reactant: N#Cc1cnc(Cl)nc1N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N=c1c2cnc(Cl)nc2[nH]c(=O)n1-c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 57.1 %

Procedure:
1.12 g of sodium hydride was added to an N,N-dimethylformamide (35 mL) solution containing 3.0 g of 4-amino-2-chloropyrimidin-5-carbonitrile, and the mixture was stirred for 5 minutes at room temperature. Then, 4.38 g of 2,6-dichlorophenyl isocyanate was added to the reaction mixture, which was then stirred for 1 hour at room temperature. Thereafter, ethyl acetate and a 1 N hydrochloric acid aqueous solution were added to the reaction mixture to separate the organic layer. After washing with saturated saline, the solution was dried with anhydrous magnesium sulfate, and the solvent was distilled away. The deposited solid was solidified using a methanol-ethyl acetate mixed solvent. After leaching, 3.8 g of a white solid was obtained as a subject compound.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]=1.[F:11][C:12]1[CH:17]=[CH:16][C:15]([SH:18])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.[NH4+].[OH-].[Cu](I)I>[F:11][C:12]1[CH:17]=[CH:16][C:15]([S:18][C:2]2[C:10]3[C:5](=[N:6][CH:7]=[CH:8][CH:9]=3)[NH:4][CH:3]=2)=[CH:14][CH:13]=1
Reactant: Ic1c[nH]c2ncccc12
Reactant: Fc1ccc(S)cc1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Fc1ccc(Sc2c[nH]c3ncccc23)cc1
Temperature: 65 °C

Procedure:
A solution of 3-iodo-1H-pyrrolo[2,3-b]pyridine (4.0 g, 16.4 mmol) in DMF is treated with 4-fluorobenzenethiol (2.09 mL, 19.7 mmol), potassium carbonate (3.40 g, 24.6 mmol), and copper iodide (4.21 g, 22.1 mmol). The reaction mixture is heated at 65° C. for 4 h, cooled, diluted with conc. aqueous NH4OH and extracted with ethyl acetate. The extracts are combined, washed with brine, dried over MgSO4 and concentrated in vacuo. Chromatography (1:50 methanol:CH2Cl2) of the residue, followed by methanol/H2O crystallization affords the title compound as an off-white solid, 3.56 g, mp 183–184° C., characterized by mass spectral and NMR analyses.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:12]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34]>CN(C=O)C.C(OCC)(=O)C>[C:20]([O:19][C:18]([NH:17][CH:12]([C:8]1([C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:3][CH:4]=2)[CH2:9][CH2:10][CH2:11]1)[CH2:13][CH:14]([CH3:16])[CH3:15])=[O:24])([CH3:22])([CH3:21])[CH3:23]
Reactant: CCOC(=O)CBr
Reactant: CC(C)CC(NC(=O)OC(C)(C)C)C1(c2ccc(O)cc2)CCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(C2(C(CC(C)C)NC(=O)OC(C)(C)C)CCC2)cc1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a stirred solution of phenol 67 (0.5 g, 0.0015 mole) in 25 mL of anhydrous DMF was added cesium carbonate (Cs2CO3). The resulting mixture was heated at 70° C. for 12 hours. The reaction mixture was cooled to room temperature and added ethyl bromoacetate. The reaction mixture was further stirred at 70° C. for 8 hours and the progress of the reaction was monitored by TLC. The reaction mixture was diluted with ethyl acetate (100 mL), washed with water (50 mL×2), dried over anhydrous sodium sulfate (Na2SO4) and evaporated. The residue was purified by silica gel column chromatography using 0-50% gradient of ethyl acetate and hexane as eluent to give the pure ester 69 as colorless liquid in 61% (0.38 g) yield. MS (ESI): m/z=420.00 (M+H+).
Reaction SMILES: O1C2=CN=CC=C2C(=O)C1.C(OC([C:16]1[O:25][C:19]2=[CH:20][N:21]=[CH:22][C:23]([Cl:24])=[C:18]2[C:17]=1[OH:26])=O)C>>[Cl:24][C:23]1[CH:22]=[N:21][CH:20]=[C:19]2[O:25][CH2:16][C:17](=[O:26])[C:18]=12
Reactant: CCOC(=O)c1oc2cncc(Cl)c2c1O
Agent: O=C1COc2cnccc21
Product: O=C1COc2cncc(Cl)c21

Procedure:
This compound was prepared using a method analogous to that of furo[2,3-c]pyridin-3(2H)-one (A.2.4.3), 4-chloro-3-hydroxyfuro[2,3-c]pyridine-2-carboxylic acid ethyl ester replacing 3-hydroxyfuro[2,3-c]pyridine-2-carboxylic acid ethyl ester;
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][C:3]=1[C:8]1[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=1.[CH2:16]([O:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][C:29]=1[F:30])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[F:30][C:29]1[CH:28]=[CH:27][C:26]([C:2]2[N:6]([CH3:7])[CH:5]=[N:4][C:3]=2[C:8]2[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=2)=[CH:25][C:24]=1[O:23][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: OB(O)c1ccc(F)c(OCc2ccccc2)c1
Reactant: Cn1cnc(-c2cc(C#N)ccn2)c1Br
Product: Cn1cnc(-c2cc(C#N)ccn2)c1-c1ccc(F)c(OCc2ccccc2)c1

Procedure:
The title compound was prepared from 2-(5-bromo-1-methyl-1H-imidazol-4-yl)pyridine-4-carbonitrile (PREPARATION 2) and 3-benzyloxy-4-fluorophenyl boronic acid according to the procedure for the preparation of Example 3, part A. [M+H] Calc'd for C23H17FN4O, 385. Found, 385.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:28]2[CH2:33][CH2:32][N:31]([C:34]([O:36]C(C)(C)C)=O)[CH2:30][CH2:29]2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:24])[NH:16][CH:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)=[CH:11][C:10]=2[N+:25]([O-:27])=[O:26])=[N:6][CH:7]=1.C(O)(C(F)(F)F)=O.CC1C(N2CCNCC2)=NC([NH:55][C:56]2[CH:71]=[CH:70][C:59]([C:60]([NH:62]C3CCN(C)CC3)=O)=[CH:58][C:57]=2[N+]([O-])=O)=NC=1.N(C1C=CC(C#N)=CC=1)=C=O.C(N(CC)CC)C>C(Cl)Cl>[C:60]([C:59]1[CH:70]=[CH:71][C:56]([NH:55][C:34]([N:31]2[CH2:32][CH2:33][N:28]([C:3]3[C:2]([CH3:1])=[CH:7][N:6]=[C:5]([NH:8][C:9]4[CH:14]=[CH:13][C:12]([C:15](=[O:24])[NH:16][CH:17]5[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH2:22]5)=[CH:11][C:10]=4[N+:25]([O-:27])=[O:26])[N:4]=3)[CH2:29][CH2:30]2)=[O:36])=[CH:57][CH:58]=1)#[N:62]
Reactant: Cc1cnc(Nc2ccc(C(=O)NC3CCN(C)CC3)cc2[N+](=O)[O-])nc1N1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Cc1cnc(Nc2ccc(C(=O)NC3CCN(C)CC3)cc2[N+](=O)[O-])nc1N1CCNCC1
Agent: N#Cc1ccc(N=C=O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: Cc1cnc(Nc2ccc(C(=O)NC3CCN(C)CC3)cc2[N+](=O)[O-])nc1N1CCN(C(=O)Nc2ccc(C#N)cc2)CC1
Reaction time: 1 h
Yield: 222 %

Procedure:
To a solution of tert-butyl 4-(5-methyl-2-((4-((1-methylpiperidin-4-yl)carbamoyl)-2-nitrophenyl)amino)pyrimidin-4-yl)piperazine-1-carboxylate (0.073 g, 0.13 mmol) in DCM (1.0 mL) was added TFA (1.0 mL) and the mixture was stirred for 1 h. An aliquot of the reaction mixture was analyzed by LCMS, which indicated that the reaction had proceeded to completion. The solvents were removed and the residue was dried on high vacuum. The crude product was used for the next step without further purification. To a solution of 4-((5-methyl-4-(piperazin-1-yl)pyrimidin-2-yl)amino)-N-(1-methylpiperidin-4-yl)-3-nitrobenzamide (0.073 mmol) in DCM (1.5 mL) was added 4-isocyanatobenzonitrile (23 mg, 0.16 mmol) and triethylamine (0.055 mL, 0.39 mmol) and the mixture was stirred at 23° C. for 16 h. reaction. The crude reaction mixture was filtered and washed with minimal volume of DCM and then hexanes to give the title compound (97 mg, 100%). MS (ES+) C30H34N10O4 requires: 598. found: 599 [M+H]+
Reaction SMILES: [F:1][C:2]1([F:36])[CH2:4][CH:3]1[CH2:5][CH2:6][O:7][C:8]1[CH:35]=[CH:34][C:11]2[N:12]=[C:13]([C:15]3[N:20]=[CH:19][C:18]([O:21][CH2:22][C@@H:23]([NH:25][C:26](=[O:32])OC(C)(C)C)[CH3:24])=[CH:17][C:16]=3[F:33])[O:14][C:10]=2[CH:9]=1.Cl.[C:38](OCC)(=O)C>C(OCC)(=O)C>[F:1][C:2]1([F:36])[CH2:4][CH:3]1[CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[N:12]=[C:13]([C:15]3[N:20]=[CH:19][C:18]([O:21][CH2:22][C@@H:23]([NH:25][C:26](=[O:32])[CH3:38])[CH3:24])=[CH:17][C:16]=3[F:33])[O:14][C:34]=2[CH:35]=1
Reactant: C[C@@H](COc1cnc(-c2nc3ccc(OCCC4CC4(F)F)cc3o2)c(F)c1)NC(=O)OC(C)(C)C
Reactant: CCOC(C)=O
Agent: Cl
Product: CC(=O)N[C@@H](C)COc1cnc(-c2nc3ccc(OCCC4CC4(F)F)cc3o2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of tert-butyl {(1S)-2-[(6-{6-[2-(2,2-difluorocyclopropyl)ethoxy]-1,3-benzoxazol-2-yl}-5-fluoropyridin-3-yl)oxy]-1-methylethyl}carbamate (910 mg), 4 M hydrogen chloride/ethyl acetate (10 mL), and ethyl acetate (10 mL) was stirred at room temperature overnight. The mixture was concentrated under reduced pressure. The residue was mixed with pyridine (10 mL) and acetic anhydride (5 mL). The mixture was stirred at room temperature overnight. 1 M hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) and recrystallization (ethyl acetate/hexane) to give the title compound (475 mg) as white crystals.
Reaction SMILES: [CH:1]([C:4]1[N:9]=[C:8]([CH2:10][N:11]2[CH2:15][CH2:14][N:13]([C@@H:16]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:17]([O:19]C(C)(C)C)=[O:18])[C:12]2=[O:28])[CH:7]=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32]>ClCCl>[CH:1]([C:4]1[N:9]=[C:8]([CH2:10][N:11]2[CH2:15][CH2:14][N:13]([C@@H:16]([C:24]([CH3:25])([CH3:27])[CH3:26])[C:17]([OH:19])=[O:18])[C:12]2=[O:28])[CH:7]=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32]
Reactant: CC(C)c1cccc(CN2CCN([C@H](C(=O)OC(C)(C)C)C(C)(C)C)C2=O)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)c1cccc(CN2CCN([C@H](C(=O)O)C(C)(C)C)C2=O)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of the product from Example 117C (0.098 mmol) in dichloromethane (0.5 mL) was treated with trifluoroacetic acid (0.5 mL) and the mixture was stirred for 1 hour at 25° C. The solvent was removed under reduced pressure and the residue was purified by reversed phase chromatography on a C18 column eluting with 5-100% acetonitrile in water (0.1% TFA) to give the title compound as the trifluroacetic acid salt (0.022 g, 52% yield).
Reaction SMILES: P([O-])([O-])([O-])=O.[S:6]([O-:10])([O-:9])(=[O:8])=[O:7].[C:11]([CH:14]([CH:16]([C:18]([O-:20])=[O:19])[OH:17])[OH:15])([O-:13])=[O:12].[K+:21].[Na+:22].C([O-])(=O)CCCCCCC/C=C\CCCCCCCC.[Na+]>>[OH:9][S:6]([OH:10])(=[O:8])=[O:7].[C:11]([CH:14]([CH:16]([C:18]([O-:20])=[O:19])[OH:17])[OH:15])([O-:13])=[O:12].[K+:21].[Na+:22]
Reactant: O=S(=O)([O-])[O-]
Agent: CCCCCCCC/C=C\CCCCCCCC(=O)[O-]
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Product: O=S(=O)(O)O
Yield: 96 %

Procedure:
By applying to the same ore the known process with depression of the phosphate by alumine sulphate and sodium-potassium tartrate, and flotation of the carbonates by sodium oleate, while using: 1760 g/t of 96% H2SO4 250 g/t of Al2 (SO4)3 -500 g/t of sodium-potassium tartrate 5000 g/t of sodium oleate, the following results (table VII) were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[CH:10])=[CH:5][CH:4]=1.I[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1>O1CCCC1.C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[CH:5][CH:4]=1
Reactant: Ic1ccncc1
Reactant: C#Cc1ccc(OC)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(C#Cc2ccncc2)cc1

Procedure:
A mixture of 4-methoxyphenylacetylene (2.86 g, 21.7 mmol), 4-iodopyridine (4.44 g, 21.7 mmol), cuprous iodide (206 mg, 1.08 mmol), bis(triphenylphosphine)palladium(II) dichloride (758 mg, 1.08 mmol) in tetrahydrofuran (40 mL) and triethylamine (20 mL) was heated at reflux for 2 h. The mixture was filtered, concentrated, and the residue chromaptographed on silica in 1:1 ethyl acetate-hexanes giving 2.45 g (54%) of a yellow solid. 1H NMR (CDCl3, 400 mHz) δ 9.2 (very broad, 2H), 7.57 (br, 2H), 7.48 (d, 2H, J=8.7 Hz), 6.88 (d, 2H, J=8.7 Hz), 3.82 (s, 3H). MS (AP+) m/e 210 (MH+).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([CH:8]([CH3:12])[C:9]([OH:11])=O)=[O:7].C(Cl)(=O)C(C)(C)C.[NH2:20][CH:21]1[C:39](=[O:40])[N:23]2[C:24]([C:36]([OH:38])=[O:37])=[C:25]([CH:28]([S:30][C:31]3[NH:35][N:34]=[N:33][N:32]=3)[CH3:29])[CH2:26][S:27][C@H:22]12.C[Si](C([Si](C)(C)C)C(N)=O)(C)C>CN(CC1C=CC=CC=1)C.C(Cl)Cl.C(N(CC)CC)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([CH:8]([CH3:12])[C:9]([NH:20][CH:21]1[C:39](=[O:40])[N:23]2[C:24]([C:36]([OH:38])=[O:37])=[C:25]([CH:28]([S:30][C:31]3[NH:32][N:33]=[N:34][N:35]=3)[CH3:29])[CH2:26][S:27][C@H:22]12)=[O:11])=[O:7]
Reactant: CC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: CC(C(=O)O)S(=O)c1cccs1
Agent: CC(C)(C)C(=O)Cl
Agent: CN(C)Cc1ccccc1
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C(NC(=O)C(C)S(=O)c3cccs3)[C@H]2SC1
Temperature: -10 °C

Procedure:
408 mg. of 2-(2-thienylsulfinyl)propionic acid of the R form were dissolved in 12 ml. of dry methylene chloride and 0.3 ml. of triethylamine and 2 drops of N,N-dimethylbenzylamine were added to the solution. The mixture was agitated and cooled to -10° C., and 0.2 g. of pivaloyl chloride was added thereto. Then the mixture was agitated at -10° C. for 2 hours, and a liquid mixture of 656 mg. of 7-amino-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid, 20 ml. of dry methylene chloride and 400 mg. of bis-trimethylsilylacetamide blended and stirred at room temperature for 1 hour, was added to the above mixture, and agitated for 30 minutes at -10° C., for 30 minutes at 0° C. and for another 1 hour at room temperature. After completion of the reaction the solvent was distilled off under reduced pressure and the residue was dissolved in 3% aqueous sodium bicarbonate solution. Then the solution was extracted with ethyl acetate 3 times, and the pH of the aqueous layer was adjusted to 3.0 by 2 N hydrochloric acid. The aqueous layer was allowed to stand in a cooling place until precipitate was formed. The precipitate was collected, dried and recrystallized from water-methanol to obtain 7-[2-(2-thienylsulfinyl)propionamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid. The filtrate separated from the precipitate was extracted with ethyl acetate. The organic layer was dried by magnesium sulfate and concentrated, and the resulting residue was dissolved in methanol. The solution was subjected to column chromatography using Sephadex LH-20(manufactured and sold by Pharmacia Fine Chemicals AB, Sweden) and the product was fractionally recovered and concentrated. The resulting powder was the same as the above crystal obtained by recrystallization from water-methanol. The total amount of the obtained product was 440 mg.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].CO[CH:14]1[CH2:18][CH2:17][CH:16](OC)O1>C(O)(=O)C>[N:1]1([C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])[CH:14]=[CH:18][CH:17]=[CH:16]1
Reactant: COC1CCC(OC)O1
Reactant: COC(=O)c1cccc(N)c1
Solvent: CC(=O)O
Product: COC(=O)c1cccc(-n2cccc2)c1

Procedure:
The mixture of methyl 3-aminobenzoate (110.0 g) and 2,5-dimethoxytetrahydrofuran (141.4 ml) in acetic acid (330 ml) was heated under reflux for 50 minutes under stirring and the solvent was removed by concentration in vacuo. To the residue was added a mixture of ethyl acetate and water, and adjusted to pH 8 with potassium carbonate. The separated organic layer was washed with water and dried over magnesium sulfate. Evaporation of a solvent gave a residue, which was purified by column chromatography on silica gel eluting with chloroform. The eluted fractions containing the desired product were collected and evaporated in vacuo to give methyl 3-(pyrrol-1-yl)benzoate (112.84 g) as an oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[C:12]([C:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([C:23]5[S:24][C:25](S(C)(=O)=O)=[N:26][N:27]=5)[CH:21]=4)[N:16](C(OC(C)(C)C)=O)[CH:15]=3)[CH:11]=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH3:39].CCOC(C)=O>CS(C)=O>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[C:12]([C:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([C:23]5[S:24][C:25]([NH2:39])=[N:26][N:27]=5)[CH:21]=4)[NH:16][CH:15]=3)[CH:11]=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CN1CCN(c2cccc(-c3cn(C(=O)OC(C)(C)C)c4ccc(-c5nnc(S(C)(=O)=O)s5)cc34)n2)CC1
Reactant: N
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CN1CCN(c2cccc(-c3c[nH]c4ccc(-c5nnc(N)s5)cc34)n2)CC1
Temperature: 120 °C
Yield: 19 %

Procedure:
A sealed tube was charged with tert-butyl 3-(6-(4-methylpiperazin-1-yl)pyridin-2-yl)-5-(5-(methylsulfonyl)-1,3,4-thiadiazol-2-yl)-1H-indole-1-carboxylate (300 mg, 0.541 mmol) followed by ammonia in DMSO (10 mL). The reaction was heated at 120° C. for 4 h. Ice/H2O and EtOAc were added to the mixture. The organic layer was separated and the aqueous layer was extracted with EtOAc. The combined organic layer was dried, filtered and concentrated. The residue was purified with RP-HPLC to give 5-(3-(6-(4-methylpiperazin-1-yl)pyridin-2-yl)-1H-indol-5-yl)-1,3,4-thiadiazol-2-amine (40 mg, 19%). MS (ESI, pos. ion) m/z: 392.1 (M+1); 1H-NMR (DMSO-d6, 300 MHz) δ 11.76 (1H, s), 10 (1H, brs), 8.8 (1H, s), 8.16 (1H, s), 7.5-7.67 (4H, m), 7.28-7.3 (1H, d), 6.75-6.79 (1H, d), 4.54-4.57 (2H, d), 3.6-3.65 (2H, d), 3.17-3.24 (4H, m), 2.91 (3H, s).
Reaction SMILES: [Cl:1][C:2]([Cl:7])([Cl:6])[C:3](Cl)=[O:4].[CH3:8][N:9]([CH3:12])[CH:10]=[O:11].C(N(CC)CC)C>O>[CH3:8][N:9]([CH3:12])[C:10](=[O:11])[C:3]([C:2]([Cl:7])([Cl:6])[Cl:1])=[O:4]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CN(C)C(=O)C(=O)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 273g (1.5 mole) portion of trichloroacetyl chloride was added over one hour to a stirred, cooled (5°C) portion of 330g (4.5 moles) of dimethylformamide. Nitrogen was passed over the solution throughout the reaction. A 152g (1.5 mole) portion of triethylamine was then added dropwise while keeping the temperature below 15°C. The mixture was stirred overnight at ambient temperature and then cooled to 5°C before 300 ml of water was added gradually. The organic products were extracted into ethyl ether, and the ethereal solution was washed with water, 10% hydrochloric acid, and with brine, dried over magnesium sulfate and concentrated. The residue was distilled under vacuum through a short-path still yielding 160g of pure N,N-dimethyl-3,3,3-trichloropyruvamide: Bp 80°-82° (0.2mm); ir(λmax, film) 5.7 (s), 6.0 (s), 9.45 (s), 11.6 (m) microns; nmr (δ , CDCl3) 3.0 and 3.05 (two singlets, 6H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][C:5]2[N:6]([CH2:28][CH2:29][CH2:30][CH2:31][F:32])[C:7]([CH2:9][N:10]3[C:14]4[CH:15]=[N:16][CH:17]=[CH:18][C:13]=4[N:12]([CH2:19][C:20]([O:22]C(C)(C)C)=[O:21])[C:11]3=[O:27])=[N:8][C:4]=2[CH:3]=1.[OH-].[Li+].Cl.ClCCl>O1CCCC1.O.O>[Cl:1][C:2]1[CH:34]=[CH:33][C:5]2[N:6]([CH2:28][CH2:29][CH2:30][CH2:31][F:32])[C:7]([CH2:9][N:10]3[C:14]4[CH:15]=[N:16][CH:17]=[CH:18][C:13]=4[N:12]([CH2:19][C:20]([OH:22])=[O:21])[C:11]3=[O:27])=[N:8][C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)Cn1c(=O)n(Cc2nc3cc(Cl)ccc3n2CCCCF)c2cnccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: O=C(O)Cn1c(=O)n(Cc2nc3cc(Cl)ccc3n2CCCCF)c2cnccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 106.2 %

Procedure:
In a 100 mL dry flask, tert-butyl (3-{[5-chloro-1-(4-fluorobutyl)-1H-benzimidazol-2-yl]methyl}-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)acetate (P33) (1.74 g, 3.49 mmol) was dissolved in 50 mL tetrahydrofuran/water mixture (3/1). Lithium hydroxide (167.3 mg, 6.98 mmol, 2 eq.) was added to the solution and the mixture was stirred for 16 hours at room temperature. The reaction mixture was diluted with water (20 mL) followed by the addition of aqueous HCl (1M) until the pH was approximately 6. Dichloromethane (40 mL) was added to the reaction mixture and the organic layer separated. The aqueous layer was evaporated to dryness and dried into the oven during 16 hours to give (3-{[5-chloro-1-(4-fluorobutyl)-1H-benzimidazol-2-yl]methyl}-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)acetic acid (P67, 1.6 g, 100%) as a white solid; LCMS m/z=432 (M+H)+