Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][C:3]1[C:17]2=[C:18]3[C:10]([C:11]4[C:16]2=[CH:15][CH:14]=[CH:13][CH:12]=4)=[CH:9][CH:8]=[CH:7][C:6]3=[CH:5][CH:4]=1.O=S(Cl)[Cl:21]>C1(C)C=CC=CC=1>[Cl:21][CH2:2][C:3]1[C:17]2=[C:18]3[C:10]([C:11]4[C:16]2=[CH:15][CH:14]=[CH:13][CH:12]=4)=[CH:9][CH:8]=[CH:7][C:6]3=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc2cccc3c2c1-c1ccccc1-3
Solvent: Cc1ccccc1
Product: ClCc1ccc2cccc3c2c1-c1ccccc1-3

Procedure:
To a RB flask equipped with magnetic stirring bar, condenser, addition funnel, thermometer and N2 inlet line with bubbler was added 1-hydroxymethylfluoranthene (3B, 12.0 g, 0.052 mol), and dry PhCH3 (500 mL). To the mixture was added SOCl2 (Aldrich, 15.73 g, 0.132 mol, 9.5 mL) dropwise over 15 min. The mixture was then heated at 80° overnight and then refluxed for 1 h. The solvent was removed by rotary evaporation to give a crude off white solid. The material was redissolved in PhCH3 (300 mL) followed again by rotary evaporation. The process was repeated two additional times to give the crude product 1-chloromethylfluoranthene which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[C:20]([NH:25][C:26](=[O:28])[CH3:27])[CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][CH:22]=[CH:21][C:20]=4[NH:25][C:26](=[O:28])[CH3:27])[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC(=O)Nc1cccc2c1CCNC2C
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Product: CC(=O)Nc1cccc2c1CCN(C(=O)c1cc3ncc(Cl)cn3n1)C2C

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with N-(1-Methyl-1,2,3,4-tetrahydro-isoquinolin-5-yl)-acetamide to provide the title compound in moderate yield.
Reaction SMILES: C([O:3][C:4](=[O:20])[CH2:5][C:6]1[C:7]([CH3:19])=[N:8][N:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:10]=1[CH3:11])C.[OH-].[K+]>O.C(O)C>[CH3:19][C:7]1[C:6]([CH2:5][C:4]([OH:20])=[O:3])=[C:10]([CH3:11])[N:9]([C:12]2[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=2)[N:8]=1
Reactant: CCOC(=O)Cc1c(C)nn(-c2ccc(C)cc2)c1C
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1ccc(-n2nc(C)c(CC(=O)O)c2C)cc1
Yield: 81.6 %

Procedure:
8.2 grams of the 3,5-dimethyl-1-(p-tolyl)pyrazol-4-acetic acid-ethyl ester, produced by the method of Example (4a), were mixed with a solution of 2.5 grams potassium hydroxide in 15 milliliters water and 15 milliliters ethanol, and the ester saponified and the free acid isolated by the method described in Example (1b). 6.0 grams of 3,5-dimethyl-1-(p-tolyl)-pyrazol-4acetic acid, melting at 119°-121° C. were obtained, representing a yield of 82%.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:32][CH3:33])[C@H:10]([O:28][C:29](=[O:31])[CH3:30])[C:11]([NH:13][NH:14][C:15](=[O:27])[C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=1)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C1COCC1>[C:1]([O:5][C:6]([NH:8][CH:9]([CH2:32][CH3:33])[C@H:10]([O:28][C:29](=[O:31])[CH3:30])[C:11]1[O:27][C:15]([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]([F:24])([F:26])[F:25])=[CH:18][CH:17]=2)=[N:14][N:13]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCC(NC(=O)OC(C)(C)C)[C@H](OC(C)=O)C(=O)NNC(=O)c1ccc(OC(F)(F)F)cc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: C1CCOC1
Product: CCC(NC(=O)OC(C)(C)C)[C@H](OC(C)=O)c1nnc(-c2ccc(OC(F)(F)F)cc2)o1
Temperature: 150 °C

Procedure:
acetic acid (S)-2-tert-butoxycarbonylamino-1-[N′-(4-trifluoromethoxy-benzoyl)-hydrazinocarbonyl]-butyl ester (0.21 mmol, 0.1 g) is dissolved in THF (5 mL) and the solution filled into a Smith Microwave synthesizer reaction vessel. 2-tert-Butylimino-2-diethylamino-1,3-dimethylperhydro-1,2,3-diazaphosphorine on polystyrene (1.05 mmol, 0.456 g, 2.3 mmol/g loading) and the p-Toluenesulfonic chloride (0.25 mmol, 0.048 g) are added and the reaction mixture heated at 150° C. for 10 min (fixed hold time) in the microwave synthesizer.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][CH:11]2[CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:9])=[CH:4][CH:3]=1.[CH2:21]([NH:23][CH2:24][CH3:25])[CH3:22]>>[CH2:21]([N:23]([CH2:24][CH3:25])[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:9])=[CH:4][CH:3]=1)[CH3:22]
Reactant: CCNCC
Reactant: O=C(c1ccc(F)cc1)N1CCCC1CN1CCCC1
Product: CCN(CC)c1ccc(C(=O)N2CCC[C@H]2CN2CCCC2)cc1

Procedure:
(4-Diethylamino-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone is prepared from (4-Fluoro-phenyl)-(2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone and diethylamine in a manner substantially similar to Procedure A. MS (APCI+) 330 (M+H)+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10]([CH:12]([C:36](OCC)=[O:37])[CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][CH:25]([C:31](OCC)=[O:32])[C:26](OCC)=[O:27])=[CH:18][CH:17]=1)=O)C.C(OCC)(=O)C.[OH-].[Na+]>O1CCCC1.O>[OH:9][CH2:10][CH:12]([CH2:36][OH:37])[CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][CH:25]([CH2:26][OH:27])[CH2:31][OH:32])=[CH:18][CH:17]=1
Reactant: CCOC(=O)C(CCCc1ccc(CCCC(C(=O)OCC)C(=O)OCC)cc1)C(=O)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OCC(CO)CCCc1ccc(CCCC(CO)CO)cc1
Temperature: 25 °C
Yield: 22.6 %

Procedure:
First, 525 mg of lithium aluminium hydride was added to 30 ml of absolute tetrahydrofuran, then 20 ml of a solution of 2.39 g 1,4-bis(4,4-diethoxycarbonylbutyl)benzene in absolute tetrahydrofuran was added dropwise thereto with stirring at a room temperature, and the mixture was refluxed for one hour. After adding 4 ml of ethyl acetate with ice-cooling, the reaction mixture was stirred for 10 minutes. To the mixture were further added successively 0.5 ml of water, 0.5 ml of 15% sodium hydroxide aqueous solution and 1.5 ml of water, and the mixture was stirred for one hour. After filtering off insoluble matter, the filtrate was evaporated under a reduced pressure. The oily residue thus obtained was applied to a silica gel column and eluted with chloroform/ethanol (5:1) to obtain 350 mg of the title compound as a colorless crystal.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:28]=[CH:29][CH:30]=1)[O:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([C:20]2[NH:24][CH:23]=[C:22]([C:25]([OH:27])=O)[CH:21]=2)[CH:15]=1)=[O:8].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.Cl.[CH3:65][O:66][C:67](=[O:79])[C@H:68]([CH2:70][CH2:71][C:72]([O:74][C:75]([CH3:78])([CH3:77])[CH3:76])=[O:73])[NH2:69].Cl>CN(C=O)C.O>[CH3:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:28]=[CH:29][CH:30]=1)[O:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([C:20]2[NH:24][CH:23]=[C:22]([C:25]([NH:69][CH:68]([CH2:70][CH2:71][C:72]([O:74][C:75]([CH3:78])([CH3:77])[CH3:76])=[O:73])[C:67]([O:66][CH3:65])=[O:79])=[O:27])[CH:21]=2)[CH:15]=1)=[O:8]
Reactant: Cc1ccoc1C(=O)Nc1cccc(Oc2ccnc(-c3cc(C(=O)O)c[nH]3)c2)c1
Reactant: COC(=O)[C@@H](N)CCC(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)C(CCC(=O)OC(C)(C)C)NC(=O)c1c[nH]c(-c2cc(Oc3cccc(NC(=O)c4occc4C)c3)ccn2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3-carboxylic acid (Example 32)(140 mg, 0.35 mmol) in 10 ml of anhydrous DMF were added HATU (160 mg, 0.42 mmol) and N,N-diisopropylethylamine (135 mg, 1.05 mmol). The mixture was stirred at room temperature for 10 minutes, followed by addition of L-Glutamic acid 5-tert-butyl 1-methyl ester hydrochloride (135 mg, 0.53 mmol). The mixture was stirred for another 5 minutes and poured into 100 ml of water. 2M HCl was added dropwise with vigorous stirring until pH=4. The precipitates were filtered, washed with water and dried in vacuo to give 5-tert-butyl 1-methyl 2-({[5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrol-3-yl]carbonyl}amino)pentanedioate as white solid. Yield: 170 mg, 81%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12](=[O:13])[CH2:11][CH2:10][C@H:9]1[C:14]([O:16][CH:17]([CH3:19])[CH3:18])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].C(OCC)(=O)C.CCCCCC>CO.O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:10][CH2:11][CH2:12][OH:13])[C:14]([O:16][CH:17]([CH3:19])[CH3:18])=[O:15])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)OC(=O)[C@@H]1CCC(=O)N1C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CCCCCC
Product: CC(C)OC(=O)[C@H](CCCO)NC(=O)OC(C)(C)C
Reaction time: 0.17 h
Yield: 63.1 %

Procedure:
To a solution of isopropyl 1-(tert-butoxycarbonyl)pyrrolidin-5-one-2(S)-carboxylate (product of step 26B, 49.5 g, 183 mmol) in methanol (300 mL) was added sodium borohydride (10.0 g, 263 mmol) in ˜1 g portions over 1.5 hours. The reaction was stirred under nitrogen for another 10 minutes. It was diluted with water, extracted with ether, combined organic fractions washed with saturated aqueous NaCl, dried (MgSO4) and evaporated to give a light yellow oil. Flash chromatography (silica gel, 20–30% ethyl acetate/hexane) gave 31.8 g (64%) of isopropyl 2(S)-(tert-butoxycarbonylamino)-5-hydroxypentanoate as a colorless syrup: 1H NMR (300 MHz, Chloroform-D) δ 5.16 (br d, 1H, J=7.3 Hz), 5.03 (sept., 1H, J=6.2 Hz), 4.28 (br d, 1H, J=6.2 Hz), 3.67 (br dd, J=10.2, 5.5 Hz), 1.94–1.79 (m, 2H), 1.76–1.67 (m, 1H), 1.66–1.56 (m, 2H), 1.43 (s, 9H), 1.25 (d, 3H, J=6.2 Hz), 1.23 (d, 3H, J=6.2 Hz). LCMS m/z 276 (M+H)+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:14]([CH3:24])[C@@H:15]([CH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)[C:16](O)=[O:17])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O.[OH-].[Na+]>C1COCC1>[CH2:7]([N:14]([CH3:24])[C@@H:15]([CH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)[CH2:16][OH:17])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CN(Cc1ccccc1)[C@H](C(=O)O)C1CCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CN(Cc1ccccc1)[C@H](CO)C1CCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of lithium aluminum hydride (2.3 g, 61.0 mmol, 1.5 eq) in anhydrous THF (200 mL) at 0° C. was added (S)-2-(benzyl(methyl)amino)-2-cyclopentylacetic acid (3) (10.0 g, 40.0 mmol, 1.0 eq) in portions at 0° C. The reaction mixture was stirred at room temperature for 2 h followed by heating to reflux for 2 h, After cooled, water (2.5 mL) was added at 0° C. followed by 5% NaOH (2.5 mL, aq). The suspension formed was filtered and washed with ethyl acetate (50 mL). Water (250 mL) was then added to the filtrate, which was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulphate and evaporated in vacuo to give the product 4 as an oil (quant); LC-MS: m/z 234 [M+H+]+
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C([O-])(=O)C.[Na+].Cl.[O:13]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[O:16][CH2:15][CH:14]1[C:23]([Cl:25])=[O:24].[OH-].[Na+]>O.CC(C)=O>[ClH:25].[O:13]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[O:16][CH2:15][CH:14]1[C:23]([N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)=[O:24]
Reactant: O=C(Cl)C1COc2ccccc2O1
Reactant: C1CNCCN1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: O=C(C1COc2ccccc2O1)N1CCNCC1
Yield: 12.3 %

Procedure:
A suspension of piperazine (11.88 g.) and sodium acetate (20.30 g.) in a mixture of water (70 ml.) and acetone (95 ml.) was stirred at 10°-15° C., then concentrated hydrochloric acid was added (about 35 ml.) until the pH of the solution reached 1.5. 1,4-Benzodioxan-2-carbonyl chloride (31.0 g.) and sodium hydroxide (5 N, about 45 ml.) were then added portionwise while maintaining the temperature at 10°-15° C., the sodium hydroxide maintaining the pH at 1.7-2.2. After the addition was complete, the pH was adjusted to 2.0 by the addition of sodium hydroxide, the suspension was stirred for a further 30 minutes. Water was then added until a homogeneous solution resulted, the acetone removed in vacuo, and the aqueous phase was basified to pH 8-9 with sodium hydroxide (5 N), re-extracted with chloroform (3×200 ml.) and the extracts washed with water, dried (MgSO4) and evaporated in vacuo. The oily residue was dissolved in ethyl acetate, treated with ethereal hydrogen chloride, evaporated in vacuo and the solid residue triturated with ether, followed by recrystallization from methanol to give N-(1,4-benzodioxan-2-carbonyl)piperazine hydrochloride (4.85 g.), M.P. 265°-267° C.
Reaction SMILES: [CH2:1]([C:4]1[C:5]([Cl:23])=[C:6]2[CH:12]=[CH:11][N:10]([S:13]([C:16]3[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[C:7]2=[N:8][CH:9]=1)[CH:2]=C.[O:24]1CCOCC1>O.CCOC(C)=O.O=[Os](=O)(=O)=O>[Cl:23][C:5]1[C:4]([CH2:1][CH:2]=[O:24])=[CH:9][N:8]=[C:7]2[N:10]([S:13]([C:16]3[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:11]=[CH:12][C:6]=12
Reactant: C1COCCO1
Reactant: C=CCc1cnc2c(ccn2S(=O)(=O)c2ccc(C)cc2)c1Cl
Agent: O=[Os](=O)(=O)=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)c(CC=O)cnc32)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-Allyl-4-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridine (3.90 g, 11.2 mmol) in 1,4-dioxane (75 mL) and water (15 mL) was treated with NaIO4 (9.62 g, 45.0 mmol) and OsO4 (2.5% in t-BuOH, 5.65 mL, 0.450 mmol). The mixture was stirred at rt for about 1 h then diluted with EtOAc (100 mL). The solids were collected by filtration and the cake was washed with EtOAc (2×100 mL). The filtrate was washed with water (100 mL) and saturated aqueous NaCl (50 mL) then dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The material was purified by flash chromatography on silica gel to give 2-(4-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acetaldehyde as a mixture of aldehyde and hydrate (1.45 g, 37%); LC/MS (Table 2, Method b) Rt=2.51 min; MS m/z 349 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:17])([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][CH:11]=[CH:10]2)[C:3](OC)=O.[CH3:18][C:19]1[CH:23]=[C:22]([C:24]2[N:29]=[N:28][C:27]([NH:30][NH2:31])=[CH:26][CH:25]=2)[S:21][N:20]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>O1CCOCC1.CCOC(C)=O>[F:1][C:2]([F:17])([C:3]1[N:28]2[N:29]=[C:24]([C:22]3[S:21][N:20]=[C:19]([CH3:18])[CH:23]=3)[CH:25]=[CH:26][C:27]2=[N:30][N:31]=1)[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][CH:11]=[CH:10]2
Reactant: Cc1cc(-c2ccc(NN)nn2)sn1
Reactant: COC(=O)C(F)(F)c1ccc2ncccc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1cc(-c2ccc3nnc(C(F)(F)c4ccc5ncccc5c4)n3n2)sn1
Temperature: 150 °C

Procedure:
A mixture of methyl 2,2-difluoro-2-(quinolin-6-yl)acetate (0.50 g, 2.1 mmol), 1-(6-(3-methylisothiazol-5-yl)pyridazin-3-yl)hydrazine (0.25 g, 1.2 mmol) and p-toluenesulfonic acid monohydrate (0.40 g, 2.1 mmol) in 5 mL of dioxane was heated at 150° C. for 1 hour in a microwave. The mixture was then diluted with 70 mL of EtOAc and 40 mL of satd. NaHCO3 solution. The organic phase was separated and washed with 40 mL of brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (EtOAc to 10% MeOH/EtOAc) to give yellow glass. The product was further purified by a prep-HPLC to give yellow glass. MS (ESI pos. ion) m/z: 395 (MH+). Calc'd exact mass for C19H12F2N6S: 394.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10](Cl)[C:9]2[C:4](=[C:5]([CH3:15])[C:6]([O:13][CH3:14])=[CH:7][CH:8]=2)[N:3]=1.ClC1C=C([O:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)C2C(=C(Cl)C(OC)=CC=2)N=1>>[Cl:1][C:2]1[CH:11]=[C:10]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)[C:9]2[C:4](=[C:5]([CH3:15])[C:6]([O:13][CH3:14])=[CH:7][CH:8]=2)[N:3]=1
Reactant: COc1ccc2c(Cl)cc(Cl)nc2c1C
Reactant: COc1ccc(COc2cc(Cl)nc3c(Cl)c(OC)ccc23)cc1
Product: COc1ccc(COc2cc(Cl)nc3c(C)c(OC)ccc23)cc1
Yield: 50 %

Procedure:
Compound 221b was synthesized from compound 220b as a white powder in 50% yield, following the procedure as described for compound 221d. 1H NMR (CDCl3, 376 MHz) δ (ppm) 2.60 (s, 3H), 3.85 (s, 3H), 3.97 (s, 3H), 5.18 (s, 2H), 6.69 (s, 1H), 6.97 (d, J=8.57 Hz, 1H), 7.19 (d, J=8.57 Hz, 1H), 7.42 (d, J=8.57 Hz, 1H), 8.02 (d, J=8.57 Hz, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][C:17]([C:24]3[N:31]4[C:27]([S:28][C:29]([C:32]5[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[C:34]([O:40][CH3:41])[CH:33]=5)=[N:30]4)=[N:26][CH:25]=3)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:42]>O1CCOCC1>[CH3:41][O:40][C:34]1[CH:33]=[C:32]([C:29]2[S:28][C:27]3=[N:26][CH:25]=[C:24]([C:17]4[CH:16]=[N:15][C:14]([N:11]5[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]5)=[C:19]([C:20]([F:22])([F:23])[F:21])[CH:18]=4)[N:31]3[N:30]=2)[CH:37]=[CH:36][C:35]=1[O:38][CH3:39].[ClH:42]
Reactant: COc1ccc(-c2nn3c(-c4cnc(N5CCN(C(=O)OC(C)(C)C)CC5)c(C(F)(F)F)c4)cnc3s2)cc1OC
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc(-c2nn3c(-c4cnc(N5CCNCC5)c(C(F)(F)F)c4)cnc3s2)cc1OC
Temperature: 25 °C
Reaction time: 6.5 h

Procedure:
To a solution of 4-{5-[2-(3,4-Dimethoxy-phenyl)-imidazo[2,1-b][1,3,4]thiadiazol-5-yl]-3-trifluoromethyl-pyridin-2-yl}-piperazine-1-carboxylic acid tert-butyl ester (0.15 g, 0.254 mmol, 1 eq) in dioxane (4 mL) was added an excess of 4M HCl in dioxane (20 eq) at 0° C. The reaction was allowed to warm to rt and it was stirred for 6.5 h. Solvents were removed under reduced pressure to afford the desired product as HCl salt (146 mg, 100%). HPLC-MS: (5-40% B in 8 min, 0.8 mL/min, 50° C.): tR=5.65 min and 5.96 min, [M+H]+ m/z 491.2; 1H NMR (300 MHz, DMSO) δ 9.24 (d, J=1.9 Hz, 1H), 8.77 (d, J=2.1 Hz, 1H), 8.03 (s, 1H), 7.56 (dd, J=8.4, 1.9 Hz, 1H), 7.50 (d, J=1.9 Hz, 1H), 7.19 (d, J=8.5 Hz, 1H), 3.88 (s, 3H), 3.85 (s, 3H), 3.45 (m, 4H), 3.24 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1[N:20]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][CH:23]=2)[C:5]2=[N:6][C:7]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[CH:8][C:9]([C:10]([O:12]C)=[O:11])=[C:4]2[N:3]=1>[Li+].[OH-].C1COCC1>[CH3:1][C:2]1[N:20]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][CH:23]=2)[C:5]2=[N:6][C:7]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[CH:8][C:9]([C:10]([OH:12])=[O:11])=[C:4]2[N:3]=1
Reactant: COC(=O)c1cc(N2CCOCC2)nc2c1nc(C)n2Cc1cccc2ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1nc2c(C(=O)O)cc(N3CCOCC3)nc2n1Cc1cccc2ccccc12
Temperature: 50 °C
Reaction time: 5 h
Yield: 49.7 %

Procedure:
A mixture of methyl 2-methyl-5-morpholino-3-(naphthalen-1-ylmethyl)-3H-imidazo[4,5-b]pyridine-7-carboxylate (134 mg, 0.32 mmol) in 2N LiOH (15 mL) and THF (15 mL) was stirred at 50° C. for 5 h. It was cooled to room temperature and the precipitate was collected by filtration. It was then poured into water (100 mL) and the suspension was acidified with formic acid to pH=1. It was filtered and the solid was purified by chromatography on silica gel eluted with MeOH/DCM=1/5 to afford the crude product. It was then made a further purification by prep-HPLC to afford the desired product as a yellow solid (64 mg, 50%); LC/MS: MS (ES+) m/e 403 (MH+); 1H NMR (300 MHz, DMSO-d6) δ ppm 2.63 (s, 3H), 3.48 (t, J=4.2 Hz, 4H), 3.65 (t, J=4.2 Hz, 4H), 6.03 (s, 2H), 6.97 (d, J=7.8 Hz, 1H), 7.28 (s, 1H), 7.42 (t, J=7.5 Hz, 1H), 7.58-7.67 (m, 2H), 7.91 (d, J=7.8 Hz, 1H), 8.01 (d, J=7.8 Hz, 1H), 8.33 (d, J=7.8 Hz, 1H).
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:35](=[O:36])[N:13]3[C:14]([C:19]([O:21][CH:22]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[O:20])=[C:15]([OH:18])[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)C(C)C)C.[CH3:46][S:47](Cl)(=[O:49])=[O:48].O>C(#N)C>[C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:35](=[O:36])[N:13]3[C:14]([C:19]([O:21][CH:22]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[O:20])=[C:15]([O:18][S:47]([CH3:46])(=[O:49])=[O:48])[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(O)CS[C@H]12
Solvent: CC#N
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)OC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2SC1
Temperature: -40 °C
Yield: 94 %

Procedure:
Benzhydryl 7β-[(phenylacetyl)amino]-3-hydroxy-3-cephem-4-carboxylate (500 g, 1 mol) was dissolved in acetonitrile (2 L) and ethyldiisopropylamine (183 mL, 1.05 mol) was added dropwise over 10 min with stirring at −40° C. Then, methanesulfonyl chloride (86 mL, 1.1 mol) was added dropwise over 10 min and the mixture was stirred at −40° C. for 40 min. The reaction mixture was poured into iced water (8 L) and the precipitate was collected by filtration. The precipitate was washed with water (2 L) and ethyl acetate (300 mL) and dried under reduced pressure to give the title compound (544 g, 0.94 mol) as pale-yellow crystals. yield: 94%.
Reaction SMILES: CN(C=O)C.[CH3:6][C:7]1([CH2:12][C:13]([OH:15])=O)[O:11][CH2:10][CH2:9][O:8]1.S(Cl)(Cl)=O.[CH2:20]([O:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH:35]=[CH:36][C:37]3[NH:43][CH2:42][CH2:41][C:40]([C:44]([NH:46][C:47]4[CH:52]=[CH:51][C:50]([CH2:53][N:54]([CH3:61])[CH:55]5[CH2:60][O:59][CH2:58][CH2:57][CH2:56]5)=[CH:49][CH:48]=4)=[O:45])=[CH:39][C:38]=3[CH:62]=2)=[CH:30][CH:29]=1)[CH2:21][CH2:22][CH3:23]>O1CCCC1.N1C=CC=CC=1>[CH2:20]([O:24][CH2:25][CH2:26][O:27][C:28]1[CH:29]=[CH:30][C:31]([C:34]2[CH:35]=[CH:36][C:37]3[N:43]([C:13](=[O:15])[CH2:12][C:7]4([CH3:6])[O:8][CH2:9][CH2:10][O:11]4)[CH2:42][CH2:41][C:40]([C:44]([NH:46][C:47]4[CH:48]=[CH:49][C:50]([CH2:53][N:54]([CH3:61])[CH:55]5[CH2:60][O:59][CH2:58][CH2:57][CH2:56]5)=[CH:51][CH:52]=4)=[O:45])=[CH:39][C:38]=3[CH:62]=2)=[CH:32][CH:33]=1)[CH2:21][CH2:22][CH3:23]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCCOC4)cc2)CCN3)cc1
Reactant: CC1(CC(=O)O)OCCO1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCCOC4)cc2)CCN3C(=O)CC2(C)OCCO2)cc1
Reaction time: 1 h

Procedure:
One droplet of DMF was added to a solution of 2-methyldioxolane-2-ylacetic acid in tetrahydrofuran (10 ml). Then, thionyl chloride (80 mg) was added at 0° C., the temperature was returned to room temperature, and the mixture was stirred under nitrogen atmosphere for 1 hour. This solution was added to a solution of 7-(4-butoxyethoxyphenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-5-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (100 mg) and pyridine (528 mg) in tetrahydrofuran (20 ml) at 0° C. The mixture was stirred under nitrogen atmosphere at room temperature overnight, the insolubles were filtered off using Celite, to the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was separated and purified with silica gel column chromatography (methanol:ethyl acetate=1:3), which was recrystallized from hexane-ethyl acetate to give 7-(4-butoxyethoxyphenyl)-1-(2-(2-methyl-1,3-dioxolan-2-yl)acetyl]-N-[4-[[N-methyl-N-(tetrahydropyran-5-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 80) (60 mg) as colorless crystals.