Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][CH2:4][CH3:5])C.[Br:6][C:7]1[CH:12]=[CH:11]C(Br)=[CH:9][N:8]=1.C([Li])CCC.CN(C)C=O>O>[Br:6][C:7]1[N:8]=[CH:9][C:5]([CH:4]=[O:3])=[CH:11][CH:12]=1
Reactant: Brc1ccc(Br)nc1
Reactant: CCOCC
Agent: [Li]CCCC
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(Br)nc1
Temperature: -78 °C
Reaction time: 0.83 h
Yield: 66 %

Procedure:
To a diethyl ether (60 mL) solution of 2,5-dibromopyridine (3.00 g, 12.7 mmol) was added n-butyl lithium (7.99 mL, 1.6 M hexane solution, 12.7 mmol) under nitrogen atmosphere at −78° C., which was stirred for 50 minutes at −78° C. Then, N,N-dimethylformamide (1.18 mL, 15.2 mmol) was added to the mixture, which was stirred for 35 minutes while the temperature was raised to room temperature. Water was added to the reaction solution at room temperature, which was extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=3:1) to obtain the title compound (1.56 g, 66%).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([CH:8]=[O:9])=[C:5]([Br:7])[N:6]=1.[BH4-].[Na+].O>CO>[Br:1][C:2]1[S:3][C:4]([CH2:8][OH:9])=[C:5]([Br:7])[N:6]=1
Reactant: O=Cc1sc(Br)nc1Br
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OCc1sc(Br)nc1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.6 %

Procedure:
To a 0° C. solution of 2,4-dibromo-1,3-thiazole-5-carbaldehyde (3.38 g, 12.3 mmol) in anhydrous methanol (130 mL) was added sodium borohydride (600 mg, 15.9 mmol). The reaction mixture was stirred at room temperature for 3 hours. Water (100 mL) was added, and the mixture was evaporated. The resultant residue was extracted with EtOAc (3×100 mL). The organic extracts were combined, washed with brine (2×100 mL), dried over MgSO4, filtered, evaporated, and dried in vacuo, affording (2,4-dibromo-1,3-thiazol-5-yl)methanol (2.64 g, 77%). The product was used without further purification.
Reaction SMILES: C1C2C(COC(=O)[NH:17][C@H:18]([C:44]([OH:46])=O)[CH2:19][S:20][CH2:21][C@H:22]([O:34][C:35](=[O:43])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH2:23][O:24][C:25](=[O:33])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])C3C(=CC=CC=3)C=2C=CC=1.[NH2:48][CH2:49][CH2:50][O:51][CH2:52][CH2:53][O:54][CH2:55][CH2:56][O:57][CH2:58][CH2:59][P:60](=[O:67])([O:64]CC)[O:61]CC>>[NH2:17][C@@H:18]([CH2:19][S:20][CH2:21][C@H:22]([O:34][C:35](=[O:43])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH2:23][O:24][C:25](=[O:33])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:44](=[O:46])[NH:48][CH2:49][CH2:50][O:51][CH2:52][CH2:53][O:54][CH2:55][CH2:56][O:57][CH2:58][CH2:59][P:60](=[O:61])([OH:67])[OH:64]
Reactant: CCOP(=O)(CCOCCOCCOCCN)OCC
Reactant: CCCCCCCC(=O)OC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)OC(=O)CCCCCCC
Product: CCCCCCCC(=O)OC[C@H](CSC[C@H](N)C(=O)NCCOCCOCCOCCP(=O)(O)O)OC(=O)CCCCCCC

Procedure:
The title product was prepared from (5R,9R)-1-(9H-fluoren-9-yl)-9-(octanoyloxy)-3,12-dioxo-2,11-dioxa-7-thia-4-azanonadecane-5-carboxylic acid (1 eq) and diethyl 2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethylphosphonate (1.3 eq, from example 18, step 4) by following the procedure described for example 20, step 6-8. 1H NMR (DMSO-d6): δ 8.18 (t, 1H), 5.04-5.11 (m, 1H), 4.27 (dd, 1H), 4.10 (dd, 1H), 3.46-3.56 (m, 8H), 3.38-3.56 (m, 4H), 3.27-3.36 (m, 1H), 3.18-3.25 (m, 2H), 2.74-2.83 (m, 2H), 2.68 (dd, 1H), 2.57 (dd, 1H), 2.21-2.33 (m, 4H), 1.55-1.67 (m, 2H), 1.44-1.55 (m, 4H), 1.16-1.32 (m, 16H), 0.85 (t, 6H). LRMS [M+H]=687.4.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:15][CH2:14][CH2:13][O:12]2)=[C:7](Br)[N:6]=1)=[O:4].[Cl:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(Cl)Cl.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:15][CH2:14][CH2:13][O:12]2)=[C:7]([C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:17])[CH:23]=2)[N:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(C2CCCO2)c(Br)n1
Reactant: OB(O)c1cccc(Cl)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C2CCCO2)c(-c2cccc(Cl)c2)n1
Yield: 94.4 %

Procedure:
A solution of 6-bromo-5-(tetrahydrofuran-2-yl)-pyridine-2-carboxylic acid methyl ester (mixture of example 101d, 0.296 g, 1 mmol), 3-chlorophenylboronic acid (CAN 63503-60-6, 0.24 g, 1.5 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride methylene chloride complex (CAN 95464-05-4, 34 mg) and cesium carbonate (CAN 534-17-8, 1 g, 3 mmol) in DMF (10 mL) was stirred overnight at 80° C. under a nitrogen atmosphere. After filtration, the reaction mixture was poured into 20 mL H2O and washed with ethyl acetate (2×20 mL). The organic layer was concentrated under reduced pressure to provide the title compound (0.3 g, 91%) as black oil which was used in the next step without further purification; MS (EI): m/e=318.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([CH3:6])([C:4]#[CH:5])[OH:3].P(=O)(O)(O)O.[C:12](OC(=O)C)(=[O:14])[CH3:13]>C(OC(=O)C)(=O)C.CO>[C:12]([O:3][C:2]([CH3:6])([CH3:1])[C:4]#[CH:5])(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: C#CC(C)(C)O
Agent: O=P(O)(O)O
Solvent: CO
Product: C#CC(C)(C)OC(C)=O
Reaction time: 8 h

Procedure:
112 g (one mole) of freshly distilled dimethylethynyl carbinol is treated with 1.2 moles of acetic anhydride containing 10 drops of 85% phosphoric acid. The acetic anhydride is added to the carbinol dropwise with shaking while maintaining the temperature under 40°. The mixture is allowed to stand overnight, washed with two 75 ml portions of cold water, and the water washings are extracted with ether. The ether extract is added to the main portion of ester and the combined ethereal solution is washed with 10% sodium carbonate solution until the washings remain basic to litmus. The solution is washed with two 75 ml portions of ice-water, dried over calcium chloride, and distilled to give the title compound.
Reaction SMILES: C([O:3][C:4](=[O:20])[C:5](=[O:19])[CH2:6][C:7]([C:10]1[CH:15]=[C:14]([Br:16])[CH:13]=[CH:12][C:11]=1[O:17][CH3:18])([CH3:9])[CH3:8])C>CO.[OH-].[Na+]>[Br:16][C:14]1[CH:13]=[CH:12][C:11]([O:17][CH3:18])=[C:10]([C:7]([CH3:9])([CH3:8])[CH2:6][C:5](=[O:19])[C:4]([OH:20])=[O:3])[CH:15]=1
Reactant: CCOC(=O)C(=O)CC(C)(C)c1cc(Br)ccc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(Br)cc1C(C)(C)CC(=O)C(=O)O

Procedure:
4-(5-Bromo-2-methoxyphenyl)-4-methyl-2-oxopentanoic acid-ethyl ester in 30 ml of methanol and 12 ml of 1 M sodium hydroxide solution are stirred for 1 hour at room temperature, and the methanol is distilled off. It is mixed with water and hexane, the water phase is acidified with dilute hydrochloric acid while being cooled with ice, and it is mixed with ethyl acetate. The ethyl acetate phase is washed with water, dried (Na2SO4) and concentrated by evaporation. After crystallization from hexane, 1.8 g of 4-(5-bromo-2-methoxyphenyl)-4-methyl-2-oxopentanoic acid is obtained. Flash point: 80° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]2([C:16]3=[CH:17][C:18]4[O:22][CH2:21][O:20][C:19]=4[CH:23]=[C:15]3[O:14][CH2:13]2)[C:5]1=[O:24].[NH:25]1[CH2:30][CH2:29][CH:28](CN2C3C(=CC=CC=3)C3(C4=CC5OCOC=5C=C4OC3)C2=O)[CH2:27][CH2:26]1.BrC1C=CC=CN=1.BrC1C=CC=CC=1>>[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:1][CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]2([C:16]3=[CH:17][C:18]4[O:22][CH2:21][O:20][C:19]=4[CH:23]=[C:15]3[O:14][CH2:13]2)[C:5]1=[O:24]
Reactant: NCCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21
Reactant: O=C1N(CC2CCNCC2)c2ccccc2C12COc1cc3c(cc12)OCO3
Agent: Brc1ccccn1
Solvent: Brc1ccccc1
Product: O=C1N(CCNc2ccccn2)c2ccccc2C12COc1cc3c(cc12)OCO3

Procedure:
Following the procedure described in EXAMPLE 10.87, and making non-critical variations using 1′-(2-aminoethyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 1′-(piperidin-4-ylmethyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and 2-bromopyridine to replace 2-bromobenzene, 1′-(2-(pyridin-2-ylamino)ethyl)-spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one was obtained as the first fraction from the chromatography as a white solid (5%): mp 61-63° C.; 1H NMR (300 MHz, CDCl3) δ 8.05 (d, 1H), 7.50-6.97 (m, 5H), 6.57 (dd, 1H), 6.50 (s, 1H), 6.38 (d, 1H), 6.03 (s, 1H), 5.85 (s, 1H), 5.84 (s, 1H), 4.84 (d, 1H), 4.79 (t, 1H), 4.60 (d, 1H), 4.15-3.94 (m, 2H), 3.81-3.64 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 178.4, 158.2, 156.0, 149.0, 148.0, 142.4, 142.38, 137.4, 132.3, 129.1, 124.0, 123.5, 119.5, 113.3, 109.0, 108.3, 103.2, 101.6, 93.7, 80.5, 58.3, 40.1, 39.9; MS (ES+) m/z 402 (M+1). 1′-(2-(dipyridin-2-ylamino)ethyl)-spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one was obtained as the second fraction from the chromatography (31%): mp 165-167° C.; 1H NMR (300 MHz, CDCl3) δ 8.31 (dd, 2H), 7.48 (d, 2H), 7.23 (t, 1H), 7.09-6.83 (m, 7H), 6.47 (s, 1H), 5.95 (s, 1H), 5.88-5.81(m, 2H), 4.73 (d, 1H), 4.67-4.49(m, 2H), 4.46 (d, 1H), 4.20 (t, 2H); 13C NMR(75 MHz, CDCl3) δ 177.6, 157.0, 156.0, 148.8, 148.4, 143.1, 142.3, 137.4, 132.3, 128.9, 123.6, 123.1, 119.6, 117.5, 114.5, 109.3, 103.4, 101.6, 93.6, 80.7, 58.2, 45.9, 39.5; MS (ES+) m/z 479 (M+1).
Reaction SMILES: Cl[C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[F:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[C:12]=1B(O)O>>[F:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[C:12]=1[C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: OB(O)c1c(F)cc(F)cc1F
Reactant: N#Cc1cccnc1Cl
Product: N#Cc1cccnc1-c1c(F)cc(F)cc1F
Yield: 82 %

Procedure:
Prepared in 82% yield from 2-chloronicotinonitrile and 2,4,6-trifluorophenylboronic acid according to the procedure described for Example 153A. MS (ESI+) m/z 235.0 (M+H)+; 1H NMR (CDCl3) δ 6.83-6.88 m, 2H), 7.51 (dd, J=8.0, 4.9 Hz, 1H), 8.12 (dd, J=8.1, 1.7 Hz, 1H), 8.94 (dd, J=5.1, 1.7 Hz, 1H).
Reaction SMILES: [C:1]1([N:7]([CH2:11][C:12]([O:14]CC)=[O:13])[CH2:8][CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)C.[OH-].[Na+]>[C:1]1([N:7]([CH2:11][C:12]([OH:14])=[O:13])[CH2:8][CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCN(CC(=O)OCC)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCN(CC(=O)O)c1ccccc1
Reaction time: 0.17 h
Yield: 67.8 %

Procedure:
To a solution of the product obtained in EXAMPLE 108 (5.0 g) in ethanol (30 ml), 3N aqueous sodium hydroxide (30 ml) was added and the mixture was stirred for 10 minutes under reflux. The aqueous solution was concentrated under reduced pressure and washed with ether, acidified to pH 3 with 2N hydrochloric acid and extracted four times with ethyl acetate. The combined organic layer was washed with saturated sodium chloride, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was crystallized from ethyl acetate-hexane to give 2.96 g (68%) of the objective compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8].C([Li])CCC.[CH2:14]([Sn:18](Cl)([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15][CH2:16][CH3:17]>O1CCCC1.CCCCCC>[CH2:23]([Sn:18]([CH2:14][CH2:15][CH2:16][CH3:17])([CH2:19][CH2:20][CH2:21][CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8])[CH2:24][CH2:25][CH3:26]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Cc1ccccc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCC[Sn](CCCC)(CCCC)c1ccccc1C
Reaction time: 0.5 h
Yield: 92.4 %

Procedure:
To a stirred solution of 3.4 g of 2-bromotoluene in 100 ml of dry tetrahydrofuran at -78° C. is slowly added 8 ml of 2.5M butyl lithium in hexane. The reaction mixture is stirred for 30 minutes and 6.5 g of tri-n-butyl tin chloride in 25 ml of tetrahydrofuran added. The reaction mixture is stirred an additional 1 hour, quenched with water and extracted with ether. The ether extract is dried over Na2SO4, filtered and the filtrate evaporated in vacuo to give 7.0 g of a residue. Mass spectrum: M+H:381.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:20][O:21][C:22]2[CH:23]=[C:24]3[N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29][N:25]3[C:26](=[O:28])[N:27]=2)[CH:6]=[N:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=1)#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:28]=[C:26]1[N:25]2[CH2:29][CH2:30][NH:31][C:24]2=[CH:23][C:22]([O:21][CH2:20][C:5]2[CH:6]=[N:7][C:8]([O:9][C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:17])([F:18])[F:19])[CH:11]=3)=[C:3]([CH:4]=2)[C:1]#[N:2])=[N:27]1
Reactant: CC(C)(C)OC(=O)N1CCn2c1cc(OCc1cnc(Oc3cccc(C(F)(F)F)c3)c(C#N)c1)nc2=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(COc2cc3n(c(=O)n2)CCN3)cnc1Oc1cccc(C(F)(F)F)c1

Procedure:
Prepared in a manner similar to that described for E60 using tert-butyl 7-((5-cyano-6-(3-(trifluoromethyl)phenoxy)pyridin-3-yl)methoxy)-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate (120 mg, 0.227 mmol) in DCM (4 mL) and TFA (0.873 mL, 11.3 mmol).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]([O:17][CH3:18])=[C:14]([NH2:16])[CH:15]=1.[N:19]([C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH2:31])(=[O:30])=[O:29])=[CH:24][CH:23]=1)=[C:20]=[S:21]>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]([O:17][CH3:18])=[C:14]([NH:16][C:20](=[S:21])[NH:19][C:22]2[CH:27]=[CH:26][C:25]([S:28]([NH2:31])(=[O:29])=[O:30])=[CH:24][CH:23]=2)[CH:15]=1
Reactant: COc1ccc(-c2cc3ccccc3[nH]2)cc1N
Reactant: NS(=O)(=O)c1ccc(N=C=S)cc1
Product: COc1ccc(-c2cc3ccccc3[nH]2)cc1NC(=S)Nc1ccc(S(N)(=O)=O)cc1

Procedure:
The product from Example 1, Step B, 5-(1H-indol-2-yl)-2-methoxy-phenylamine (0.12 g, 0.1 mmol) was reacted with 4-isothiocyanatobenzene sulfonamide (0.108 g, 0.1 mmol) according to the procedure for Example 2 to give the product (0.14 g).
Reaction SMILES: [C:1]([O:5][C:6]1[CH:11]=[C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[N:14](S(C3C=CC=CC=3)(=O)=O)[CH:13]=2)[CH:9]=[C:8]([Cl:30])[N:7]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[K+]>C(O)C.O>[C:1]([O:5][C:6]1[CH:11]=[C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH:9]=[C:8]([Cl:30])[N:7]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)Oc1cc(-c2cn(S(=O)(=O)c3ccccc3)c3ncccc23)cc(Cl)n1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)Oc1cc(-c2c[nH]c3ncccc23)cc(Cl)n1
Temperature: 50 °C

Procedure:
To a suspension of EXAMPLE 34B (2.15 g, 4.87 mmol) in 60 mL ethanol/water (5:1) was added powdered potassium hydroxide (1.09 g, 19.46 mmol). The suspension was heated at 50° C. for 3 hours, at which time the reaction was homogeneous. The solvent was removed and the crude material was dissolved in ethyl acetate, washed with water, and brine, dried over magnesium sulfate, filtered and concentrated. The crude material was purified by flash chromatography (Analogix280, gradient elution, 20-100% ethyl acetate/hexane) to give the title compound. MS (ESI) m/e 301.9 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH3:14]>>[Cl:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:14])=[O:5]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1Cl
Reactant: N
Product: NC(=O)c1ccc([N+](=O)[O-])cc1Cl
Yield: 90 %

Procedure:
Thereafter, 2-chloro-4-nitrobenzoyl chloride (460 g, 2.1 m) was added dropwise to a stirred 28% ammonia solution (2000 ml) at between 10° and 15° C. The precipitate was washed with water and 30% methanol and then dried to yield 2-chloro-4-nitrobenzamide (379 g, 90%, mp 168°-170° C.).
Reaction SMILES: C(N1CCN(C2C=CC(N)=CC=2C)CC1)(=O)C.[Cl:18][C:19]1[C:20]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[N:21][CH:22]=[C:23]([N+:25]([O-])=O)[CH:24]=1>>[Cl:18][C:19]1[CH:24]=[C:23]([NH2:25])[CH:22]=[N:21][C:20]=1[N:28]1[CH2:29][CH2:30][O:31][CH2:32][CH2:33]1
Reactant: O=[N+]([O-])c1cnc(N2CCOCC2)c(Cl)c1
Agent: CC(=O)N1CCN(c2ccc(N)cc2C)CC1
Product: Nc1cnc(N2CCOCC2)c(Cl)c1

Procedure:
The title compound was prepared by the general procedure of Intermediate 36 using 4-(3-chloro-5-nitro-pyridin-2-yl)-morpholine.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]=[C:7]=[O:8].[NH2:9][C:10]([CH3:18])([CH3:17])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]>C(Cl)Cl>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]([NH:9][C:10]([CH3:18])([CH3:17])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:8]
Reactant: CCOC(=O)CC(C)(C)N
Reactant: O=C=NCCCCBr
Solvent: ClCCl
Product: CCOC(=O)CC(C)(C)NC(=O)NCCCCBr
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
A solution of 4-bromobutylisocyanate (15.1 g) in methylene chloride (50 ml) is added to a stirred solution of ethyl 3-amino-3-methylbutanoate (12.3 g), dissolved in methylene chloride (50 ml) at -20° C. The mixture is stirred for 30 minutes at -20° C. and then for an additional 2 hours at room temperature. Evaporation of the solvent yields a residue of ethyl 3-[(4-bromobutyl)aminocarbonylamino]-3-methylbutanoate (26 g).
Reaction SMILES: [CH:1]1([O:6][N:7]=[C:8]([C:35]2[N:36]=[C:37]([NH:40]C=O)[S:38][CH:39]=2)[C:9]([NH:11][CH:12]2[C:33](=[O:34])[N:14]3[C:15]([C:30]([OH:32])=[O:31])=[C:16]([CH2:19][S:20][C:21]4[CH:22]=[CH:23][C:24]5[N:25]([N:27]=[N:28][N:29]=5)[N:26]=4)[CH2:17][S:18][C@H:13]23)=[O:10])[CH2:5][CH2:4][CH:3]=[CH:2]1.Cl.O1CCCC1.C(=O)(O)[O-].[Na+]>CO.O.C(OCC)(=O)C>[CH:1]1([O:6][N:7]=[C:8]([C:35]2[N:36]=[C:37]([NH2:40])[S:38][CH:39]=2)[C:9]([NH:11][CH:12]2[C:33](=[O:34])[N:14]3[C:15]([C:30]([OH:32])=[O:31])=[C:16]([CH2:19][S:20][C:21]4[CH:22]=[CH:23][C:24]5[N:25]([N:27]=[N:28][N:29]=5)[N:26]=4)[CH2:17][S:18][C@H:13]23)=[O:10])[CH2:5][CH2:4][CH:3]=[CH:2]1
Reactant: O=CNc1nc(C(=NOC2C=CCC2)C(=O)NC2C(=O)N3C(C(=O)O)=C(CSc4ccc5nnnn5n4)CS[C@H]23)cs1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1nc(C(=NOC2C=CCC2)C(=O)NC2C(=O)N3C(C(=O)O)=C(CSc4ccc5nnnn5n4)CS[C@H]23)cs1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 61.6 %

Procedure:
A suspension of 7-[2-(2-cyclopenten-1-yl)oxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(tetrazolo[1,5-b]pyridazin-6-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer)(1.7 g) in methanol (12.0 ml) and conc.hydrochloric acid (0.56 g) was stirred and then thereto was added tetrahydrofuran (12.0 ml) to give a homogenous solution, which was stirred for 2 hours and 50 minutes at room temperature. To the reaction mixture were added water and sodium bicarbonate so that the pH was adjusted to 5.0. After the concentration of the mixture, to the concentrate were added ethyl acetate, water and sodium bicarbonate so that the pH was adjusted to 7.5. The aqueous layer was separated, washed with ethyl acetate (×2), concentrated and adjusted to pH 3.0 with 10% hydrochloric acid. The precipitates were collected by filtration, washed with water, dried over phosphorus pentoxide under reduced pressure to give 7-[2-(2-cyclopenten-1-yl)oxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(tetrazolo[1,5-b]pyridazin- 6-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer)(1.00 g). mp. 178° to 180° C. (dec.).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]2[CH:6]=[CH:7][O:8][C:4]=2[CH:3]=1.[C:11]([O:15][CH2:16][CH3:17])(=[O:14])[CH:12]=[CH2:13].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C([O-])(=O)C.[Na+]>CN(C=O)C.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:16]([O:15][C:11](=[O:14])[C:12]([C:2]1[CH:10]=[CH:9][C:5]2[CH:6]=[CH:7][O:8][C:4]=2[CH:3]=1)=[CH2:13])[CH3:17]
Reactant: C=CC(=O)OCC
Reactant: Brc1ccc2ccoc2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: O
Product: C=C(C(=O)OCC)c1ccc2ccoc2c1
Temperature: 100 °C

Procedure:
A mixture of the 6-bromobenzofuran 15-3 (1.74 g, 8.79 mmol), ethyl acrylate (1.09 g, 10.98 mmol), Pd(OAc)2 (0.099 g, 0.44 mmol), tri-o-tolylphosphine (0.268 g, 0.880 mmol), and sodium acetate (3.60 g, 43.9 mmol) in DMF (10 mL) was heated to 100° C. in a sealed tube for 4 h. The mixture was cooled to room temperature, diluted with water, and extracted with Et20 (2×40 mL). The combined organic extracts were washed with brine (30 mL), dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography (10% ethyl acetate/hexanes) to give the ester 15-4 as an off-white solid.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([NH2:11])[C:8]([O:12][CH3:13])=[C:7]2[C:3]=1[C:4]1[CH:17]=[C:16]([CH3:18])[CH:15]=[N:14][C:5]=1[NH:6]2.[CH2:19]([S:21]([C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1)(=[O:23])=[O:22])[CH3:20].O1CCOCC1.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:19]([S:21]([C:24]1[CH:29]=[C:28]([C:2]2[CH:10]=[C:9]([NH2:11])[C:8]([O:12][CH3:13])=[C:7]3[C:3]=2[C:4]2[CH:17]=[C:16]([CH3:18])[CH:15]=[N:14][C:5]=2[NH:6]3)[CH:27]=[CH:26][CH:25]=1)(=[O:22])=[O:23])[CH3:20]
Reactant: COc1c(N)cc(Br)c2c1[nH]c1ncc(C)cc12
Reactant: CCS(=O)(=O)c1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCS(=O)(=O)c1cccc(-c2cc(N)c(OC)c3[nH]c4ncc(C)cc4c23)c1
Temperature: 140 °C
Yield: 81.9 %

Procedure:
A 5 mL microwave vial was charged with Compound 238 (500 mg, 1.63 mmol), 3-(ethylsulfonyl)phenylboronic acid (419 mg, 1.96 mmol) and Pd(PPh3)4 (188 mg, 0.16 mmol). To the mixture was added dioxane (5 mL) and a saturated aqueous solution of K2CO3 (2.5 mL). The reaction mixture was heated at 140° C. for 20 min. in microwave. The reaction was diluted with EtOAc and washed with aqueous water and brine. The organic extracts were dried (Na2SO4) and concentrated and purified by flash chromatography to yield the title compound (528 mg, 82%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:18])[C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[N:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[Cl:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=1>>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]([NH:9][C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([NH:1][C:24](=[O:25])[C:23]3[CH:27]=[CH:28][C:20]([Cl:19])=[CH:21][CH:22]=3)[CH:3]=2)=[O:18])=[CH:12][N:13]=1
Reactant: O=C(O)c1ccc(Cl)cc1
Reactant: Nc1cc(NC(=O)c2ccc(Cl)nc2)ccc1Cl
Product: O=C(Nc1ccc(Cl)c(NC(=O)c2ccc(Cl)cc2)c1)c1ccc(Cl)nc1

Procedure:
N-(3-amino-4-chlorophenyl)-6-chloronicotinamide (0.71 mmol) was used in general procedure 2 with 4-chlorobenzoic acid (0.78 mmol). The product was purified by RP-HPLC to give 6-chloro-N-(4-chloro-3-(4-chlorobenzamido)phenyl)nicotinamide. MS (Q1) 419.8 (M)+
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[C:8]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:17]>>[CH3:17][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([N+:14]([O-:16])=[O:15])[C:8]=1[N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: Cc1cccc([N+](=O)[O-])c1Br
Reactant: C1CNCCN1
Product: Cc1cccc([N+](=O)[O-])c1N1CCNCC1

Procedure:
1-(2-Methyl-6-nitrophenyl]piperazine was prepared in a manner similar to Preparation 1A except that piperazine was coupled to 2-bromo-1-methyl-3-nitro-benzene. LRMS (ESI+): 222.4 (M+1)