Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[C:23]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]=2[C:14]([C:24]#[N:25])=[C:13]([N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[CH:12]=1.[H-].[Na+].C1C[O:37]CC1>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[C:23]2[C:22](=[O:37])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]=2[C:14]([C:24]#[N:25])=[C:13]([N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[CH:12]=1
Reactant: C1CCOC1
Reactant: N#Cc1c(N2CCCCC2)cc(-c2ccc3ccccc3c2)c2c1-c1ccccc1C2
Agent: [H-]
Agent: [Na+]
Product: N#Cc1c(N2CCCCC2)cc(-c2ccc3ccccc3c2)c2c1-c1ccccc1C2=O
Temperature: 2.5 °C

Procedure:
A solution of 1-(naphthalen-2-yl)-3-(piperidin-1-yl)-9H-fluorene-4-carbonitrile (400 mg) in THF was added sodium hydride (39 mg) and was stirred at 0-5° C. for less than five minutes. After completion, the reaction solvent was evaporated under vacuum and the crude solid obtained was quenched with ice water and subsequently neutralized by dilute HCl. The precipitate thus obtained was filtered and purified on a silica gel column using ethyl acetate-hexane as eluent. Yellow solid; mp 166-167° C.; ESIMS 415 (M++1); IR (KBr) 2218 (CN), 1712 cm−1 (CO); HRMS calcd. for C9H22N2O 414.1732. Found 414.1735.
Reaction SMILES: [N+:1]([C:4]1[C:12]2[NH:11][C:10]3[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C:9]=3[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[C:12]2[NH:11][C:10]3[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C:9]=3[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3c([N+](=O)[O-])cccc3c2C1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCc2[nH]c3c(N)cccc3c2C1
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 6-nitro-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (15.6 g, 49.15 mmol) in ethanol (250 mL) was added a spatula tip of 10% Pd/C. The reaction mixture was shaken under a hydrogen atmosphere (15 psi, Parr apparatus) for 2 h. Upon removal from the Parr apparatus, the reaction mixture was filtered through Celite. The Celite was washed with ethanol and the combined filtrates were concentrated in vacuo to give tert-butyl 6-amino-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate, quantitatively as a white solid: 1H NMR (CDCl3, 500 MHz) δ 1.42–1.67 (m, 9H), 2.74–2.85 (m, 2H), 3.58 (brs, 2H), 3.79 (brs, 2H), 4.60 (brs, 2H), 6.53–6.56 (m, 1H), 6.89–6.99 (m, 2H), 7.77 (brs, 1H) ppm.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([NH:14][C:15]3C=[CH:19][C:18](OC)=[CH:17][C:16]=3[CH3:23])=[CH:10][C:11]=2[CH3:13])[C:6](=[O:24])[CH:5]([C:25]([O:27]C)=[O:26])[C:4]1=[O:29])[CH3:2].[OH-].[Na+].C(#[N:34])C>O1CCOCC1.O>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([NH:14][C:15]3[C:16]([CH3:23])=[CH:17][CH:18]=[CH:19][N:34]=3)=[CH:10][C:11]=2[CH3:13])[C:6](=[O:24])[CH:5]([C:25]([OH:27])=[O:26])[C:4]1=[O:29])[CH3:2]
Reactant: CC#N
Reactant: CCN1C(=O)C(C(=O)OC)C(=O)c2cc(Nc3ccc(OC)cc3C)cc(C)c21
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCN1C(=O)C(C(=O)O)C(=O)c2cc(Nc3ncccc3C)cc(C)c21
Temperature: 60 °C

Procedure:
Methyl 1-ethyl-6-(4-methoxy-2-methylphenylamino)-8-methyl-4-oxo-1,4-dihydroquinolone-3-carboxylate (30 mg) was dissolved in 5 ml of dioxane, 2.5 equivalents of a 1 N NaOH solution were added, and the mixture was heated at 60° C. for 4 h. Removal of the solvent in vacuo was followed by chromatography on an HPLC system to purify the product. The pure product was isolated from the reaction solution by chromatography on an HPLC system. This entailed use of a Merck Purospher-RP18 column and an acetonitrile:water mixture as eluent; the initial acetonitrile content was 15% and rose to 95% over the course of 20 minutes.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]([C@@H:19]3[CH:24]4[CH2:25][CH2:26][N:21]([CH2:22][CH2:23]4)[CH2:20]3)=[O:18])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[C:27]1([CH2:33][S:34](Cl)(=[O:36])=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>N1C=CC=CC=1>[CH2:33]([S:34]([NH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17]([C@@H:19]3[CH:24]4[CH2:23][CH2:22][N:21]([CH2:26][CH2:25]4)[CH2:20]3)=[O:18])=[CH:14][CH:15]=2)=[CH:6][CH:5]=1)(=[O:36])=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Nc1ccc(-c2ccc(NC(=O)[C@H]3CN4CCC3CC4)cc2)cc1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(Nc1ccc(-c2ccc(NS(=O)(=O)Cc3ccccc3)cc2)cc1)[C@H]1CN2CCC1CC2

Procedure:
A solution of 80 mg (0.20 mmol) of ((3R)—N-(4′-aminobiphenyl-4-yl)quinuclidine-3-carboxamide dihydrochloride (Example 7A) and 77.4 mg (0.41 mmol) of phenylmethanesulfonyl chloride in 1.0 ml of pyridine is stirred at room temperature for 18 h. The reaction mixture is concentrated in vacuo and the residue is purified by preparative HPLC. The product fractions are concentrated, mixed with 3 ml of 1 N hydrochloric acid, again concentrated and dried under high vacuum. 34 mg (32.7% of theory) of the title compound are obtained.
Reaction SMILES: [CH3:1][CH2:2][O:3][P:4]([SH:9])([O:6][CH2:7][CH3:8])=[S:5].[Br:10][C:11]1[CH:12]=[C:13]([C:17](=[O:23])[CH:18]=[CH:19][C:20]([OH:22])=[O:21])[CH:14]=[CH:15][CH:16]=1>CC(C)=O>[Br:10][C:11]1[CH:12]=[C:13]([C:17](=[O:23])[CH:18]=[C:19]([S:5][P:4]([O:6][CH2:7][CH3:8])([O:3][CH2:2][CH3:1])=[S:9])[C:20]([OH:22])=[O:21])[CH:14]=[CH:15][CH:16]=1
Reactant: CCOP(=S)(S)OCC
Reactant: O=C(O)C=CC(=O)c1cccc(Br)c1
Solvent: CC(C)=O
Product: CCOP(=S)(OCC)SC(=CC(=O)c1cccc(Br)c1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.1 %

Procedure:
1.12 g (0.006 mole) of O,O-diethyldithiophosphoric acid were added dropwise to a solution of 1.28 g (0.005 mole) of 4-(3-bromophenyl)-4-oxo-2-butenoic acid in 20 ml of acetone, and then the mixture was stirred overnight at room temperature. At the end of this time, the solvent was distilled off and the residue was extracted with diethyl ether. The extract was washed with water and dried over anhydrous sodium sulphate, after which the solvent was distilled off. The residue was subjected to column chromatography through silica gel, eluted with a 4:1 by volume mixture of benzene and ethyl acetate. The resulting solid was recrystallised from a mixture of benzene and hexane, to give 1.54 g (yield 69.8%) of the desired 4-(3-bromophenyl)-2-diethoxyphosphinothioylthio-4-oxobutenoic acid, melting at 107°-111° C.
Reaction SMILES: [C:1]1([S:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([Cl:19])[CH:17]=3)[NH:12][C:11]=2[C:20]([OH:22])=O)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:23][N:24]1[C:28]([CH2:29][CH2:30][NH2:31])=[CH:27][N:26]=[CH:25]1>>[CH3:23][N:24]1[C:28]([CH2:29][CH2:30][NH:31][C:20]([C:11]2[NH:12][C:13]3[C:18]([C:10]=2[S:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:9])=[O:8])=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)=[O:22])=[CH:27][N:26]=[CH:25]1
Reactant: Cn1cncc1CCN
Reactant: O=C(O)c1[nH]c2ccc(Cl)cc2c1S(=O)(=O)c1ccccc1
Product: Cn1cncc1CCNC(=O)c1[nH]c2ccc(Cl)cc2c1S(=O)(=O)c1ccccc1

Procedure:
Reaction of 3-phenylsulfonyl-5-chloroindole-2-carboxylic acid with 3-methylhistamine under the conditions of Example 37 gave the title compound, mp 257°-258.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1I.[C:10]([Si](C)(C)C)#[CH:11].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>[Cu](I)I.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:10]#[CH:11]
Reactant: C#C[Si](C)(C)C
Reactant: Clc1ccc(Cl)c(I)c1
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Product: C#Cc1cc(Cl)ccc1Cl
Yield: 89.3 %

Procedure:
The title compound was prepared according to the procedure described in step-5 and step-6 of Intermediate-2 by using 1,4-dichloro-2-iodobenzene (1.0 g, 3.6 mmol), ethynyl(trimethyl)silane (0.541 g, 5.5 mmol), copper iodide (0.027 g, 0.14 mmol), bis(triphenylphosphine) palladium(II) chloride (0.050 g, 0.072 mmol), TBAF (catalytic) and DCM to afford 0.550 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 4.73 (s, 1H), 7.50 (d, J=8.7 Hz, 1H), 7.58 (d, J=8.7 Hz, 1H), 7.71 (s, 1H).
Reaction SMILES: [C:1]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[N:20][C:6]1=2)(=[O:4])[CH:2]=[CH2:3].[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>O1CCOCC1>[N:21]1([CH2:3][CH2:2][C:1]([N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:9](=[O:16])[NH:8][C:7]3[CH:17]=[CH:18][CH:19]=[N:20][C:6]2=3)=[O:4])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: C1CCNCC1
Reactant: C=CC(=O)N1c2ccccc2C(=O)Nc2cccnc21
Solvent: C1COCCO1
Product: O=C1Nc2cccnc2N(C(=O)CCN2CCCCC2)c2ccccc21

Procedure:
4.9 gm of 11-acryloyl-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one were after addition of 15 ml of piperidine, refluxed in 150 ml of dioxane for 2 hours. The solvent and excess amine were then distilled off in vacuo, and the residue was recrystallized from n-propanol.
Reaction SMILES: Cl.[CH3:2][C@H:3]1[N:8]([C:9]2[C:10]3[CH:17]=[CH:16][S:15][C:11]=3[N:12]=[CH:13][N:14]=2)[C@@H:7]([CH3:18])[CH2:6][N:5]([CH2:19][C:20]([OH:22])=O)[CH2:4]1.[NH2:23][C:24]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:25]=1[CH:26]=[CH:27][N:28]=[CH:29]2>>[CH3:18][C@H:7]1[N:8]([C:9]2[C:10]3[CH:17]=[CH:16][S:15][C:11]=3[N:12]=[CH:13][N:14]=2)[C@@H:3]([CH3:2])[CH2:4][N:5]([CH2:19][C:20]([NH:23][C:24]2[CH:33]=[CH:32][CH:31]=[C:30]3[C:25]=2[CH:26]=[CH:27][N:28]=[CH:29]3)=[O:22])[CH2:6]1
Reactant: Nc1cccc2cnccc12
Reactant: C[C@@H]1CN(CC(=O)O)C[C@H](C)N1c1ncnc2sccc12
Agent: Cl
Product: C[C@@H]1CN(CC(=O)Nc2cccc3cnccc23)C[C@H](C)N1c1ncnc2sccc12

Procedure:
The title product was prepared from the product of step (ii) (0.2 g) and 5-aminoisoquinoline (0.084 g) by the method of Example 8 step (v) as a white solid. Yield 0.11 g.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[H][H]>C(OCC)(=O)C.[Pd]>[NH2:11][C:8]1[CH:9]=[CH:10][C:2]([F:1])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1F
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc(F)c(C(=O)O)c1

Procedure:
One hundred eleven g of 2-fluoro-5-nitrobenzoic acid was dissloved in 1 liter of ethyl acetate. To this solution was added 5 g of 5 percent palladium on charcoal. The mixture was hydrogenated on a Parr apparatus for 24 hours at 20° C. at 50 psi of hydrogen. The theoretical amount of hydrogen was absorbed. The solution was filtered, then evaporated to dryness to provide a tan residue of 95.2 g of 5-amino-2-fluorobenzoic acid.
Reaction SMILES: C(OC[N:9]1[C:13]([CH2:14][O:15][C:16]2[C:17]([CH3:22])=[N:18][CH:19]=[CH:20][CH:21]=2)=[CH:12][N:11]=[N:10]1)(=O)C(C)(C)C.[OH-].[Na+].N1NN=C(COC2C=CC(N3C=NN=N3)=NC=2)C=1>>[NH:9]1[C:13]([CH2:14][O:15][C:16]2[C:17]([CH3:22])=[N:18][CH:19]=[CH:20][CH:21]=2)=[CH:12][N:11]=[N:10]1
Reactant: Cc1ncccc1OCc1cnnn1COC(=O)C(C)(C)C
Agent: [Na+]
Agent: [OH-]
Agent: c1cc(-n2cnnn2)ncc1OCc1cn[nH]n1
Product: Cc1ncccc1OCc1cnn[nH]1

Procedure:
The title compound was synthesized using (5-((2-methylpyridin-3-yloxy)methyl)-1H-1,2,3-triazol-1-yl)methyl pivalate and sodium hydroxide in a manner similar as that described in Intermediate 13, Step 4.
Reaction SMILES: [CH:1]([C:4]1[C:5]([C:30]([C:32]2[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=2)[CH:35]=O)=[O:31])=[N:6][C:7]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=[N:8][C:9]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)([CH3:3])[CH3:2].[C:40]([CH2:42]P(=O)(OCC)OCC)#[N:41].CC(C)([O-])C.[K+]>C1COCC1>[CH:1]([C:4]1[C:5]([C:30]([C:32]2[CH:33]=[C:34]([CH:35]=[CH:42][C:40]#[N:41])[CH:37]=[CH:38][CH:39]=2)=[O:31])=[N:6][C:7]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=[N:8][C:9]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc(COc2nc(OCc3ccc(OC)cc3)c(C(C)C)c(C(=O)c3cccc(C=O)c3)n2)cc1
Reactant: CCOP(=O)(CC#N)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(COc2nc(OCc3ccc(OC)cc3)c(C(C)C)c(C(=O)c3cccc(C=CC#N)c3)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.5 %

Procedure:
To a stirred mixture of 3-[5-isopropyl-2,6-bis-(4-methoxy-benzyloxy)-pyrimidine-4-carbonyl]-benzaldehyde (1.73 g, 3.22 mmol) and diethyl cyanomethylphosphonate (0.52 ml, 3.22 mmol) in anhydrous THF (10 ml) at 0° C. (ice bath) under nitrogen atmosphere, was added potassium t-butoxide (397 mg, 3.54 mmol). After 1 hr., the mixture was stirred for overnight at room temperature. The mixture was then partitioned between ether and water. The ether layer was taken, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo to give a pale yellow syrup. The crude product was purified by silica gel column chromatography (eluent, EA:hexanes (2:7)) to afford 1.46 g (81%) of a pale yellow syrup. 1H NMR (200 MHz, CDCl3) δ 1.19 (6H, d, J=7.0 Hz), 2.86 (1H, m), 3.82 (3H, s), 3.85 (3H, s), 5.31 (2H, s), 5.46 (2H, s), 5.93 (1H, d J=16.8 Hz), 6.81-6.97 (4H, m), 7.28-7.93 (8H, m).
Reaction SMILES: [C:1]([OH:5])(=O)[CH2:2][OH:3].[Cl:6][C:7]1[CH:8]=[C:9]([NH:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][C:30]=3[O:32][CH2:33][CH2:34][NH:35][CH:36]3[CH2:38][CH2:37]3)[N:25]=[CH:24][N:23]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1>>[Cl:6][C:7]1[CH:8]=[C:9]([NH:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][C:30]=3[O:32][CH2:33][CH2:34][N:35]([CH:36]3[CH2:38][CH2:37]3)[C:1](=[O:5])[CH2:2][OH:3])[N:25]=[CH:24][N:23]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1
Reactant: O=C(O)CO
Reactant: Clc1cc(Nc2ncnc3cccc(OCCNC4CC4)c23)ccc1OCc1ccccn1
Product: O=C(CO)N(CCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12)C1CC1
Yield: 19 %

Procedure:
The procedure described in Example 1 was repeated using glycolic acid and N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[2-(cyclopropylamino)ethoxy]quinazolin-4-amine (obtained as described in Example 13, preparation of starting materials) to give the title compound in 19% yield; NMR spectrum (DMSO-d6) 0.73-0.80 (m, 4H), 2.73-2.80 (m, 1H), 3.90 (t, 2H), 4.24 (s, 3H), 4.44 (t, 2H), 5.31 (s, 2H), 7.20 (d, 1H), 7.25 (d, 1H), 7.35 (d, 1H), 7.36-7.40 (m, 1H), 7.57-7.62 (m, 2H), 7.71-7.76 (m, 1H), 7.86-7.92 (m, 1H), 8.01 (d, 1H), 8.46 (s, 1H), 8.61 (d, 1H), 9.80 (s, 1H); Mass spectrum MH+ 520.
Reaction SMILES: CS(Cl)(=O)=O.[Cl:6][C:7]1[CH:11]=[C:10]([C:12]([OH:14])=O)[N:9]([C:15]2[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][N:16]=2)[N:8]=1.N1C=CC=CC=1.[NH2:28][C:29]1[C:37]([CH3:38])=[CH:36][C:35]([Cl:39])=[CH:34][C:30]=1[C:31](O)=[O:32]>C(#N)C.O>[Cl:39][C:35]1[CH:36]=[C:37]([CH3:38])[C:29]2[N:28]=[C:12]([C:10]3[N:9]([C:15]4[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][N:16]=4)[N:8]=[C:7]([Cl:6])[CH:11]=3)[O:14][C:31](=[O:32])[C:30]=2[CH:34]=1
Reactant: O=C(O)c1cc(Cl)nn1-c1ncccc1Cl
Reactant: Cc1cc(Cl)cc(C(=O)O)c1N
Agent: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: O
Solvent: CC#N
Product: Cc1cc(Cl)cc2c(=O)oc(-c3cc(Cl)nn3-c3ncccc3Cl)nc12
Temperature: -5 °C
Reaction time: 0.08 h

Procedure:
Methanesulfonyl chloride (1.0 mL, 1.5 g, 13 mmol) was dissolved in acetonitrile (10 mL), and the mixture was cooled to −5° C. A solution of 3-chloro-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid (i.e. the carboxylic acid product of Example 8, Step D) (2.58 g, 10 mmol) and pyridine (1.4 mL, 1.4 g, 17 mmol) in acetonitrile (10 mL) was added dropwise over 5 minutes at −5 to 0° C. A slurry formed during the addition. The mixture was stirred 5 minutes at this temperature, and then 2-amino-3-methyl-5-chlorobenzoic acid (i.e. the product from Example 6, Step A) (1.86 g, 10 mmol) was added all at once. Then a solution of pyridine (2.8 mL, 2.7 g, 35 mmol) in acetonitrile (10 mL) was added dropwise in 5 min at −5 to 0° C. The mixture was stirred 15 minutes at −5 to 0° C., and then methanesulfonyl chloride (1.0 mL, 1.5 mL, 13 mmol) in acetonitrile (5 mL) was added dropwise in 5 min at −5 to 0° C. The reaction mixture was stirred 15 minutes at this temperature, then allowed to warm slowly to room temperature, and stirred 4 h. Water (15 mL) was added dropwise, and the mixture was stirred 15 minutes. Then the mixture was filtered, and the solids were washed with 2:1 acetonitrile-water (3×3 mL), then with acetonitrile (2×2 mL), and dried under nitrogen to afford the title product as a pale yellow powder, 3.83 g (94.0% crude yield), melting at 199-201° C. HPLC of the product using a Zorbax® RX-C8 chromatography column (4.6 mm×25 cm, eluent 25-95% acetonitrile/pH 3 water) showed a major peak corresponding to the title compound and having 97.8% of total chromatogram peak area.
Reaction SMILES: C1(C([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:73])[C@@H:24]([NH:25][C:26](=[O:72])/[C:27](/[C:47]4[N:48]=[C:49]([NH:52]C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[S:50][CH:51]=4)=[N:28]\[O:29][CH2:30][C:31]([O:33]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:32])[C@H:21]3[S:20][CH2:19][C:18]=2[S:74][CH:75](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[S:76][C:77]2[N:78]=[N:79][NH:80][CH:81]=2)=[O:16])C2C=CC=CC=2)C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-].C(=O)([O-])O.[Na+:109]>C(O)=O.O.C1(OC)C=CC=CC=1.Cl>[Na+:109].[NH2:52][C:49]1[S:50][CH:51]=[C:47](/[C:27](=[N:28]/[O:29][CH2:30][C:31]([O:33][Na:109])=[O:32])/[C:26]([NH:25][C@@H:24]2[C:23](=[O:73])[N:22]3[C:17]([C:15]([O-:14])=[O:16])=[C:18]([S:74][CH2:75][S:76][C:77]4[N:78]=[N:79][NH:80][CH:81]=4)[CH2:19][S:20][C@H:21]23)=[O:72])[N:48]=1
Reactant: O=C(CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(SC(Sc3c[nH]nn3)C(c3ccccc3)(c3ccccc3)c3ccccc3)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1)OC(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Al+3]
Solvent: O=CO
Solvent: COc1ccccc1
Solvent: O
Product: Nc1nc(/C(=N/OCC(=O)O[Na])C(=O)N[C@@H]2C(=O)N3C(C(=O)[O-])=C(SCSc4c[nH]nn4)CS[C@H]23)cs1
Temperature: 25 °C
Reaction time: 3 h
Yield: 26 %

Procedure:
A solution of 7β-[(Z)-2-(2-tritylaminothiazol-4-yl)-2-(diphenylmethoxycarbonylmethoxyimino)acetamido]-3-(trityl-1,2,3-triazol-4-ylthio-methylthio)-3-cephem-4-carboxylic acid diphenylmethyl ester (1.04 g: 0.749 mMol.) in a mixture of 98% formic acid (16 ml) and water (0.8 ml) is stirred at room temperature for 3 hours. The reaction mixture is concentrated. The residue is washed with ether, filtered, end dried. To a solution of this residue in a mixture of anisole (2 ml) and nitro- methane (8 ml) at -40° C. is added a solution of aluminum chloride (0.50 g: 3.76 mMol.) in anisole (2 ml), and the mixture is stirred at -30° to -40° C. for 1 hour. The reaction mixture is diluted with 1N-hydrochloric acid (3.8 ml) and water, washed with ethyl acetate, and concentrated under reduced pressure to remove organic solvents. The remaining aqueous solution is subjected to chromatography over styrene-divinyl-benzene copolymer (methanol: water=4:1). The residue is washed with ethyl acetate and resulting powder is dissolved in dilute aqueous sodium hydrogen carbonate, and purified by chromatography over analytical styrene-divinylbenzene (water). The eluate is lyophilized and pulverized with ethyl acetate to give 7β-[(Z)-2-(2-aminothiazol-4-yl)-2-(sodiooxycarbonylmethoxyimino)acetamido]-3-(1,2,3-triazol-4-ylthiomethylthio)-3-cephem-4-carboxylic acid sodium salt (121 mg) as pale yellow white powder. Yield: 26%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([C@:8]2([CH3:19])[C:13]([F:15])([F:14])[C:12]([CH3:17])([CH3:16])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1.[CH:21]1([CH2:24][O:25][C:26]2[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][N:27]=2)[CH2:23][CH2:22]1>>[NH2:18][C:10]1[O:11][C:12]([CH3:16])([CH3:17])[C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:30](=[O:31])[C:29]3[CH:33]=[CH:34][C:26]([O:25][CH2:24][CH:21]4[CH2:22][CH2:23]4)=[N:27][CH:28]=3)[CH:3]=[CH:4][C:5]=2[F:20])([CH3:19])[N:9]=1
Reactant: CC1(C)OC(N)=N[C@](C)(c2cc(N)ccc2F)C1(F)F
Reactant: O=C(O)c1ccc(OCC2CC2)nc1
Product: CC1(C)OC(N)=N[C@](C)(c2cc(NC(=O)c3ccc(OCC4CC4)nc3)ccc2F)C1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4,6,6-trimethyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-2) and 6-cyclopropylmethoxy-nicotinic acid (CAS1019546-29-2, WO2008130320) following procedure I yielded the title compound as a light yellow solid. MS (ISP): m/z=463.2 [M+H]+.
Reaction SMILES: [C:1]([NH:8][C:9]([N:18]1[CH:22]=[CH:21]C=N1)=[N:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N)C[NH2:25]>C1COCC1>[C:11]([NH:10][C:9]([NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])=[N:18][CH2:22][CH2:21][NH2:25])([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12]
Reactant: NCCN
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)n1cccn1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(=NCCN)NC(=O)OC(C)(C)C

Procedure:
With continued reference to Scheme J, a solution of the N,N′-bis-(Boc)-1H-Pyrazole-1-carboxamidine (2 g, 6.45 mmol) in THF (50 ml) was added dropwise to ethylene diamine (4 ml, 59.6 mmol) in THF (100 ml). After 30 min of mixing at room temperature solvent was evaporated then toluene (100 ml) was added and evaporated in order to remove remaining traces of the ethylene diamine. The resulting product (Compound XXIV) was treated immediately according to scheme K since it decomposes at room temperature. 1H NMR (CDCl3, 400 MHz) δ 1.40-1.61 (m, 18H), 2.87-2.90 (t, 2H,), 3.47-3.50 (m, 2H), 6.31-6.34 (t, 0.61H), 7.61-7.62 (d, 1H), 8.45-8.66 (broad s).
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]2[N:19]=[C:18]([NH2:20])[C:17]([O:21]C)=[CH:16][N:15]=2)=[N:6]1.C(=O)([O-])[O-].[K+].[K+].Cl[C:34]1[CH:39]=[CH:38][N:37]=[CH:36][C:35]=1[C:40]([NH2:42])=[O:41]>CN(C)C=O>[F:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]2[N:19]=[C:18]([NH:20][C:34]3[CH:39]=[CH:38][N:37]=[CH:36][C:35]=3[C:40]([NH2:42])=[O:41])[C:17]([OH:21])=[CH:16][N:15]=2)=[N:6]1
Reactant: NC(=O)c1cnccc1Cl
Reactant: COc1cnc(-c2nn(Cc3ccccc3F)c3ccccc23)nc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)c1cnccc1Nc1nc(-c2nn(Cc3ccccc3F)c3ccccc23)ncc1O
Temperature: 100 °C
Reaction time: 48 h

Procedure:
25 mg of 4-amino-2-[1-(2-fluorobenzyl)-1H-indazol-3-yl]pyrimidin-5-ol (1-11-1, 0.075 mmol, 1. eq.) were dissolved in 1.5 ml of N,N-dimethylformamide. 51.52 mg of potassium carbonate (0.373 mmol, 5 eq.) and 23.35 mg of 4-chloropyridine-3-carboxamide (0.149 mmol, 2 eq.) were added. The reaction mixture was stirred at 100° C. bath temperature in a pressure pipe for 48 h ours. The reaction mixture was filtered off. The residue was purified by preparative HPLC to yield 2.07 mg (0.004 mmol, 5.6%) of the analytically pure target compound.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([C:10]#[C:11][C:12]2[S:13][C:14]3[CH:20]=[C:19]([O:21]C)[CH:18]=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:6][C:3]=1[NH:4][CH3:5].B(Br)(Br)Br.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:9]=[C:8]([C:10]#[C:11][C:12]2[S:13][C:14]3[CH:20]=[C:19]([OH:21])[CH:18]=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:6][C:3]=1[NH:4][CH3:5]
Reactant: CNc1ccc(C#Cc2nc3ccc(OC)cc3s2)cc1F
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CNc1ccc(C#Cc2nc3ccc(O)cc3s2)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 25 mL round bottomed flask equipped with a magnetic stir bar containing DCM (5.2 mL) was placed 8 (0.08 g, 0.26 mmol). The reaction mixture was cooled to O° C. and BBr3 (0.75 mL of 1M in DCM) was added drop wise. The reaction was stirred at RT for 8 hr. The reaction was then neutralized with sat. NaHCO3 and extracted into DCM (2×10 mL). The combined organic extracts were washed with water (10 mL), brine (10 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified over silica gel using EtOAc:Hexanes (1:3) as the eluent to afford W366 (0.02 g, 26%) as a brown solid. 1H NMR (400 MHz, DMSO-d6), δ: 2.5 (d, J=10.4 Hz, 3H), 6.06-6.08 (m, 1H), 6.42 (t, J=8.8 Hz, 1H), 6.74 (dd, J=8.8, 2.4 Hz, 1H), 7.05-7.14 (m, 2H), 7.54 (d, J=8.8, 1H), 9.76 (br s, 1H); MS (ESI): 299.0 (M+H+).