Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.[N+:16]([C:19]1[CH:24]=[C:23]([Cl:25])[C:22]([Cl:26])=[CH:21][C:20]=1[CH2:27][C:28]([N:30]([CH3:49])[C@@H:31]1[C:40]2[C:35](=[CH:36][CH:37]=[C:38]([N+:41]([O-:43])=[O:42])[CH:39]=2)CC[C@H:32]1[N:44]1[CH2:48][CH2:47][CH2:46][CH2:45]1)=[O:29])([O-:18])=[O:17].[N+](C1C=C([Cl:59])C(Cl)=CC=1CC(O)=O)([O-])=O.N1C=CC=CC=1.Cl.O(CC)CC.Cl>>[N+:16]([C:19]1[CH:24]=[C:23]([Cl:25])[C:22]([Cl:26])=[CH:21][C:20]=1[CH2:27][C:28]([N:30]([CH3:49])[C@@H:31]([C:40]1[CH:35]=[CH:36][CH:37]=[C:38]([N+:41]([O-:43])=[O:42])[CH:39]=1)[CH2:32][N:44]1[CH2:48][CH2:47][CH2:46][CH2:45]1)=[O:29])([O-:18])=[O:17].[ClH:59]
Reactant: O=C(O)Cc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Reactant: CN(C(=O)Cc1cc(Cl)c(Cl)cc1[N+](=O)[O-])[C@@H]1c2cc([N+](=O)[O-])ccc2CC[C@H]1N1CCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCC
Product: CN(C(=O)Cc1cc(Cl)c(Cl)cc1[N+](=O)[O-])[C@H](CN1CCCC1)c1cccc([N+](=O)[O-])c1

Procedure:
This compound was prepared via the general DCC/pyr coupling procedure from 8 (0.3690 g, 1.4801 mmol), 2-nitro-4,5-dichlorophenylacetic acid (0.7301 g, 2.920 mmol), DCC(0.6213 g, 3.01 mmol), and pyridine (0.24 mL, 3.01 mmol). The crude product was converted to the HCl salt with Et2O—HCl without chromatography and crystallized from MeOH to yield 13 HCl.(0.3232 g, 42%): m.p. (HCl salt) 165° C. (dec); 1H NMR (HCl salt, DMSO-d6) δ2.0 (br s, 4H, —CH2CH2—), 2.93 (s, 3H, —NCH3), 3.1-4.3 (complex, 6H, 3 —CH2—), 4.4 (s, 2H, benzylic methylene), 6.2 (m, 1H, —CH—), 7.7-7.8 (m, 2H, aromatic), 7.9 (s, 1H, aromatic), 8.14 (s, 1H, aromatic), 8.27 (d, J=7.7 Hz, 1H, aromatic), 8.43 (s, 1H, aromatic). MS(FAB) m/z 481. Anal. (C, H, N) C21H22N4O5Cl2 .HCl.0.5MeOH.
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].[CH2:13](Br)[CH:14]=[CH2:15]>>[CH2:15]([O:12][C:10]1[CH:9]=[CH:8][C:6]2[N:7]=[C:3]([C:1]#[N:2])[S:4][C:5]=2[CH:11]=1)[CH:14]=[CH2:13]
Reactant: N#Cc1nc2ccc(O)cc2s1
Reactant: C=CCBr
Product: C=CCOc1ccc2nc(C#N)sc2c1

Procedure:
In greater detail, 2-cyano-6-methoxybenzothiazole is used as a starting material and reacted with pyridine hydrochloride to yield 2-cyano-6-hydroxybenzothiazole. Next, the 2-cyano-6-hydroxybenzothiazole is reacted with allyl bromide to yield 6-allyloxy-benzothiazole-2-carbonitrile.
Reaction SMILES: C(OC([N:8]1[C:16]2[CH:15]=[C:14]([O:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[F:25])[C:13](=[O:26])[N:12]([CH3:27])[C:11]=2[C:10]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[Cl:34])=[N:9]1)=O)(C)(C)C.C[O-].[Na+]>CO>[Cl:34][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[C:10]1[C:11]2[N:12]([CH3:27])[C:13](=[O:26])[C:14]([O:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[F:25])=[CH:15][C:16]=2[NH:8][N:9]=1
Reactant: Cn1c(=O)c(Oc2ccc(F)cc2F)cc2c1c(-c1ccccc1Cl)nn2C(=O)OC(C)(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cn1c(=O)c(Oc2ccc(F)cc2F)cc2[nH]nc(-c3ccccc3Cl)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
A mixture of the crude 3-(2-chlorophenyl)-6-(2,4-difluorophenoxy)-4-methyl-5-oxo-4,5-dihydro-pyrazolo[4,3-b]pyridine-1-carboxylic acid tert-butyl ester (0.0298 mmol) in a solution of 0.5 M sodium methoxide in methanol (Aldrich) (7 mL) was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure at 55° C., and the resulting residue was diluted with ethyl acetate (35 mL) and water (25 mL). The organic layer was separated, washed with brine (1×25 mL), dried over magnesium sulfate, filtered, concentrated, and purified by Preparative Thin Layer Chromatography eluting with 60% ethyl acetate in hexanes to give the title compound (5.2 mg, (M+H)+=388) as a white powder.
Reaction SMILES: CS(O[C@@:6]1([CH3:44])[CH2:10][C@H:9]([S:11][C:12]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][N:7]1[C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=1)=[O:32])(=O)=O.[OH:45][CH2:46][C@@H:47]1[CH2:51][CH2:50][CH2:49][NH:48]1.C(N(CC)CC)C>CN(C)C=O>[OH:45][CH2:46][C@@H:47]1[CH2:51][CH2:50][CH2:49][N:48]1[CH2:44][C@@H:6]1[CH2:10][C@H:9]([S:11][C:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:8][N:7]1[C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=1)=[O:32]
Reactant: OC[C@@H]1CCCN1
Reactant: C[C@]1(OS(C)(=O)=O)C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CN1CCC[C@H]1CO
Temperature: 100 °C
Reaction time: 5 h
Yield: 65.1 %

Procedure:
To a solution of (2S,4S)-2-(methanesulfonyloxy)-methyl-1-(4-nitrobenzyloxycarbonyl)-4-(triphenylmethylthio)pyrrolidine (8.76 g) in dimethylformamide (80 ml) were added (2S)-2-(hydroxymethyl)pyrrolidine (8.72 g) and triethylamine (3.86 ml) and the mixture was stirred at 100° C. for 5 hours. The reaction mixture was poured into ice-water (300 ml) and extracted twice with ethyl acetate (200 ml). The extract was washed with saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated in vacuo. The resulting residue was chromatographed on silica gel (150 g) eluting with a mixture of dichloromethane and acetone (2:1, V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4S)-2-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]methyl-1-(4-nitrobenzyloxycarbonyl)-4-(triphenylmethylthio)pyrrolidine (5.75 g).
Reaction SMILES: C[Si]([Br:5])(C)C.[Cl:6][C:7]1[CH:8]=[C:9]([CH:12]=[C:13]([Cl:26])[C:14]=1[C:15]1[S:16][C:17]2[C:18](Cl)=[N:19][CH:20]=[C:21]([F:24])[C:22]=2[N:23]=1)[C:10]#[N:11].C([O-])(O)=O.[Na+]>C(#N)CC>[Br:5][C:18]1[C:17]2[S:16][C:15]([C:14]3[C:7]([Cl:6])=[CH:8][C:9]([C:10]#[N:11])=[CH:12][C:13]=3[Cl:26])=[N:23][C:22]=2[C:21]([F:24])=[CH:20][N:19]=1
Reactant: C[Si](C)(C)Br
Reactant: N#Cc1cc(Cl)c(-c2nc3c(F)cnc(Cl)c3s2)c(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCC#N
Product: N#Cc1cc(Cl)c(-c2nc3c(F)cnc(Br)c3s2)c(Cl)c1
Temperature: 85 °C
Reaction time: 48 h
Yield: 90.3 %

Procedure:
Trimethylsilyl bromide (0.14 mL, 1.08 mmol) was added to a solution of 3,5-dichloro-4-(4-chloro-7-fluorothiazolo[5,4-c]pyridin-2-yl)-benzonitrile (0.130 g, 0.36 mmol) in propionitrile (3 mL) at room temperature under a nitrogen atmosphere. The reaction mixture was heated at 85° C. for 18 hours then allowed to stand at room temperature for 48 hours. The resultant mixture was poured into an ice-cooled saturated solution of NaHCO3 and extracted with EtOAc (×2). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure to afford the title compound as an off-white solid (131 mg, 90% yield). 1H NMR (400 MHz, CDCl3): δ 8.42 (d, J=1.8 Hz, 1H), 7.78 (s, 2H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.C(N=C=NCCCN(C)C)C.[NH2:29][C:30]1[S:31][C:32]2[C:37]([N:38]=1)=[CH:36][CH:35]=[C:34]([C:39]1[CH:40]=[C:41]([CH:55]=[CH:56][CH:57]=1)[C:42]([NH:44][C:45]1[CH:50]=[CH:49][CH:48]=[C:47]([C:51]([F:54])([F:53])[F:52])[CH:46]=1)=[O:43])[N:33]=2.[F:58][C:59]([F:64])([F:63])[C:60]([OH:62])=[O:61]>CN(C)C1C=CN=CC=1.CN(C=O)C.C(OCC)(=O)C.ClCCl>[F:53][C:51]([F:52])([F:54])[C:47]1[CH:46]=[C:45]([NH:44][C:42]([C:41]2[CH:40]=[C:39]([C:34]3[N:33]=[C:32]4[S:31][C:30]([NH:29][C:14]([CH:11]5[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]5)=[O:16])=[N:38][C:37]4=[CH:36][CH:35]=3)[CH:57]=[CH:56][CH:55]=2)=[O:43])[CH:50]=[CH:49][CH:48]=1.[C:60]([OH:62])([C:59]([F:64])([F:63])[F:58])=[O:61]
Reactant: Nc1nc2ccc(-c3cccc(C(=O)Nc4cccc(C(F)(F)F)c4)c3)nc2s1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cccc(C(F)(F)F)c1)c1cccc(-c2ccc3nc(NC(=O)C4CCNCC4)sc3n2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (15 mg, 0.07 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (26 mg, 0.14 mmol), 4-dimethylaminopyridine (8 mg, 0.07 mmol) in DMF was added 3-(2-aminothiazolo[5,4-b]pyridin-5-yl)-N-(3-(trifluoromethyl)phenyl)benzamide (28 mg, 0.07 mmol). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with ethyl acetate (5 mL) and washed 1N aqueous HCl and brine. The organic layer was dried over MgSO4 and the solvent removed in vacuo. To a solution of the crude mixture in dichloromethane (1 mL) was added trifluoroacetic acid (30 μL, 0.34 mmol). The reaction mixture was stirred for 4 h. The majority of the organic solvent was removed in vacuo and the crude product was diluted with DMSO (1 mL) and purified by preparative HPLC to give title compound in a TFA salt form.
Reaction SMILES: [CH2:1]([C:8]1[S:9][CH:10]=[CH:11][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:13][C:14]1[N:19]=[CH:18][CH:17]=[CH:16][N:15]=1>>[CH2:1]([C:8]1[S:9][C:10]([C:16]2[CH:17]=[CH:18][N:19]=[C:14]([Cl:13])[N:15]=2)=[CH:11][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(Cc2cccs2)cc1
Reactant: Clc1ncccn1
Product: Clc1nccc(-c2ccc(Cc3ccccc3)s2)n1

Procedure:
The title compound was prepared from 2-benzylthiophene and 2-chloropyrimidine in a manner analogous to Example 255, Step 1. MS (M+H)+ 287.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH:15]=[C:14]([O:17][Si](C)(C)C)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[B-](F)(F)(F)[F:23].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C(#N)C.C(O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14](=[O:17])[CH:13]([F:23])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)OC1=CCN(C(=O)OCc2ccccc2)CC1
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Solvent: CCO
Product: O=C1CCN(C(=O)OCc2ccccc2)CC1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.2 %

Procedure:
To a stirred solution of 4-trimethylsilanyloxy-3,6-dihydro-2H-pyridine-1-carboxylic acid benzyl ester (5 g, 16.4 mmol) in acetonitrile at 0° C. was added 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane ditetrafluoroborate (6.4 g, 18 mmol). The solution was stirred overnight at room temperature, concentrated, diluted with EtOAc and washed with water. The organics were dried over sodium sulfate, filtered, concentrated, and purified by column chromatography using 40-60% EtOAc in hexanes to give 3-fluoro-4-oxo-piperidine-1-carboxylic acid benzyl ester (3.1 g) To a stirred solution of 3-fluoro-4-oxo-piperidine-1-carboxylic acid benzyl ester (500 mg, 2 mmol) in ethanol (6 mL) was added sodium borohydride (100 mg, 2.6 mmol). After 0.5 hr, the mixture was concentrated, diluted with EtOAc and washed with water. The organics were dried over sodium sulfate, filtered, concentrated, and purified by column chromatography using 40-70% EtOAc in hexanes to give (±)-trans-3-fluoro-4-hydroxy-piperidine-1-carboxylic acid benzyl ester (120 mg).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:8]([OH:10])=[O:9])=[C:5]([CH3:7])[N:6]=1.[Li]CCCC.[F:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[C:27]([CH:28]=[O:29])=[CH:26][O:25][N:24]=2)=[N:21][CH:22]=1>C1COCC1>[F:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[C:27]([CH:28]([OH:29])[CH2:1][C:2]3[S:3][C:4]([C:8]([OH:10])=[O:9])=[C:5]([CH3:7])[N:6]=3)=[CH:26][O:25][N:24]=2)=[N:21][CH:22]=1
Reactant: Cc1nc(C)c(C(=O)O)s1
Reactant: O=Cc1conc1-c1ccc(F)cn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1nc(CC(O)c2conc2-c2ccc(F)cn2)sc1C(=O)O
Temperature: 25 °C
Yield: 55.4 %

Procedure:
To a stirred solution of 2,4-dimethyl-thiazole-5-carboxylic acid (1.36 g, 8.63 mmol) in THF (72 mL) at −70° C. and under argon was added BuLi (1.6M in hexanes, 10.8 mL, 17.27 mmol) dropwise. After 2 h a solution of 3-(5-fluoro-pyridin-2-yl)-isoxazole-4-carbaldehyde (1.78 g, 8.63 mmol) in THF (26 mL) was added dropwise. After 1 h the reaction mixture was quenched with citric acid solution (5%, 55 mL) then warmed to room temperature and extracted with ethyl acetate. The combined extracts were washed with brine, water, dried over sodium sulfate, filtered and concentrated. Purification by recrystallization (ethyl acetate) afforded the title compound (1.67 g, 55%) as a light yellow solid. MS: m/e=348.2 [M−H]−.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:23])=[C:4]([CH:20]=[CH:21][CH:22]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([CH:16]=O)[CH:14]=2)[N:9]=[CH:8][N:7]=1.[CH3:24][N:25]([CH3:29])[CH2:26][CH2:27][NH2:28]>>[Cl:1][C:2]1[C:3]([F:23])=[C:4]([NH:5][C:6]2[C:15]3[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([CH2:16][NH:28][CH2:27][CH2:26][N:25]([CH3:29])[CH3:24])[CH:14]=3)[N:9]=[CH:8][N:7]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1C=O
Reactant: CN(C)CCN
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CNCCN(C)C

Procedure:
4-(3-Chloro-2-fluoroanilino)-7-methoxyquinazoline-6-carbaldehyde was coupled with N,N-dimethylethane-1,2-diamine using an analogous method to that described for the equivalent step in Example 1 to give N′-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)-N,N-dimethylethane-1,2-diamine; 1H NMR Spectrum: (DMSO-d6) 2.12 (s, 6H); 2.37 (t, 2H); 2.65 (t, 2H); 3.85 (s, 2H); 3.97 (s, 3H); 7.21 (s, 1H); 7.28 (t, 1H); 7.51 (m, 2H); 8.32 (s, 1H); 8.43 (s, 1H); 9.78 (s, 1H); Mass Spectrum: (M+H)+ 404.
Reaction SMILES: [C:1]([S:3][C:4]1[CH:5]=[C:6]([C:10]([O:12][CH3:13])=[O:11])[N:7]([CH3:9])[CH:8]=1)#N.CI.C[O-].[Na+]>CO>[CH3:13][O:12][C:10]([C:6]1[N:7]([CH3:9])[CH:8]=[C:4]([S:3][CH3:1])[CH:5]=1)=[O:11]
Reactant: COC(=O)c1cc(SC#N)cn1C
Agent: C[O-]
Agent: [Na+]
Solvent: CI
Solvent: CO
Product: COC(=O)c1cc(SC)cn1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.1 %

Procedure:
4-Cyanothio-2-methoxycarbonyl-1-methylpyrrole (2.8 g, 14.3 mmol) is dissolved in 50 ml of methanol under nitrogen. Methyliodide (1.25 ml, 20 mmol) is added followed by 1.08 g (20 mmole) of sodium methoxide. After stirring for about 30 minutes at room temperature, the reaction mixture is concentrated to a paste and then diluted with 100 ml of ethylether. The resulting precipitate is filtered off and the filtrate concentrated to give an oil which is distilled at 100° to 104° at 0.25 mm-Hg to afford 2.2 g (86%) of 2-methoxycarbonyl-4-methylthio-1-methylpyrrole.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[CH3:25][O:26][C:27]([C:29]1([CH2:35][NH2:36])[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1)=[O:28]>CO>[CH3:25][O:26][C:27]([C:29]1([CH2:35][NH:36][C:3]([C:5]2[N:6]=[C:7]([C:23]#[N:24])[C:8]3[C:13]([C:14]=2[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:9]=3)=[O:4])[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1)=[O:28]
Reactant: COC(=O)C1(CN)CCOCC1
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Solvent: CO
Product: COC(=O)C1(CNC(=O)c2nc(C#N)c3cc(Oc4ccccc4)ccc3c2O)CCOCC1

Procedure:
After a mixture of 1-cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (151 mg), 4-aminomethyl-tetrahydro-pyran-4-carboxylic acid methyl ester (205 mg; commercially available) in MeOH (2 mL) was microwaved at 150° C. for 500 min; cooled, concentrated, the residue was partitioned between EtOAc and diluted HCl solution, EtOAc phase was washed with water and diluted NaCl solution, dried over anhydrous sodium sulfate, filtered, concentrated and column purified to give product (154 mg). LC MS ESI+: 462 (M+1)+.
Reaction SMILES: IC1C2C(=NC=NC=2N)N(C(C)C)N=1.[CH:15]1([N:20]2[C:24]3=[N:25][CH:26]=[N:27][C:28]([NH2:29])=[C:23]3[C:22](I)=[N:21]2)[CH2:19][CH2:18][CH2:17][CH2:16]1.CC1(C)C(C)(C)OB([C:39]2[CH:51]=[CH:50][C:42]3[N:43]=[C:44]([NH:46][C:47](=[O:49])[CH3:48])[S:45][C:41]=3[CH:40]=2)O1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.CCO.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[NH2:29][C:28]1[N:27]=[CH:26][N:25]=[C:24]2[N:20]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[N:21]=[C:22]([C:39]3[CH:51]=[CH:50][C:42]4[N:43]=[C:44]([NH:46][C:47](=[O:49])[CH3:48])[S:45][C:41]=4[CH:40]=3)[C:23]=12
Reactant: Nc1ncnc2c1c(I)nn2C1CCCC1
Reactant: CC(=O)Nc1nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2s1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)n1nc(I)c2c(N)ncnc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCO
Product: CC(=O)Nc1nc2ccc(-c3nn(C4CCCC4)c4ncnc(N)c34)cc2s1
Temperature: 80 °C
Reaction time: 4 h
Yield: 35.9 %

Procedure:
A mixture of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (601 (1.21 g, 3.68 mmol), N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-yl)acetamide (I-5) (1.18 g, 3.71 mmol), Pd(OAc)2 (0.17 g, 0.75 mmol), triphenyl phosphine (0.59 g, 2.22 mmol) and Na2CO3 (1.98 g, 18.6 mmol) was dissolved in a mixture of DMF (3 mL), EtOH (1.5 mL) and H2O (1.5 mL). The resulting mixture was degassed and back-filled with argon three times and then stirred at 80° C. for 4 h. The mixture was allowed to cool to room temperature and filtered. The filtrate was concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel (200-300 mesh) eluting with DCM/MeOH (20/1) to give the desired product, N-(6-(4-amino-1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d]thiazol-2-yl)acetamide (602) (0.52 g, 35.9%) as an off-white solid. ESI-MS (M+H)+ m/z: 394.1.
Reaction SMILES: C([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][CH2:17][CH2:18][O:19][CH3:20])[C:9]=2[C:10]=1[CH3:11])=[O:5])C.[Li+].[OH-].Cl>O1CCCC1.CO>[CH3:20][O:19][CH2:18][CH2:17][CH2:16][C:12]1[C:9]2[C:10]([CH3:11])=[C:6]([C:4]([OH:5])=[O:3])[O:7][C:8]=2[CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)c1oc2cccc(CCCOC)c2c1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COCCCc1cccc2oc(C(=O)O)c(C)c12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 0.1 %

Procedure:
To a solution of 4-(3-methoxy-propyl)-3-methyl-benzofuran-2-carboxylic acid ethyl ester (2.213 g, 8.018 mol) in tetrahydrofuran (25 mL) and methanol (9 mL) at room temperature was added 1N LiOH (16.838 mL). The resulting yellow solution was stirred at room temperature for 2.5 hours, neutralized with 1N HCl and was then partitioned between ethyl acetate and water. The organic layer was dried over sodium sulfate, filtered and reduced to dryness furnishing 1.98 g (98%) of 4-(3-methoxy-propyl)-3-methyl-benzofuran-2-carboxylic acid as a white solid. MS (ES) m/z: 249.11214 (M+H)+, 497.21700 (2M+H).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[CH:11]=[CH:12][S:13][C:3]=12.[NH2:14][C@H:15]1[CH2:20][CH2:19][C@H:18]([CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:17][CH2:16]1.C(N(CC)CC)C>C(O)(C)C>[N+:8]([C:7]1[C:2]([NH:14][C@H:15]2[CH2:20][CH2:19][C@H:18]([CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:26])[CH3:28])[CH2:17][CH2:16]2)=[C:3]2[S:13][CH:12]=[CH:11][C:4]2=[N:5][CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cnc2ccsc2c1Cl
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](N)CC1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](Nc2c([N+](=O)[O-])cnc3ccsc23)CC1
Temperature: 90 °C

Procedure:
A mixture of 7-chloro-6-nitrothieno[3,2-b]pyridine (220 mg, 1.0 mmol), tert-butyl [(trans-4-aminocyclohexyl)methyl]carbamate (250 mg, 1.1 mmol) and triethylamine (0.43 mL, 3.1 mmol) in isopropyl alcohol (8 mL) was heated at 90° C. for 2 h. The solvent was removed and the resulting residue was purified by flash chromatography (0-80% EtOAc/Hexanes) to give the desired product (0.32 g, 77%). LCMS calculated for C19H27N4O4S (M+H)+: m/z=407.2. Found: 407.0.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:30]/[O:31][CH:32]([C:48]([O:50]C(C)(C)C)=[O:49])[S:33][C:34]2[CH:39]=[CH:38][C:37]([O:40]C(=O)C)=[C:36]([O:44]C(=O)C)[CH:35]=2)/[C:8]([NH:10][C@@H:11]2[C:28](=[O:29])[N:13]3[C:14]([C:25]([O-:27])=[O:26])=[C:15]([CH2:18][S:19][C:20]4[S:24][N:23]=[N:22][CH:21]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.C(=O)([O-])O.[Na+:59]>O>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:30]/[O:31][CH:32]([C:48]([OH:50])=[O:49])[S:33][C:34]2[CH:39]=[CH:38][C:37]([OH:40])=[C:36]([OH:44])[CH:35]=2)/[C:8]([NH:10][C@@H:11]2[C:28](=[O:29])[N:13]3[C:14]([C:25]([O-:27])=[O:26])=[C:15]([CH2:18][S:19][C:20]4[S:24][N:23]=[N:22][CH:21]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+:59].[Na+:59].[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:30]/[O:31][CH:32]([S:33][C:34]2[CH:39]=[CH:38][C:37]([OH:40])=[C:36]([OH:44])[CH:35]=2)[C:48]([OH:50])=[O:49])/[C:8]([NH:10][C@@H:11]2[C:28](=[O:29])[N:13]3[C:14]([C:25]([O-:27])=[O:26])=[C:15]([CH2:18][S:19][C:20]4[S:24][N:23]=[N:22][CH:21]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CC(=O)Oc1ccc(SC(O/N=C(\C(=O)N[C@@H]2C(=O)N3C(C(=O)[O-])=C(CSc4cnns4)CS[C@H]23)c2csc(N)n2)C(=O)OC(C)(C)C)cc1OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Nc1nc(/C(=N/OC(Sc2ccc(O)c(O)c2)C(=O)O)C(=O)N[C@@H]2C(=O)N3C(C(=O)[O-])=C(CSc4cnns4)CS[C@H]23)cs1
Reaction time: 2.5 h

Procedure:
950 mg of 7β-[(Z)-2-(2-amino-4-thiazolyl)-2-[[(R S)-(tert-butoxycarbonyl)(3,4-diacetoxyphenylthio)methoxy]imino]acetamido]-3-(1,2,3-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylate obtained from Example 22 was suspended in 30 ml of water, and saturated sodium hydrogen carbonate aqueous solution was added therein at the room temperature in order to make pH 8. After stirring for 2.5 hrs. at the room temperature, the aqueous solution was adsorbed on Diaion HP-20 and was eluted with water-methanol. The fraction containing the desired product was collected, concentrated and then, lyophilized to give 419 mg of disodium 7β-[(Z)-2-(2-amino-4-thiazolyl)-2-[[(R S)-(carboxy)(3,4-dihydroxyphenylthio)methoxy]imino]acetamido]-3-(1,2,3-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylate.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([OH:11])[CH:7]=[CH:6][CH:5]=2.S(C1C=CC([N+]([O-])=O)=CC=1)(O[CH2:16][C@H:17]1[O:19][CH2:18]1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>>[O:19]1[CH2:18][C@H:17]1[CH2:16][O:11][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[CH:10]=[C:2]([CH3:1])[NH:3]2
Reactant: Cc1cc2c(O)cccc2[nH]1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cc2c(OC[C@@H]3CO3)cccc2[nH]1
Yield: 50.7 %

Procedure:
Prepared from 2-methyl-4-hydroxyindole (5 g, 33 mmol), (S)-glycidyl nosylate (8.78 g, 33 mmol) and potassium carbonate (4.56 g, 33 mmol) according to the procedure used for Intermediate 1 to give 3.4 g product as a white solid.
Reaction SMILES: [C:1]([C:3]1[C:4]2[N:37](COCC[Si](C)(C)C)[CH:36]=[N:35][C:5]=2[C:6]([CH2:26][C:27]2[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:34])=[N:7][C:8]=1[NH:9][C:10]1[CH:23]=[CH:22][C:13]([C:14]([NH:16][CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])=[O:15])=[CH:12][C:11]=1[O:24][CH3:25])#[N:2].S(=O)(=O)(O)[OH:47]>O>[Cl:34][C:28]1[CH:29]=[CH:30][CH:31]=[C:32]([Cl:33])[C:27]=1[CH2:26][C:6]1[C:5]2[N:35]=[CH:36][NH:37][C:4]=2[C:3]([C:1]([NH2:2])=[O:47])=[C:8]([NH:9][C:10]2[CH:23]=[CH:22][C:13]([C:14](=[O:15])[NH:16][CH2:17][CH2:18][N:19]([CH3:20])[CH3:21])=[CH:12][C:11]=2[O:24][CH3:25])[N:7]=1
Reactant: COc1cc(C(=O)NCCN(C)C)ccc1Nc1nc(Cc2c(Cl)cccc2Cl)c2ncn(COCC[Si](C)(C)C)c2c1C#N
Reactant: O=S(=O)(O)O
Solvent: O
Product: COc1cc(C(=O)NCCN(C)C)ccc1Nc1nc(Cc2c(Cl)cccc2Cl)c2nc[nH]c2c1C(N)=O

Procedure:
A solution of the product of Example 31C (60 mg, 0.1 mmol) in concentrated sulfuric acid (3 mL) and water (0.5 mL) was stirred for 10 minutes at 0° C. and at 90° C. for 1.5 hours. The mixture was quenched with crushed ice and adjusted pH 9 with sodium bicarbonate solution. The precipitate was filtered off and the filtrate was extracted with 4/1 dichloromethane/methane (5×50 mL). The organic layers were collected, concentrated and purified by preparative HPLC using a gradient of 10/90 to 80/20 acetonitrile/water (containing 0.1% trifluoroacetic acid) to give the title compound. 1H NMR (DMSO-d6, 300 MHz): δ 12.2 (s, 1H), 9.59 (s, 1H), 9.38 (s, 1H), 8.58-8.62 (d, J=12 Hz, 2H), 7.88-7.92 (m, 2H), 7.59-7.62 (m, 2H), 7.39-7.47 (m, 2H), 7.06 (m, 2H), 4.75 (s, 2H), 3.89 (s, 3H), 3.58-3.60 (d, J=6 Hz, 2H), 3.25-3.27 (d, J=6 Hz, 2H), 3.88 (s, 6H). MS: 556 (M+H+).