Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5](OB(O)O)=[C:4]([O:13][CH3:14])[CH:3]=1.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-].Br[C:27]1[N:32]2[N:33]=[C:34]([CH2:39][CH3:40])[C:35]([N+:36]([O-:38])=[O:37])=[C:31]2[C:30]([O:41][CH3:42])=[CH:29][CH:28]=1>C(OCCOCC)C.O>[CH2:39]([C:34]1[C:35]([N+:36]([O-:38])=[O:37])=[C:31]2[C:30]([O:41][CH3:42])=[CH:29][CH:28]=[C:27]([C:5]3[C:6]([CH3:8])=[CH:7][C:2]([CH3:1])=[CH:3][C:4]=3[O:13][CH3:14])[N:32]2[N:33]=1)[CH3:40]
Reactant: CCc1nn2c(Br)ccc(OC)c2c1[N+](=O)[O-]
Reactant: COc1cc(C)cc(C)c1OB(O)O
Agent: CCOCCOCC
Agent: [Ba+2]
Agent: [OH-]
Solvent: O
Product: CCc1nn2c(-c3c(C)cc(C)cc3OC)ccc(OC)c2c1[N+](=O)[O-]
Temperature: 80 °C
Yield: 98.3 %

Procedure:
After adding 4,6-dimethyl-2-methoxyphenylboric acid (191 mg), barium hydroxide octahydrate (334 mg) and tetrakis(triphenylphosphine)palladium(0) complex (123 mg) to a solution of 7-bromo-2-ethyl-4-methoxy-3-nitropyrazolo[1,5-a]pyridine (159 mg) in a mixture of ethyleneglycol diethyl ether (15 mL) and water (7.5 mL), the mixture was heated at 80° C. for 30 minutes. Water was added, extraction was performed with ethyl acetate, the extract was washed with saturated aqueous sodium hydrogencarbonate and brine and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (20 g), and the title compound (185 mg) was obtained from the n-hexane:ethyl acetate (5:1) fraction as yellow crystals.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[C:18]3[NH:17][C:16]4[CH:19]5[CH2:25][CH2:24][N:22]([CH2:23][C:15]=4[C:14]=3[CH:13]=[CH:12][CH:11]=2)[CH2:21][CH2:20]5)=[CH:4][CH:3]=1>O=[Pt]=O.C(O)C>[CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[C:18]3[NH:17][C:16]4[CH:19]5[CH2:25][CH2:24][N:22]([CH2:23][C:15]=4[C:14]=3[CH:13]=[CH:12][CH:11]=2)[CH2:21][CH2:20]5)=[CH:4][CH:3]=1
Reactant: Cc1ccc(/C=C/c2cccc3c4c([nH]c23)C2CCN(CC2)C4)cn1
Agent: O=[Pt]=O
Solvent: CCO
Product: Cc1ccc(CCc2cccc3c4c([nH]c23)C2CCN(CC2)C4)cn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Adam's catalyst (PtO2, 7 mg, 0.031 mmol; Aldrich) was added to a solution of the product of Example 1D (60 mg, 0.18 mmol) in ethanol (5 mL). The reaction flask was evacuated and purged with nitrogen (3 cycles) then evacuated and purged with hydrogen (4 cycles), and the mixture was stirred under hydrogen (1 atm) at room temperature for 18 hours. The flask was evacuated and purged with nitrogen (3 cycles), and the reaction mixture was filtered. The filtrate was concentrated under vacuum, and the residue was purified by reverse-phase HPLC [Waters XBridge™ RP18 column, 5 μm, 30×100 mm, flow rate 40 mL/minute, 35-99% gradient of methanol in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to afford the title compound: 1H NMR (500 MHz, methanol-d4) δ ppm 2.06 (td, J=7.3, 3.7 Hz, 4 H), 2.45 (s, 3 H), 2.99 (t, J=7.6 Hz, 2 H), 3.01-3.09 (m, 3 H), 3.11 (t, J=7.6 Hz, 2 H), 3.23 (dq, J=7.3, 7.1 Hz, 2 H), 4.20 (s, 2 H), 6.77 (d, J=7.0 Hz, 1 H), 6.88 (t, J=7.5 Hz, 1 H), 7.13 (d, J=7.6 Hz, 1 H), 7.14 (d, J=7.9 Hz, 1 H), 7.49 (dd, J=7.9, 2.1 Hz, 1 H), 8.11 (d, J=1.8 Hz, 1 H); MS (APCI) m/z 332 (M+H)+.
Reaction SMILES: S(Cl)(Cl)=O.[F:5][C:6]([F:16])([F:15])[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=O.[CH3:17][O:18][C:19]([C:21]1[CH:26]=[CH:25][N:24]=[C:23]([NH2:27])[CH:22]=1)=[O:20].[OH-].[Na+]>N1C=CC=CC=1>[F:5][C:6]([F:16])([F:15])/[C:7](=[N:27]\[C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][N:24]=1)[C:19]([O:18][CH3:17])=[O:20])/[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(c1ccccc1)C(F)(F)F
Reactant: COC(=O)c1ccnc(N)c1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccnc(/N=C(/c2ccccc2)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.7 %

Procedure:
Thionyl chloride (2.2 ml) was added at 0° C. to a pyridine (4.8 ml) solution of 2,2,2-trifluoro-1-phenylethanone (5.1 g) and 2-aminopyridine-4-carboxylic acid methyl ester (4.5 g). The temperature of the reaction solution was increased to room temperature, and the reaction solution was then stirred for 1 hour. Thereafter, the reaction solution was poured into a 1 N sodium hydroxide aqueous solution, and the mixed solution was then extracted with ethyl acetate. Organic layers were gathered, and the gathered organic layer was then dried over anhydrous sodium sulfate. After that, the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (silica gel: eluent; heptane:ethyl acetate=2:1-1:1), so as to obtain the title compound (2.5 g) in the form of a yellow liquid.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.C([O-])([O-])=O.[Cs+].[Cs+].[N+:22]([C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=1)([O-:24])=[O:23]>CN(C=O)C.[Cl-].[Na+].O>[CH2:12]([NH:11][C:9]1[N:8]=[C:7]2[C:3]([N:4]=[CH:5][N:6]2[CH2:29][C:28]2[CH:31]=[CH:32][C:25]([N+:22]([O-:24])=[O:23])=[CH:26][CH:27]=2)=[C:2]([NH2:1])[N:10]=1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCNc1nc(N)c2nc[nH]c2n1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCNc1nc(N)c2ncn(Cc3ccc([N+](=O)[O-])cc3)c2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 70 %

Procedure:
6-amino-2-butylamino-9H-purine, intermediate 1 (9.93 g, 48.2 mmol) and Cs2CO3 (15.69 g, 48.2 mmol) were suspended in DMF (200 mL). 4-nitrobenzyl bromide (12.48 mg, 57.8 mmol) was added thereto and the mixture was stirred at rt for 18 h. After condensing the suspension in vacuo, to the residue was added brine and the mixture was extracted with ethyl acetate. The organic layer was washed the mixture was with brine, dried on MgSO4, filtered and the solvent was evaporated in vacuo. The residue was purified on column of silica gel (5% MeOH/DCM) to give the subject compound (11.51 g, yield 70%). Intermediate 59 was characterized by the following spectroscopic data: 1H NMR (DMSO-d6, 300 MHz) δ (ppm) 8.19 (d, 2H), 7.83 (s, 1H), 7.49 (d, 2H), 6.69 (sl, 2H), 6.25 (t, 1H), 5.34 (s, 2H), 3.17 (m, 2H), 1.41 (m, 2H), 1.25 (q, 2H), 0.83 (t, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:11])=[N:7][NH:8]2)=[CH:4][CH:3]=1.[CH3:12][C:13]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:14]=1[CH2:15]Cl.C(N1C2C(=CC=C(C(O)=O)C=2)C=C1)C1C=CC=CC=1>>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:11])=[N:7][N:8]2[CH2:15][C:14]2[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:13]=2[CH3:12])=[CH:4][CH:3]=1
Reactant: Cc1n[nH]c2cc(Br)ccc12
Reactant: Cc1ccc(C)c(CCl)c1
Agent: O=C(O)c1ccc2ccn(Cc3ccccc3)c2c1
Product: Cc1ccc(C)c(Cn2nc(C)c3ccc(Br)cc32)c1
Yield: 68.4 %

Procedure:
The titled compound (158 mg) as a white solid was prepared from 6-bromo-3-methyl-1H-indazole (148 mg) obtained with the method described in the document (JP 2009-528363 W) and 2,5-dimethylbenzyl chloride (164 mg) according to the method of the process (1) of Example 66.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[CH:13]=[CH:14][C:15]([F:26])=[C:16]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:17]=1)[N:5]=2.[CH:27]1([C:30](Cl)=[O:31])[CH2:29][CH2:28]1.O>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[CH:27]1([C:30]([NH:1][C:2]2[S:3][C:4]3[C:9]([N:10]=2)=[CH:8][CH:7]=[C:6]([O:11][C:12]2[CH:13]=[CH:14][C:15]([F:26])=[C:16]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:23])[CH3:24])[CH:17]=2)[N:5]=3)=[O:31])[CH2:29][CH2:28]1
Reactant: O=C(Cl)C1CC1
Reactant: CC(C)(C)OC(=O)Nc1cc(Oc2ccc3nc(N)sc3n2)ccc1F
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)ccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.5 %

Procedure:
To a solution of tert-butyl {5-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-2-fluorophenyl}carbamate (1.13 g, 3.0 mmol) and N,N-dimethylpyridin-4-amine (1.22 g, 10 mmol) in pyridine (10 mL) was added dropwise cyclopropanecarbonyl chloride (1.05 g, 10 mmol) under ice-cooling, and the mixture was stirred at room temperature overnight. Water (200 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL×2). The ethyl acetate layers were combined and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was triturated with diethyl ether to give the title compound (0.78 g, 59%) as a pale-yellow powder.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[CH2:44]([CH2:54][C:55](=[CH:57][CH2:58][CH2:59]/[C:60](=[CH:62]/[CH2:63]O)/[CH3:61])[CH3:56])/[CH:45]=[C:46](/[CH2:48][CH2:49][CH:50]=[C:51]([CH3:53])[CH3:52])\[CH3:47]>C1COCC1>[CH3:61]/[C:60](/[CH2:59][CH2:58]/[CH:57]=[C:55](\[CH3:56])/[CH2:54][CH2:44]/[CH:45]=[C:46](\[CH3:47])/[CH2:48][CH2:49][CH:50]=[C:51]([CH3:53])[CH3:52])=[CH:62]\[CH2:63][O:1][N:2]1[C:3](=[O:12])[C:4]2=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]2[C:6]1=[O:7]
Reactant: CC(C)=CCC/C(C)=C/CCC(C)=CCC/C(C)=C/CO
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CON1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.8 %

Procedure:
A solution of N-hydroxyphthalimide (1.12 g, 6.88 mmol), triphenylphosphine (1.81 g, 6.88 mmol) and diethylazodicarboxylate (1.19 mL, 7.57 mmol) in anhydrous THF (60 mL) was treated with geranylgeraniol (2.0 g, 6.88 mmol) and the resulting mixture was stirred for 18 h at rt. After addition of triphenylphosphine (0.905 g, 3.44 mmol) and diethylazodicarboxylate (0.595 mL, 3.78 mmol), the mixture was stirred at rt for another 24 h. The solvent was evaporated and the residue was purified on 230-400 mesh silica gel (Macherey-Nagel Silica Gel 60 Art. Nr. 81538) eluting with CH2Cl2-hexane (6:4) and collecting 10 mL fractions. The appropriate fractions were combined and evaporated to give the intermediate 20 (2.63 g, 88%) as a white solid: mp 40-41° C.; 1H-NMR (CDCl3, 80 Mhz) δ 1.58 (s, 9H, 3×CH3), 1.67 (s, 3H, CH3), 1.71 (s, 3H, CH3), 2.03 (m, 12H, 6×CH2), 4.71 (d, 2H, J=7.2 Hz, CH2), 5.07 (br, 3H, 3×CH), 5.52 (t, 1H, J=7.2 Hz, CH), 7.73 (m, 4H, Ar); Anal. Calcd for C28H37NO3 (MW 435.3); C, 77.26; H, 8.50; N, 3.22. Found: C, 77.38; H, 8.38; N, 3.04.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].Cl[C:17](=[O:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19]>>[CH2:14]([O:13][C:11]([CH2:10][C:2]1[NH:1][C:9]2[C:4]([C:3]=1[C:17](=[O:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:5][CH:6]=[CH:7][CH:8]=2)=[O:12])[CH3:15]
Reactant: CCOC(=O)Cc1cc2ccccc2[nH]1
Reactant: CCOC(=O)C(=O)Cl
Product: CCOC(=O)Cc1[nH]c2ccccc2c1C(=O)C(=O)OCC

Procedure:
In step (1) of Reaction Scheme VII, ethyl 1H-indol-2-ylacetate is reacted with ethyl chlorooxoacetate to provide ethyl (2-ethoxycarbonylmethyl-1H-indol-3-yl)oxoacetate. The reaction can be carried out using the general method described in step (1) of Reaction Scheme I. Ethyl 1H-indol-2-ylacetate is known.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])[N:3]=1.Cl.[NH:19]1[CH2:24][CH2:23][CH2:22][CH:21]([NH:25][C:26]2[N:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][CH:27]=2)[CH2:20]1.C(N(CC)C(C)C)(C)C>CS(C)=O>[C:32]([C:29]1[CH:28]=[CH:27][C:26]([NH:25][CH:21]2[CH2:22][CH2:23][CH2:24][N:19]([C:2]3[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[C:4]([C:10]4[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=4[Cl:17])[N:3]=3)[CH2:20]2)=[N:31][CH:30]=1)#[N:33]
Reactant: N#Cc1ccc(-c2ccc(Cl)cc2Cl)nc1Cl
Reactant: N#Cc1ccc(NC2CCCNC2)nc1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(NC2CCCN(c3nc(-c4ccc(Cl)cc4Cl)ccc3C#N)C2)nc1
Temperature: 120 °C

Procedure:
60 mg (0.21 mmol) of 2-chloro-6-(2,4-dichlorophenyl)pyridine-3-carbonitrile, 63 mg (0.25 mmol) of 6-(piperidin-3-ylamino)pyridine-3-carbonitrile hydrochloride (Example 10A) and 0.184 ml (1.06 mmol) of N,N-diisopropylethylamine were initially charged in 2 ml of DMSO. The mixture was heated at 120° C. in a microwave for 30 min. The crude product was purified by means of preparative HPLC (method 13). 61 mg (64% of theory) of the product were obtained in solid form.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8](F)[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[N+:15]([O-:17])=[O:16].[Br:19][C:20]1[N:21]=[CH:22][NH:23][CH:24]=1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([N:23]2[CH:24]=[C:20]([Br:19])[N:21]=[CH:22]2)[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[N+:15]([O-:17])=[O:16]
Reactant: Brc1c[nH]cn1
Reactant: COC(=O)c1cc(F)c(C(F)(F)F)cc1[N+](=O)[O-]
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(-n2cnc(Br)c2)c(C(F)(F)F)cc1[N+](=O)[O-]
Yield: 95.2 %

Procedure:
In a similar way as in the previous example a solution of 5-fluoro-2-nitro-4-trifluoromethyl-benzoic acid methyl ester (1 g, 3.73 mmol), 4-bromo-imidazole (0.68 g, 4.5 mmol) and N-ethyl-diisopropyl-amine (2.62 ml, 14.9 mmol) in 10 ml of dioxane is heated to reflux for 16 hours. After a similar workup procedure 1.4 g (3.55 mmol, 95%) of 5-(4-bromo-imidazol-1-yl)-2-nitro-4-trifluoromethyl-benzoic acid methyl ester are obtained, m.p. 90° C., ES-MS: m/z 395 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([OH:18])([CH3:17])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])[CH:5]=[CH:4][N:3]=1.[C:19]([N:27]=C=O)(=[O:26])C1C=CC=CC=1.C(O)C.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[OH:18][C:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:19]([NH2:27])=[O:26])[CH:7]=1)([CH3:17])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:16]
Reactant: O=C=NC(=O)c1ccccc1
Reactant: Cc1ccccc1CC(C)(O)c1ccnc(N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: ClCCl
Product: Cc1ccccc1CC(C)(O)c1ccnc(NC(N)=O)c1
Temperature: 50 °C
Yield: 19.2 %

Procedure:
2-(2-Amino-pyridin-4-yl)-1-o-tolyl-propan-2-ol (37 mg, 0.15 mmol) is dissolved in DCM (1 mL) and benzoyl isocynate (27 mg, 0.18 mmol) is added. The reaction is sealed and heated at 50° C. for 16 hrs. Then the solvent is removed and to the residue are added ethanol (1 mL) and potassium carbonate (32 mg, 0.23 mmol). The mixture is heated at 80° C. for 55 min. The solvent is removed and the residue is partitioned between water (25 mL) and EtOAc (35 mL). The aqueous layer is separated and extracted with EtOAc (2×30 mL). The organic layers are combined and concentrated to give the crude product. Purification by silica flash column chromatography using MeOH in DCM (gradient from 0% to 10%) followed by Gilson preparative HPLC affords 8.2 mg of the titled product.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([CH3:27])=[C:8]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15](B3OC(C)(C)C(C)(C)O3)=[CH:14][CH:13]=2)[CH:9]=1)=[O:4].Br[C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][C:30]=1[CH3:37]>>[CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([CH3:27])=[C:8]([CH2:10][O:11][C:12]2[CH:13]=[CH:14][C:15]([C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][C:30]=3[CH3:37])=[CH:16][CH:17]=2)[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(COc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c(C)o1
Reactant: COc1ccc(Br)c(C)c1
Product: COC(=O)c1cc(COc2ccc(-c3ccc(OC)cc3C)cc2)c(C)o1

Procedure:
Compound (143) was prepared from compound (119) and 1-bromo-4-methoxy-2-methyl-benzene by adapting the procedure of Example 31(a). LC/MS System A; Rt=4.24 mins.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].[Br:6][CH2:7][C:8](Br)=[O:9]>ClCCl>[Br:6][CH2:7][C:8]([NH:5][CH2:4][CH2:3][O:2][CH3:1])=[O:9]
Reactant: COCCN
Reactant: O=C(Br)CBr
Solvent: ClCCl
Product: COCCNC(=O)CBr
Temperature: 0 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
2-methoxyethylamine (3.73 g, 0.0496 mol) was dissolved in dichloromethane (250 ml) and cooled to 0° C. Bromoacetyl bromide (2.16 ml, 0.0248 mol) was added dropwise, and the reaction was stirred overnight at room temperature. The reaction mixture was then washed with water (100 ml) and saturated aqueous sodium chloride (2×100 ml). The organic layer was separated and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to afford 2-bromo-N-(2-methoxyethyl)acetamide as a white solid in 75% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10](Cl)[C:11]([C:14]#[N:15])=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.C[O-].[Na+].CCCCCC.[C:26](OCC)(=[O:28])C>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([O:28][CH3:26])[C:11]([C:14]#[N:15])=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(C)=O
Reactant: N#Cc1ncc(-c2cccc(Cl)c2)cc1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: O
Product: COc1cc(-c2cccc(Cl)c2)cnc1C#N
Temperature: 5 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
A 20 L reactor equipped with a mechanical stirred, condenser, thermometer and nitrogen inlet was charged with 5-(3-chlorophenyl)-3-chloro-2-cyanopyridine, 1, (558 g, 2.24 mol) and sodium methoxide (25% solution in methanol, 726.0 g, 3.36 mol). With agitation, the reaction solution was heated to reflux for 24 hours, resulting in a beige-colored suspension. The reaction was determined to be complete due to the disappearance of 5-(3-chlorophenyl)-3-chloro-2-cyanopyridine as measured by TLC analysis using hexane/ethyl acetate (6:3) as the mobile phase and UV 435 nm to visualize the reaction components. The reaction mixture was cooled to 5° C. and then charged with water (5580 mL). The resulting slurry was agitated for 3 hours at 5° C. The solid product was isolated by filtration and washed with water (5580 mL) until the filtrate had a pH of 7. The filter cake was air dried under vacuum for 16 hours. The filter cake was then charged back to the reactor and triturated in MeOH (2210 g, 2794 mL) for 1 hour at ambient temperature. The solid was collected by filtration and washed with MeOH (882 g, 1116 mL, 5° C.) followed by heptane (205 mL, 300 mL), and dried under high vacuum at 45° C. for 72 hours to afford 448 g (82% yield) of the desired product as an off-white solid. Purity by HPLC was 97.9%. 1H NMR (DMSO-d6) δ 8.68 (d, 1H), 8.05 (d, 1H), 8.01 (s, 1H) 7.86 (m, 1H), 7.59 (s, 1H), 7.57 (s, 1H) and 4.09 (s, 3H).
Reaction SMILES: [CH3:1][N:2]([CH3:12])[S:3]([N:6]1[CH:10]=[C:9](Br)[N:8]=[CH:7]1)(=[O:5])=[O:4].[F:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>[Pd].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.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.O>[CH3:1][N:2]([CH3:12])[S:3]([N:6]1[CH:10]=[C:9]([C:17]2[CH:18]=[CH:19][C:14]([F:13])=[CH:15][CH:16]=2)[N:8]=[CH:7]1)(=[O:5])=[O:4]
Reactant: CN(C)S(=O)(=O)n1cnc(Br)c1
Reactant: OB(O)c1ccc(F)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CN(C)S(=O)(=O)n1cnc(-c2ccc(F)cc2)c1
Yield: 72.5 %

Procedure:
A mixture of the bromide from Step 1 (0.543 g), 4-fluorophenylboronic acid (0.31 g), tetrakis(triphenylphosphine) palladium (0) (0.2 g), 2M aqueous sodium carbonate (2.2 mL) and toluene (10 mL) was refluxed under N2 for 1.5 hours. The mixture was cooled, poured into water (75 mL) and extracted with ethyl actetate (2×25 mL). The extracts were dried over Na2SO4, filtered and concentrated. Flash column chromatography, eluting with 40% ethyl acetate-isohexane, gave 1-(dimethylaminosulfonyl)-4-(4-fluorophenyl)imidazole (0.417 g, 72%) as a yellow solid. MS (ES+) 270 ([MH]+).
Reaction SMILES: [CH2:1]([CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:18][NH:19][S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])[CH:16]=2)[CH2:11][CH2:10][CH:9]1[NH:25]C(=O)OC(C)(C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:25][CH:9]1[CH:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:17]2[CH:16]=[C:15]([CH2:18][NH:19][S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])[CH:14]=[CH:13][C:12]=2[CH2:11][CH2:10]1
Reactant: CCS(=O)(=O)NCc1ccc2c(c1)C(Cc1ccccc1)C(NC(=O)OC(C)(C)C)CC2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)NCc1ccc2c(c1)C(Cc1ccccc1)C(N)CC2

Procedure:
tert-Butyl 1-benzyl-7-(ethylsulfonamidomethyl)-1,2,3,4-tetrahydronaphthalen-2-ylcarbamate (0.652 g, 1.422 mmol) was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (0.5 mL, 6.49 mmol) and stirred overnight at room temperature. The solution was evaporated and partitioned between saturated aqueous NaHCO3 and ethyl acetate. Water was extracted with ethyl acetate (2×30 mL). The collected organic extracts were dried on MgSO4 and evaporated under reduced pressure to give a brown oil.
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].C(N(CC)CC)C.Cl[S:14]([C:17]1[N:18]=[CH:19][N:20]2[CH:24]=[CH:23][S:22][C:21]=12)(=[O:16])=[O:15].C(OCC)(=O)C>CN(C=O)C>[CH3:5][O:4][N:3]([CH3:2])[S:14]([C:17]1[N:18]=[CH:19][N:20]2[CH:24]=[CH:23][S:22][C:21]=12)(=[O:15])=[O:16]
Reactant: O=S(=O)(Cl)c1ncn2ccsc12
Reactant: CNOC
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CON(C)S(=O)(=O)c1ncn2ccsc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N,O-Dimethylhydroxylamine hydrochloride (0.23 g) and 0.56 ml of triethylamine were added to a solution of 0.44 g of 7-chlorosulfonylimidazo[5,1-b]thiazole in 5 ml of DMF. The mixture was stirred at room temperature for one hr. Ethyl acetate was added thereto, followed by washing with water and saturated brine in that order. The organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by distillation. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:2) to give 0.44 g off 7-(N-methoxy-N-methylsulfamoyl)imidazo[5,1-b]thiazole.