Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[C:9](/[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)\[C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.C1C(=O)N([Br:27])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:27][CH2:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:8]=[C:9](/[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)\[C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=1
Reactant: COC(=O)/C(=C\c1ccc(C)cc1)c1ccccc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)/C(=C\c1ccc(CBr)cc1)c1ccccc1
Temperature: 25 °C
Yield: 73.6 %

Procedure:
To a solution of the product of Step B (31 mg, 0.123 mmol) in dry CCl4 (1 mL) under N2 were added NBS (20 mg, 0.9 eq) and a catalytic amount of AIBN. The mixture was stirred at reflux under N2 for 1.5 hours. The mixture was cooled to room temperature, diluted with EtO2 and filtered to remove the precipitated succinimide. The filtrate was concentrated in vacuo and the residue was purified on a silica gel flash chromatography column eluted with 15:1 hexane/EtOAc to afford 27.4 mg (67%) of the title compound.
Reaction SMILES: [I-].[F:2][C:3]1[CH:15]=[CH:14][C:6]2[N:7]3[C:12]([CH3:13])=[CH:11][S:10][C:8]3=[NH+:9][C:5]=2[CH:4]=1.C([O-])(O)=O.[Na+]>>[F:2][C:3]1[CH:15]=[CH:14][C:6]2[N:7]3[C:12]([CH3:13])=[CH:11][S:10][C:8]3=[N:9][C:5]=2[CH:4]=1
Reactant: Cc1csc2[nH+]c3cc(F)ccc3n12
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Product: Cc1csc2nc3cc(F)ccc3n12
Yield: 75.4 %

Procedure:
1 g (2.99 mmol) of 7-fluoro-3-methyl[1,3]thiazolo[3,2-a]benzimidazol-9-ium iodide obtained in stage B2 was poured in a NaHCO3 saturated aqueous solution (50 mL). The mixture was extracted 3×50 mL of CH2Cl2; the organic layer was dried with MgSO4 and evaporated under reduced pressure to yield 7-fluoro-3-methyl[1,3]thiazolo[3,2-a]benzimidazole (465 mg, yellow powder, 75%). Mp=148° C.; 1H NMR (300 MHz, CDCl3) δ=2.68 (3H, d, J=0.8, CH3), 6.34 (1H, q, J=0.8, H5), 6.91-7.66 (3H, in, Ar); 13C NMR (75 MHz, CDCl3) δ=14.3, 104.8, 104.9 (d, J=23), 108.7 (d, J=26), 110.6 (d, J=10), 126.9, 129.7, 149.0 (d, J=12), 158.5, 159.6 (d, J=239); HRMS m/z C10H8N2FS [M+H]+ calcd: 207.0387, found: 207.0386 400 mg (1.94 mmol) of 7-fluoro-3-methyl[1,3]thiazolo[3,2-a]benzimidazole were solubilised in acetone (10 mL), then CH3I (10 eq, 1.2 mL) was added and the solution stirred at r.t. for 12 h. 7-Fluoro-3-methyl[1,3]thiazolo[3,2-a]benzimidazol-9-ium iodide was recovered by filtration (white powder, 641 mg, 95%). Mp=>270° C.; 1H NMR (300 MHz, DMSO-d6) δ=2.86 (3H, d, J=1.3, CH3), 4.09 (3H, s, NCH3), 7.46 (1H, q, J=1.3, H5), 7.51-7.58 (1H, in, Ar), 8.09-8.12 (1H, m, Ar), 8.28-8.33 (1H, m, Ar); 13C NMR (75 MHz, DMSO-d6) δ=13.43, 33.22, 100.23 (d, J=29), 112.25, 112.51 (d, J=26), 115.47 (d, J=10), 126.67 (d, J=1), 133.02, 137.37 (d, J=14), 156.10, 160.45 (d, J=244); HRMS m/z C11H10N2FS [M−I]+ calcd: 221.0543, found: 221.0546.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH:9]1[O:13][C:12](=[O:14])[N:11]([C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH:26]=[CH:25][C:24](=[O:27])[CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[CH2:10]1)(C)(C)C.[F:29][CH:30]([F:36])[C:31](OCC)=[O:32]>>[F:29][CH:30]([F:36])[C:31]([NH:7][CH2:8][CH:9]1[O:13][C:12](=[O:14])[N:11]([C:15]2[CH:16]=[CH:17][C:18]([N:21]3[CH:26]=[CH:25][C:24](=[O:27])[CH2:23][CH2:22]3)=[CH:19][CH:20]=2)[CH2:10]1)=[O:32]
Reactant: CC(C)(C)OC(=O)NCC1CN(c2ccc(N3C=CC(=O)CC3)cc2)C(=O)O1
Reactant: CCOC(=O)C(F)F
Product: O=C1C=CN(c2ccc(N3CC(CNC(=O)C(F)F)OC3=O)cc2)CC1

Procedure:
The compound is prepared from {3-[4-(4-oxo-3,4-dihydro-2H-pyridin-1-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-carbamic acid tert-butyl ester (250 mg, 0.64 mmol) and ethyl difluoroacetate (120 mg, 0.96 mmol) following the method described for Example 5 (using ethyl difluoroacetate as starting agent). The product is purified by silica gel column chromatography (eluent 1% MeOH in EtOAc) and recrystallized from MeOH to provide the title compound. MS (m/z): 366 [M+1]. 1H NMR (300 MHz, DMSO) δ 9.16 (t, J=5.8 Hz, 1H), 7.73 (d, J=8.0 Hz, 1H), 7.53 (d, J=9.1 Hz, 2H), 7.28 (d, J=9.1 Hz, 2H), 6.24 (t, J=53.0 Hz, 1H), 4.98 (d, J=7.7 Hz, 1H), 4.80–4.75 (m, 1H), 4.14 (t, J=9.1 Hz, 1H), 3.97–3.92 (m, 2H), 3.76 (dd, J=6.3 and 9.1 Hz, 1H), 3.52 (t, J=5.5 Hz, 2H), 2.47 (t, J=7.1 Hz, 2H).
Reaction SMILES: [CH2:1]([N:4]([CH2:19][CH2:20][CH3:21])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([O:15][CH2:16][CH2:17][NH2:18])[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].C(=O)([O-])[O-].[K+].[K+].[CH2:28]([N:30]([CH2:34][CH3:35])[C:31](Cl)=[O:32])[CH3:29].C(OC(C)C)(C)C.C(O)C>C1(C)C=CC=CC=1>[CH2:19]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([O:15][CH2:16][CH2:17][NH:18][C:31]([N:30]([CH2:34][CH3:35])[CH2:28][CH3:29])=[O:32])[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:20][CH3:21]
Reactant: CCN(CC)C(=O)Cl
Reactant: CCCN(CCC)C1CCc2cccc(OCCN)c2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)OC(C)C
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCCN(CCC)C1CCc2cccc(OCCNC(=O)N(CC)CC)c2C1
Reaction time: 2 h

Procedure:
1.45 g (5 mmol) of 2-dipropylamino-8-(2-aminoethoxy)-1,2,3,4-tetrahydronaphthalene and 1.38 g (10 mmol) of potassium carbonate were initially introduced into 20 ml of toluene. 0.77 g (5.5 mmol) of diethylcarbamoyl chloride was then added dropwise, and the mixture was stirred for 2 h at +100° C. The mixture was then filtered and evaporated. The product was obtained by chromatography over silica gel 60, 40-63 μm, using diisopropyl ether/ethanol, 3:2.
Reaction SMILES: [C:1]12([CH3:11])[C:8]([CH3:10])([CH3:9])[CH:5]([CH2:6][CH2:7]1)[CH2:4][C:2]2=[O:3].C[O-].[Na+].[CH2:15]([O:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1)[CH2:16][CH2:17][CH3:18].O>C1(C)C=CC=CC=1>[CH2:15]([O:19][C:20]1[CH:21]=[CH:22][C:23]([CH:24]=[C:4]2[CH:5]3[C:8]([CH3:10])([CH3:9])[C:1]([CH3:11])([CH2:7][CH2:6]3)[C:2]2=[O:3])=[CH:26][CH:27]=1)[CH2:16][CH2:17][CH3:18]
Reactant: CC12CCC(CC1=O)C2(C)C
Reactant: CCCCOc1ccc(C=O)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCOc1ccc(C=C2C(=O)C3(C)CCC2C3(C)C)cc1

Procedure:
A solution of 100 millimols (15.2 g) of camphor in 250 ml of toluene is heated for 1 hour at the boil with 100 mmols (5.4 g) of sodium methylate. After cooling, 100 mmols (17.8 g) of p-butoxybenzaldehyde are introduced and the mixture is heated at the reflux temperature for 4 hours. The reaction mixture is cooled and 50 ml of water are then added; the toluene phase is separated off, washed with water, dried over sodium sulphate and concentrated to dryness. The solid residue is crystallised from aqueous isopropanol. After drying, 12 g of a white powder, which melts at 62°, are collected.
Reaction SMILES: [C:1]([CH:4]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[C:15]([CH3:16])[C:10]=2[N:9]=[C:8]1[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)(O)=[O:2].[NH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[N:33]1([C:1]([CH:4]([CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:5][CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[C:15]([CH3:16])[C:10]=3[N:9]=[C:8]2[CH2:17][O:18][C:19]2[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=2)=[O:2])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: Cc1cccc2c1nc(COc1ccc(Cl)cc1)n2CCC(Cc1ccccc1)C(=O)O
Reactant: C1CCNCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1cccc2c1nc(COc1ccc(Cl)cc1)n2CCC(Cc1ccccc1)C(=O)N1CCCCC1
Temperature: 25 °C
Reaction time: 64 h
Yield: 162.1 %

Procedure:
To a stirring solution of 1-[3-carboxy-4-phenylbutyl]-2-[(4-chlorophenoxy)methyl]-4-methylbenzimidazole (1.0 g, 2.2 mmol) in N,N-dimethylformamide (75 ml) were added sequentially piperidine (206 mg, 1.1 eq), 1-hydroxy-benzotriazole (327 mg, 1.1 eq), and dicyclohexylcarbodiimide (500 mg, 1.1 eq). The resulting mixture was then stirred under a nitrogen atmosphere at room temperature for 64 hours. The reaction mixture was then filtered and the resulting filtrate was concntrated under reduced pressure. This residue was taken into ethyl acetate (200 ml) and washed once with water (200 ml), dried over potassium carbonate. The solvents were removed in vacuo to yield 1.84 grams of a tan foam.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[NH:7]1[CH:11]=[C:10](B(O)O)[CH:9]=[N:8]1.FC(F)(F)S(O[C:21]1[CH:22]=[CH:23][C:24]2[N:30]3[C:31]([CH3:34])=[N:32][N:33]=[C:29]3[C@H:28]([CH2:35][C:36]([NH:38][CH2:39][CH3:40])=[O:37])[N:27]=[C:26]([C:41]3[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][CH:42]=3)[C:25]=2[CH:48]=1)(=O)=O.C(OCC)(=O)C>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:47][C:44]1[CH:43]=[CH:42][C:41]([C:26]2[C:25]3[CH:48]=[C:21]([C:10]4[CH:9]=[N:8][NH:7][CH:11]=4)[CH:22]=[CH:23][C:24]=3[N:30]3[C:31]([CH3:34])=[N:32][N:33]=[C:29]3[C@H:28]([CH2:35][C:36]([NH:38][CH2:39][CH3:40])=[O:37])[N:27]=2)=[CH:46][CH:45]=1
Reactant: OB(O)c1cn[nH]c1
Reactant: CCNC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2cc(OS(=O)(=O)C(F)(F)F)ccc2-n2c(C)nnc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: CCNC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2cc(-c3cn[nH]c3)ccc2-n2c(C)nnc21
Temperature: 120 °C
Yield: 7.2 %

Procedure:
Sodium carbonate (43.0 mg), 1H-pyrazole-4-boronic acid (24.8 mg) and bis(triphenylphosphine)palladium(II) chloride (13.0 mg) were added to a 2-5 ml microwave vial. A solution of (4S)-6-(4-chlorophenyl)-4-[2-(ethylamino)-2-oxoethyl]-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-8-yl trifluoromethanesulfonate (100 mg, intermediate 3) in DME (3 ml) and water (1 ml) was added. The reaction mixture was heated at 120° C. for 30 min (microwave). Ethyl acetate (2 ml) was added and the water layer was separated. The organic layer was dried and the solvent evaporated. The residue was purified by MDAP (formate modifier). The product was loaded on a 1 g SCX-2 column in methanol and eluted with ammonia in methanol (2M) to give 2-[(4S)-6-(4-chlorophenyl)-1-methyl-8-(1H-pyrazol-4-yl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide as a white oil (6.1 mg).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:12][CH2:13][C@@H:14]2[CH2:16][C@@H:15]2[CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[N:9][CH:10]=1)(=[O:4])=[O:3].[CH:23]1([CH2:29][C:30](O)=[O:31])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH:23]1([CH2:29][C:30]([N:20]2[CH2:21][CH2:22][CH:17]([C@H:15]3[CH2:16][C@H:14]3[CH2:13][CH2:12][O:11][C:8]3[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:10][N:9]=3)[CH2:18][CH2:19]2)=[O:31])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: CS(=O)(=O)c1ccc(OCC[C@@H]2C[C@@H]2C2CCNCC2)nc1
Reactant: O=C(O)CC1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(OCC[C@@H]2C[C@@H]2C2CCN(C(=O)CC3CCCCC3)CC2)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 23 mg (0.071 mmol) of 5-(methylsulfonyl)-2-{2-[(1S,2R)-2-piperidin-4-ylcyclopropyl]ethoxy}pyridine in 0.6 ml anhydrous N,N-dimethylformamide at ambient temperature was added 0.020 ml (0.14 mmol) cyclohexylacetic acid, followed by 27 mg (0.14 mmol) EDCl, 9.6 mg (0.071 mmol) HOBt, and 0.062 ml (0.35 mmol) diisopropylethylamine. The solution was stirred overnight at ambient temperature. The crude in N,N-dimethylformamide was purified directly by reverse phase HPLC (TMC Pro-Pac C18; 30-100% acetonitrile/0.1% formic acid in water gradient). The pure fractions were lyophilized to yield the title compound as white solid. 1H NMR (DMSO): δ 8.65 (d, J=2.1 Hz, 1H), δ 8.15 (dd, J=8.8 Hz, 2.5 Hz, 1H), δ 7.01 (d, J=8.7 Hz, 1H), δ 4.43 (t, J=6.8 Hz, 2H), δ 4.36 (t, J=12.0 Hz, 1H), δ 3.85 (t, J=13.7 Hz, 1H), δ 3.31 (s, 1H), δ 3.28 (s, 1H), δ 3.24 (s, 3H), δ 2.94 (t, J=12.7 Hz, 1H), δ 2.15 (d, J=6.5 Hz, 2H), δ 2.00-2.04 (m, 1H), δ 1.51-1.75 (m, 9H), δ 1.08-1.23 (m, 6H), δ 0.83-0.94 (m, 3H), δ 0.53-0.59 (m, 2H). LC/MS 589.3 (M+1). GPR119 Human EC50: 11.8 nM
Reaction SMILES: [CH3:1][N:2]([CH3:7])[S:3]([CH3:6])(=[O:5])=[O:4].[Li]CCCC.Cl[C:14]1[N:19]=[C:18]([S:20][CH3:21])[N:17]=[C:16]2[N:22]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[N:23]=[C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[Cl:31])[C:15]=12>C1COCC1>[Cl:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:24]1[C:15]2[C:16](=[N:17][C:18]([S:20][CH3:21])=[N:19][C:14]=2[CH2:6][S:3]([N:2]([CH3:7])[CH3:1])(=[O:5])=[O:4])[N:22]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:37])([CH3:39])[CH3:38])[N:23]=1
Reactant: CSc1nc(Cl)c2c(-c3ccccc3Cl)nn(COCC[Si](C)(C)C)c2n1
Reactant: CN(C)S(C)(=O)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CSc1nc(CS(=O)(=O)N(C)C)c2c(-c3ccccc3Cl)nn(COCC[Si](C)(C)C)c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.5 %

Procedure:
To a solution of N,N-dimethyl methanesulfonamide (419 mg, 3.40 mmol) in 5 mL dry THF at 5° C. was added n-BuLi (2.2 mL of 1.6M solution in hexanes 3.50 mmol) dropwise. To this stirring solution was added dropwise a solution of 4-Chloro-3-(2-chloro-phenyl)-6-methylsulfanyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidine (0.500 g, 1.13 mmol) in 1 mL dry THF. The reaction mixture was stirred for 2 hours and allowed to warm to room temperature during this time. The reaction was quenched by addition of 10 mL water and 1 mL of 1.2M HCl, and the resulting aqueous solution was extracted twice with 20 mL methylene chloride. The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (0% to 30% EtOAc in hexanes) to give 421 mg of C-[3-(2-Chloro-phenyl)-6-methylsulfanyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-N,N-dimethyl-methanesulfonamide.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6](F)[N:5]=[CH:4][N:3]=1.[CH2:10]([OH:14])[C:11]#[C:12][CH3:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:10]([O:14][C:6]1[C:7]([F:8])=[C:2]([F:1])[N:3]=[CH:4][N:5]=1)[C:11]#[C:12][CH3:13]
Reactant: CC#CCO
Reactant: Fc1ncnc(F)c1F
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC#CCOc1ncnc(F)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.5 %

Procedure:
0.5 g of 4,5,6-trifluoropyrimidine, 0.31 g of 2-butyn-1-ol and 0.62 ml of triethylamine were added to 1 ml of toluene, then the mixture was stirred at room temperature for 1 hour. Then the reaction mixture was subjected to silica gel column chromatography to obtain 0.56 g of 4-(2-butynyloxy)-5,6-difluoropyrimidine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)=[CH:11][C:10]([C:23]([NH2:25])=O)=[N:9]2)=[CH:4][CH:3]=1.CS(Cl)(=O)=O>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)=[CH:11][C:10]([C:23]#[N:25])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(-c2cc(C(N)=O)nn2-c2ccc(F)cc2)cc1
Agent: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)c1ccc(-c2cc(C#N)nn2-c2ccc(F)cc2)cc1
Temperature: 50 °C
Reaction time: 6 h
Yield: 93.6 %

Procedure:
A mixture of 1-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]pyrazole-3-carboxamide (2.7 g) and methanesulfonyl chloride (3.4 ml) in pyridine (25 ml) was stirred at 50° C. for 6 hours. The solvent was evaporated, and ethyl acetate and water were added to the residue. The precipitates were filtered and washed with water and ethyl acetate. The filtrate was separated, and the organic layer was washed with dilute hydrochloric acid, dried and concentrated to dryness. The residue and the former precipitates were combined and recrystallized from a mixture of ethanol and ethyl acetate to give colorless crystals of 1-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]pyrazole-3-carbonitrile (2.4 g).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([O:8][CH3:9])[CH:5]=[CH:6][CH:7]=1.[C:10]1([C:16]#[CH:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(S([O-])(=O)=O)=CC=2C(C)C)CCCCC1.[Na+].C(#N)C>[CH3:9][O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:17]#[C:16][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:3]=1
Reactant: C#Cc1ccccc1
Reactant: COc1cccc(Cl)c1
Agent: CC(C)c1cc(S(=O)(=O)[O-])cc(C(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: COc1cccc(C#Cc2ccccc2)c1
Yield: 95.1 %

Procedure:
The general procedure described in Example 27 was used with 3-chloroanisole (0.063 mL, 0.50 mmol), phenylacetylene (0.072 mL, 0.65 mmol), PdCl2(CH3CN)2 (3.2 mg, 0.0125 mmol, 1.25 mol %), sodium 2′-(dicyclohexyl-phosphanyl)-2,6-diisopropyl-biphenyl-4-sulfonate (20.0 mg, 0.0375 mmol, 3.75 mol %), Cs2CO3 (650 mg, 2.00 mmol), water (1.0 mL), acetonitrile (1.5 mL), 12 h, 100° C. The product was isolated as a white solid (99 mg, 95%). Mp=70° C. (lit. 72-74° C.). 1H NMR (400 MHz, CDCl3) δ: 7.62 (m, 2H), 7.41 (m, 3H), 7.32 (t, 1H, J=7.6 Hz), 7.23 (dt, 1H, J=1.2 Hz, 7.6 Hz), 7.15 (m, 1H), 6.96 (qd, 1H, J=1.2 Hz, 2.4 Hz, 7.6 Hz). 13C NMR (125 MHz, CDCl3) δ: 159.5, 131.8, 129.6, 128.5, 128.48, 124.4, 124.3, 123.3, 116.5, 115.1, 89.5, 89.4, 55.4.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[C:6]([Cl:24])[CH:7]=[C:8]([CH2:13][C@@H:14]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:15]([O:17]C)=O)[C:9]=2[CH2:11]O)[NH:4][N:3]=1.S(Cl)(Cl)=O.[NH2:29][CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.C(=O)([O-])[O-].[K+].[K+].C(O)(=O)C>C(#N)C>[Cl:1][C:2]1[C:10]2[C:9]3[CH2:11][N:29]([CH2:30][CH2:31][N:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)[C:15](=[O:17])[C@H:14]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:13][C:8]=3[CH:7]=[C:6]([Cl:24])[C:5]=2[NH:4][N:3]=1
Reactant: NCCN1CCCCC1
Reactant: COC(=O)C[C@H](Cc1cc(Cl)c2[nH]nc(Cl)c2c1CO)C(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O=S(Cl)Cl
Solvent: CC#N
Product: COC(=O)C[C@@H]1Cc2cc(Cl)c3[nH]nc(Cl)c3c2CN(CCN2CCCCC2)C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 51 %

Procedure:
(S)-Dimethyl 2-((3,7-dichloro-4-(hydroxymethyl)-1H-indazol-5-yl)methyl)succinate (990 mg, 2.64 mmol) was dissolved in thionyl chloride (2.0 M in dichloromethane) (20 mL, 40.0 mmol). Mixture stirred at room temperature for 3 hours. Mixture was concentrated by roto-vap. Residue was dissolved in ethyl acetate. Mixture was washed twice with aqueous sodium bicarbonate. Organics were dried MgSO4, filtered and then concentrated to dryness. A portion of the residue (460 mg, 1.169 mmol) was dissolved in acetonitrile (15 mL). 1-(2-Aminoethyl)-piperidine (600 μl, 4.21 mmol) was added to the mixture followed by potassium carbonate (200 mg, 1.447 mmol). Mixture was warmed to reflux and held with stirring for 1 hour. Mixture was cooled to room temperature and then filtered over celite. Filtrate was concentrated by roto-vap. Residue was dissolved in toluene (15 mL). Acetic acid (1.0 mL, 17.47 mmol) was added to the mixture. Reaction was warmed to reflux and held with stirring for 16 hours. Mixture was cooled to room temperature and then concentrated by roto-vap. Residue was suspended in ethyl acetate. Mixture was washed twice with aqueous sodium bicarbonate and the aqueous phase was discarded. Organics were dried MgSO4, filtered and then concentrated to dryness. Silica gel chromatography eluting 2M ammonia in methanol-dichloromethane afforded the title compound as amber oil in 51% yield. (M+H)+=453.0, 455.0.
Reaction SMILES: C([O:3][C:4](=[O:37])[C:5]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH2:33][C:34]([OH:36])=[O:35])[CH:27]=2)[S:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:17])=[CH:10][CH:9]=1)([CH3:7])[CH3:6])C.O[Li].O>C1COCC1.O>[C:34]([CH2:33][O:32][C:28]1[CH:27]=[C:26]([CH:31]=[CH:30][CH:29]=1)[CH2:25][N:15]([CH2:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]([CH3:7])([CH3:6])[C:4]([OH:37])=[O:3])=[CH:9][CH:10]=1)[S:16]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)(=[O:18])=[O:17])([OH:36])=[O:35]
Reactant: CCOC(=O)C(C)(C)c1ccc(CN(Cc2cccc(OCC(=O)O)c2)S(=O)(=O)c2cccnc2)cc1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C(=O)O)c1ccc(CN(Cc2cccc(OCC(=O)O)c2)S(=O)(=O)c2cccnc2)cc1
Temperature: 25 °C
Yield: 94.5 %

Procedure:
To a solution of 2-(4-{[(3-carboxymethoxy-benzyl)-(pyridine-3-sulfonyl)-amino]-methyl}-phenyl)-2-methyl-propionic acid ethyl ester (83 mg, 0.157 mmol) in THF (10 mL) was added water (1 mL) and LiOH.H2O (66 mg, 1.58 mmol). The reaction was heated at reflux for 24 h. Additional LiOH.H2O (66 mg, 1.58 mmol) in water (2 mL) was added and the reaction was heated at reflux for 30 h. The mixture was concentrated in vacuo and to the residue was added THF (3 mL) and water (1.5 mL). The reaction was heated at reflux for 24 h and was cooled to room temperature. The solution was diluted with water and the pH was adjusted to about 5 by addition of 1N HCl. Sodium chloride was added and the aqueous solution was washed with EtOAc (3×). The combined organic solutions were dried (MgSO4), filtered, and concentrated to provide the title compound (74 mg). 1H NMR (400 MHz, CDCl3) δ 8.94 (s, 1H), 8.73 (s, 1H), 8.13 (d, 1H), 7.55 (m, 1H), 7.23 (d, 2H), 7.11 (m, 3H), 6.78 (d, 1H), 6.73 (d, 1H), 6.68 (s, 1H), 4.90 (s, 2H), 4.39 (s, 2H), 3.30 (s, 2H), 1.50 (s, 6H); MS 497 (M−1).
Reaction SMILES: [PH2](O)=O.C(OC)(OC)OC.[PH2:11]([O:13][CH3:14])=[O:12].[N+:15]([C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[CH2:23])=[CH:20][CH:19]=1)([O-:17])=[O:16].C(N(C(C)C)CC)(C)C.C(=O)(O)[O-].[Na+]>CO.O>[CH3:14][O:13][PH:11]([CH2:23][CH2:22][C:21]1[CH:20]=[CH:19][C:18]([N+:15]([O-:17])=[O:16])=[CH:25][CH:24]=1)=[O:12]
Reactant: C=Cc1ccc([N+](=O)[O-])cc1
Reactant: CO[PH2]=O
Agent: O=C([O-])O
Agent: O=[PH2]O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: COC(OC)OC
Product: CO[PH](=O)CCc1ccc([N+](=O)[O-])cc1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
0.665 g of crystalline hypophosphorous acid was treated under nitrogen with 1.73 g of trimethyl orthoformate and the mixture was stirred at 20° C. for 2 hours. The resulting solution of crude methyl hypophosphite was added dropwise at 0° C. to a solution of 1 g of 4-nitrostyrene and 0.43 g of diisopropylethylamine in 5 ml of methanol. After 65 hours at 20° C. the same amount of methyl hypophosphite was again added and the mixture was stirred at 20° C. for a further 24 hours. The mixture was diluted with 30 ml of water and the pH was adjusted to 7 with aqueous sodium bicarbonate solution. After extraction with dichloromethane and chromatography on silica gel using 10% methanol in ethyl acetate for the elution there was obtained 0.5 g of 1-[2-(methoxyphosphinyl)ethyl]-4-nitrobenzene in the form of a yellow liquid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[C:3]=1[S:12](Cl)(=[O:14])=[O:13].[CH3:16][O:17][CH2:18][CH2:19][NH:20][CH2:21][CH2:22][O:23][CH3:24].C(N(CC)CC)C>>[CH3:16][O:17][CH2:18][CH2:19][N:20]([CH2:21][CH2:22][O:23][CH3:24])[S:12]([C:3]1[C:4]([Cl:11])=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[Cl:1])(=[O:14])=[O:13]
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)Cl)c1Cl
Reactant: COCCNCCOC
Solvent: CCN(CC)CC
Product: COCCN(CCOC)S(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1Cl
Yield: 89.1 %

Procedure:
Following the general procedure for sulfonamide formation outlined in example 15, 2,6-dichloro-3-nitrobenzenesulfonyl chloride (1.82 g, 6.26 mmol), bis(2-methoxyethyl)amine (830 mg, 6.26 mmol) and triethylamine(1.7mL, 12.52 mmol) were reacted to form the desired product (2.16 g, 89%). LC-MS (m/z) 387.2 (M+).