Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.[NH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8](=O)[CH2:9]Br)[N:7]=1.[C:12]([CH2:15][NH:16][C:17](=[O:19])[CH3:18])(=[S:14])[NH2:13]>C(O)C>[C:17]([NH:16][CH2:15][C:12]1[S:14][CH:9]=[C:8]([C:6]2[N:7]=[C:3]([NH2:2])[S:4][CH:5]=2)[N:13]=1)(=[O:19])[CH3:18]
Reactant: Nc1nc(C(=O)CBr)cs1
Reactant: CC(=O)NCC(N)=S
Agent: Br
Solvent: CCO
Product: CC(=O)NCc1nc(-c2csc(N)n2)cs1
Temperature: 25 °C
Reaction time: 24 h
Yield: 49.7 %

Procedure:
A suspension of 2-amino-4-bromoacetylthiazole hydrobromide (14.0 g) and N-[(thiocarbamoyl)methyl]-acetamide (6.1 g) in ethanol (300 ml) was stirred at room temperature for 24 hours. The insoluble material was removed by filtration. The solvent was removed under reduced pressure. The residue was suspended in water (300 ml). The mixture was alkalized to pH 10 with a saturated aqueous potassium carbonate solution and then was extracted with a mixture of ethyl acetate (500 ml) and tetrahydrofuran (100 ml). The extract was dried over magnesium sulfate and then was evaporated to afford 4-(2-acetylaminomethylthiazol-4-yl)-2-aminothiazole (5.83 g).
Reaction SMILES: [C:1]([NH2:8])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:9]([O:12]C(=O)C)(=[O:11])[CH3:10].N1C=CC=CC=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([NH2:8])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:9]([O-:12])(=[O:11])[CH3:10]
Reactant: CC(=O)OC(C)=O
Agent: CC(C)(C)OC(N)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)[O-]
Reaction time: 3 h

Procedure:
To a solution of the Boc-amine (3, 540 mg, 0.451 mmol) in DCM (250 mL) is added acetic anhydride (0.100 mL, 0.979 mmol), pyridine (1.0 mL, 12.4 mmol) and DMAP (20 mg, 0.169 mmol). The reaction is stirred for 3 h, concentrated directly onto SiO2 and chromatographed (gradient elution: 50-70% EtOAc/hexanes) which provides 465 mg of Boc-amine-acetate (4). 1H NMR (400 MHz, d6-DMSO) δ 10.38 (br s, 1H), 9.20 (br d, 1H), 8.79 (br d, 1H), 8.61 (br d, 1H), 8.56 (s, 1H), 8.44-8.41 (m, 1H), 8.38 (d, 1H), 8.24 (s, 1H), 8.11 (d, 1H), 7.48 (br s, 1H), 7.42 (s, 2H), 7.35-7.29 (m, 6H), 6.14 (s, 1H), 5.47 (t, 1H), 5.31-5.26 (m, 1H), 5.19 (dd, 1H), 4.97 (s, 3H), 4.26 (dd, 1H), 3.72 (dd, 1H), 3.38 (s, 3H), 2.70-2.65 (m, 1H), 2.59 (s, 3H), 2.45 (d, 3H), 2.22-2.14 (m, 1H), 1.96 (s, 3H), 1.57-1.50 (m, 1H), 1.49 (s, 9H), 0.88 (d, 3H), 0.84 (d, 3H). LCMS: Rt=1.81 min, [M+H]+ 1238.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10]Br)[CH:5]=1.[OH:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][C:18]2[CH:19]=[CH:20][C:15]([CH2:14][OH:13])=[CH:16][CH:17]=2)[CH:5]=1
Reactant: OCc1ccc(B(O)O)cc1
Reactant: COC(=O)c1cccc(CBr)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(Cc2ccc(CO)cc2)c1
Temperature: 85 °C
Yield: 80.8 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (550 mg, 0.476 mmol) is added to a mixture of 3-bromomethyl-benzoic acid methyl ester (3.0 g, 13.09 mmol) and 4-(hydroxymethyl)-phenylboronic acid (2.99 g, 19.68 mmol) in a mixture of toluene (125 mL) and 2M sodium carbonate (62 mL). The mixture was degassed, placed under nitrogen and heated at 85° C. for 16 hours. After cooling to room temperature, the mixture is concentrated in vacuo and the black residue is partitioned between saturated sodium bicarbonate and dichloromethane. After the layers are separated, the aqueous layer is extracted two more times with dichloromethane. The combined organic layers are washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by flash chromatography (20% tetrahydrofuran in hexanes) to give 2.71 g of the title compound as a yellow oil: MS (m/z): 239 (M−OH); 1H NMR (CDCl3) δ 7.92 (m, 2H), 7.42-7.36 (m, 2H), 7.34-7.29 (m, 2H), 7.21 (d, J=8.0 Hz, 2H), 4.69 (s, 2H), 4.05 (s, 2H), 3.93 (s, 3H), 1.79 (s, 1H).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([CH:11]2[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:14]([CH:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:13](=[O:30])[NH:12]2)[CH:7]=[C:8]([F:10])[CH:9]=1.Br[CH2:32][C:33]([O:35][CH3:36])=[O:34]>CN(C=O)C>[F:3][C:4]1[CH:5]=[C:6]([CH:11]2[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:14]([CH:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)[C:13](=[O:30])[N:12]2[CH2:32][C:33]([O:35][CH3:36])=[O:34])[CH:7]=[C:8]([F:10])[CH:9]=1
Reactant: COC(=O)CBr
Reactant: CC(C)(C)OC(=O)N1CC(c2cc(F)cc(F)c2)NC(=O)C1C1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CN1C(=O)C(C2CCOCC2)N(C(=O)OC(C)(C)C)CC1c1cc(F)cc(F)c1
Temperature: 0 °C

Procedure:
At 0° C. 0.16 g (3.7 mmol) sodium hydride was added to 1.30 g (3.3 mmol) tert-butyl 5-(3,5-difluorophenyl)-3-oxo-2-(tetrahydro-2H-pyran-4-yl)piperazine-1-carboxylate (isomer mixture 2) in 20 ml DMF. After 20 min 0.36 ml (3.7 mmol) methyl bromoacetate were added dropwise while cooling with an ice bath. Then the mixture was stirred for 30 min in the ice bath and for 5 h at RT. The reaction mixture was poured onto water and extracted with ethyl acetate. The organic phase was washed with water, dried and evaporated down.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[O:4][CH2:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=O)=[O:7].NCC[N:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.C(Cl)CCl.C1C=CC2N(O)N=[N:42][C:40]=2C=1.CCN(C(C)C)C(C)C>CN(CC1C=C(CN(C)C)C(O)=C(CN(C)C)C=1)C>[Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[O:4][CH2:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([NH:42][CH2:40][C:30]1[CH:31]=[N:26][CH:27]=[CH:28][CH:29]=1)=[O:14])=[O:7]
Reactant: NCCN1CCCCC1
Reactant: On1nnc2ccccc21
Reactant: O=C(COc1ccc(Cl)cc1Cl)Nc1cccc(C(=O)O)c1
Agent: CN(C)Cc1cc(CN(C)C)c(O)c(CN(C)C)c1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(COc1ccc(Cl)cc1Cl)Nc1cccc(C(=O)NCc2cccnc2)c1
Temperature: 25 °C
Yield: 70.4 %

Procedure:
To solution of 3-[2-(2,4-dichloro-phenoxy)acetylamino]-benzoic acid (68 mg, 0.2 mmol), 1-(2-aminoethyl)-piperidine (0.043 ml, 0.3 mmol) in DMF 3.0 mL was added EDC (57.5 mg, 0.3 mmol), HOBt (40.6 mg, 0.3 mmol) and DIPEA (0.052 ml, 0.3 mmol). Reaction mixture was stirred at room temperature, and separated by EtoAC and brine. The organic phase was dried (MgSO4 anh) and concentrated. The residue was purified by silica gel column chromatography (CH2Cl2:MeOH=20:1) to give 3-[2-(2,4-dichloro-phenoxy)-acetylamino]-N-pyridine-3-ylmethyl-benzamide as a white solid (60.6 mg, 70% yield).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]1[C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:10][C:11]2[C:16]([N:17]=1)=[CH:15][C:14]([C:18]([O:20]C)=[O:19])=[CH:13][CH:12]=2.[OH-].[Na+]>CO.O>[OH:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]1[C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:10][C:11]2[C:16]([N:17]=1)=[CH:15][C:14]([C:18]([OH:20])=[O:19])=[CH:13][CH:12]=2
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCC[C@H]3CO)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc2nc(-c3ccccc3)c(N3CCC[C@H]3CO)nc2c1
Temperature: 70 °C
Reaction time: 5 h

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of (S)-methyl 3-(2-(hydroxymethyl)pyrrolidin-1-yl)-2-phenylquinoxaline-6-carboxylate (104 mg, 0.29 mmol, 1.00 equiv) and sodium hydroxide (57.3 mg, 1.43 mmol, 5.00 equiv) in methanol/H2O (20/5 mL). The reaction was stirred for 5 h at 70° C., concentrated to dryness, dissolved in 20 mL of H2O and washed with 10 mL EtOAc. The aqueous layer was adjusted pH to 7 with 1N HCl and extracted with DCM/MeOH (10/1, 20 mL×5). The organic layer was combined, dried over Na2SO4, and concentrated in vacuo. This resulted 45 mg (43%) of (S)-3-(2-(hydroxymethyl)pyrrolidin-1-yl)-2-phenylquinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: C([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[O:10][C:9]([C:18]2[N:23]=[CH:22][N:21]3[CH:24]=[CH:25][CH:26]=[C:20]3[CH:19]=2)=[CH:8]1)(C)(C)C.Cl.[Cl:28][CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>>[ClH:28].[N:31]1([CH2:30][CH2:29][O:17][C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[O:10][C:9]([C:18]2[N:23]=[CH:22][N:21]4[CH:24]=[CH:25][CH:26]=[C:20]4[CH:19]=2)=[CH:8][C:7]3=[N:6][OH:5])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: ClCCN1CCCCC1
Reactant: CC(C)(C)ON=c1cc(-c2cc3cccn3cn2)oc2ccc(O)cc12
Agent: Cl
Product: ON=c1cc(-c2cc3cccn3cn2)oc2ccc(OCCN3CCCCC3)cc12

Procedure:
6-(2-Piperidin-1-yl-ethoxy)-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one oxime, hydrochloride was prepared in 27% overall yield using the method described in example 85, starting from 6-hydroxy-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one O-tert-butyl oxime (example 81A) and 1-(2-chloroethyl)-piperidine hydrochloride.
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:5][OH:6])[OH:4].[C:7]([O:14][CH3:15])(=O)[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>[Pd]>[CH2:7]([O:1][CH2:2][CH:3]([CH2:5][OH:6])[OH:4])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH3:2][CH2:15][O:14][CH2:7][CH3:8]
Reactant: CCCCCC(=O)OC
Reactant: OCC(O)CO
Agent: [Pd]
Product: CCCCCCOCC(O)CO
Product: CCOCC
Temperature: 140 °C

Procedure:
A stirred autoclave was charged, at room temperature, with 65.61 g (712 mmol) of glycerol, 2.29 g (17.6 mmol) of methyl caproate, 0.23 g (10 wt %) of AMBERLYST® (a polymer based catalyst) 15 resin and 0.23 g (1 mol %) of Pd/C at 5%. The autoclave was then pressurized at 50 bar of dihydrogen gas H2, and then it was heated at 140° C. for 16 h, stirring vigorously. After 16 h of reaction, the reaction mixture was brought back to room temperature. The catalyst was then filtered on a MILLIPORE® filter (a membrane filter) (0.45 pm) and was rinsed with absolute ethanol. The solvents were then evaporated and the organic products were extracted from the glycerol phase by extraction with CH2Cl2 (3×50 ml). The organic phase was washed with water (2×20 ml) and the CH2Cl2 was then evaporated at reduced pressure. The crude reaction product was analyzed by GC/MS. 1-O-hexyl-glycerol ether was obtained at 62% GC yield.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:11][CH:10]=1)[C:5]([O:7][CH3:8])=[O:6].[CH2:23]([O:27][C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1)[C:24]#[C:25][CH3:26].C(N(CC)CC)C>ClCCl>[CH2:23]([O:27][C:28]1[CH:33]=[CH:32][C:31]([S:34]([NH:3][CH:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][N:18]3[CH2:19][CH2:20][CH2:21][CH2:22]3)=[CH:11][CH:10]=2)[C:5]([O:7][CH3:8])=[O:6])(=[O:36])=[O:35])=[CH:30][CH:29]=1)[C:24]#[C:25][CH3:26]
Reactant: CC#CCOc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)C(N)c1ccc(OCCN2CCCC2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC#CCOc1ccc(S(=O)(=O)NC(C(=O)OC)c2ccc(OCCN3CCCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.6 %

Procedure:
To a 0° solution of methyl amino{4-[2-(1-pyrrolidinyl)ethoxy]phenyl}acetate dihydrochloride (1.67 g; 4.55 mmol) in dichloromethane (10 mL) was added 4but-2-ynyloxy-benzenesufonyl chloride followed by triethyl amine was dropped in. The mixture was stirred at room temperature overnight and then diluted with dichloromethane. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated. The residue was purified using column chromatography on silica gel eluting with ethyl acetate to obtain 2.52 g of methyl ({[4-(2-butynyloxy)phenyl]sulfonyl}amino){4-[2-(1-pyrrolidinyl)ethoxy]phenyl}acetate as an oil. Yield 92.6%. Electrospray Mass Spec 487.1 (M+H)+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]3[CH:15]=[C:16]([CH3:22])[C:17]([C:20]#[N:21])=[C:18]([CH3:19])[C:13]=3[N:12]=[C:11]2[CH2:23][CH3:24])=[CH:6][CH:5]=1.[OH-:25].[Na+]>OS(O)(=O)=O>[Cl:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:14]3[CH:15]=[C:16]([CH3:22])[C:17]([C:20]([NH2:21])=[O:25])=[C:18]([CH3:19])[C:13]=3[N:12]=[C:11]2[CH2:23][CH3:24])=[CH:8][CH:9]=1
Reactant: [OH-]
Reactant: CCc1nc2c(C)c(C#N)c(C)cc2n1-c1ccc(CCCl)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCc1nc2c(C)c(C(N)=O)c(C)cc2n1-c1ccc(CCCl)cc1
Yield: 83 %

Procedure:
A solution of 1-[4-(2-chloroethyl)phenyl]-2-ethyl-4,6-dimethyl-1H-benzimidazole-5-carbonitrile (Example 329, step 6, 997 mg, 2.95 mmol) in c.H2SO4 (50 ml) was stirred at 80° C. for 15 h. The mixture was poured onto ice and was neutralized with NaOH. The mixture was extracted with ethyl acetate (600 ml). The organic layer was washed with brine (300 ml), then dried (Na2SO4). The solvent was removed to afford 871 mg (83%) of the title compound as white solids.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:20]=[CH:19][C:9]([O:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=2)=[CH:8][CH:7]=1)(=[O:4])=[O:3].C(O)(=O)C.[Cl:25][CH2:26][CH2:27][NH:28][CH2:29][CH2:30][Cl:31].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C)C=O.O>[Cl:25][CH2:26][CH2:27][N:28]([CH2:15][C:14]1[CH:17]=[CH:18][C:11]([O:10][C:9]2[CH:19]=[CH:20][C:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:7][CH:8]=2)=[CH:12][CH:13]=1)[CH2:29][CH2:30][Cl:31]
Reactant: CS(=O)(=O)Nc1ccc(Oc2ccc(C=O)cc2)cc1
Reactant: ClCCNCCCl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1ccc(Oc2ccc(CN(CCCl)CCCl)cc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 43.4 %

Procedure:
To a solution of 4-(4-methylsulfonylaminophenoxy)benzaldehyde (1.27 g) in dimethylformamide (5 mL)/acetic acid (0.5 mL) was added N,N-bis(2-chloroethyl)amine (856 mg) and the solution was stirred at room temperature for 10 minutes. Sodium triacetoxyborohydride (31.39 g) was added to the solution, which was stirred at room temperature overnight. Water was added to the reaction mixture, which was extracted with ethyl acetate three times. The extract was washed with brine (30 mL), dried over anhydrous sodium sulfate and concentrated. The obtained residue purified by column chromatography on silica gel (hexane:ethyl acetate=5:1) to give the title compound (790 mg) having the following physical data.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].S(OC)(O[CH3:15])(=O)=O>[OH-].[Na+]>[Br:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[O:10][CH3:15]
Reactant: COS(=O)(=O)OC
Reactant: Cc1cc(Br)cc(Br)c1O
Agent: [Na+]
Agent: [OH-]
Product: COc1c(C)cc(Br)cc1Br
Reaction time: 0.08 h

Procedure:
To a stirred solution of the product of stage (a) (266 g) in 4 N aqueous sodium hydroxide (900 ml), dimethyl sulphate (192 ml) was added whilst maintaining the temperature at 35°-40° C. The mixture was stirred for 5 minutes, then 4 N aqueous sodium hydroxide (450 ml) was added and dimethyl sulphate (96 ml) was added dropwise. The temperature rose to 55° C. The mixture was then stirred overnight, and the product was extracted into dichloromethane, washed with water, dried over magnesium sulphate, filtered, and the solvent evaporated off to give a brown oil (280 g). Distillation gave the title product as a colourless oil, bp 96°-98° C./0.3 mm Hg.
Reaction SMILES: [Br:1][C:2]1[C:3](OS(C(F)(F)F)(=O)=O)=[C:4]([C:7]([O:9][CH3:10])=[O:8])[S:5][CH:6]=1.[C:19]([O-])([O-])=O.[K+].[K+].CB(O)O>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:1][C:2]1[C:3]([CH3:19])=[C:4]([C:7]([O:9][CH3:10])=[O:8])[S:5][CH:6]=1
Reactant: COC(=O)c1scc(Br)c1OS(=O)(=O)C(F)(F)F
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CB(O)O
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1scc(Br)c1C
Temperature: 70 °C
Yield: 83.4 %

Procedure:
To a solution of methyl 4-bromo-3-{[(trifluoromethyl)sulfonyl]oxy}-2-thiophenecarboxylate (825 mg, 2.25 mmol) in dioxane/H2O (5 mL/1 mL) was added K2CO3 (930 mg, 6.75 mmol), tetrakistriphenylphosphine Pd(0) (260 mg, 0.22 mmol), and methylboronic acid (175 mg, 2.91 mmol). The reaction mixture was heated to 70° C. in a sealed tube for 12 h. The reaction solution was concentrated under vacuum and purified on silica gel (hexanes/EtOAc, 9:1) to give the title compound (441 mg, 84%) as a brown solid: LC-MS (ES) m/z 236 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[C:10]([N:14]3[CH2:19][CH2:18][CH:17]([C:20]([OH:22])=O)[CH2:16][CH2:15]3)=[N:11][S:12][N:13]=2)=[CH:3][CH:2]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[F:56][C:57]([F:66])([F:65])[C:58]1[CH:59]=[C:60]([NH2:64])[CH:61]=[CH:62][CH:63]=1>CCOC(C)=O.CN(C=O)C>[F:56][C:57]([F:65])([F:66])[C:58]1[CH:59]=[C:60]([NH:64][C:20]([CH:17]2[CH2:16][CH2:15][N:14]([C:10]3[C:9]([O:8][CH2:7][C:4]4[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=4)=[N:13][S:12][N:11]=3)[CH2:19][CH2:18]2)=[O:22])[CH:61]=[CH:62][CH:63]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: O=C(O)C1CCN(c2nsnc2OCc2ccncc2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccc(C(F)(F)F)c1)C1CCN(c2nsnc2OCc2ccncc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.8 %

Procedure:
1-[4-(Pyridin-4-ylmethoxy)-[1,2,5]thiadiazol-3-yl]-piperidine-4-carboxylic acid (280 mg, 0.87 mmol), HATU (328 mg, 0.86 mmol), DMF (1.5 mL) and DIEA (0.5 mL, 3.87 mmol) were combined and vortexed until a homogeneous mixture was obtained. 3-Trifluoromethyl-phenylamine (0.109 mL, 0.87 mmol) was added and the resulting mixture stirred at room temperature overnight. The reaction mixture was diluted with EtOAc and washed with sat'd NaHCO3 (3×), sat'd NaCl (1×), dried (Na2SO4), and concentrated in vacuo. The crude product was purified by column chromatography (4:1 hexanes:EtOAc, followed by 1:1 hexanes:EtOAc) to give 100 mg (25%) of 1-[4-(Pyridin-4-ylmethoxy)-[1,2,5]thiadiazol-3-yl]-piperidine-4-carboxylic acid (3-trifluoromethyl-phenyl)-amide as a white solid after lyophilization from H2O—AcCN. 1H NMR (CD3OD) 8.54 (d, 2H), 8.02 (s, 1H), 7.74 (d, 1H), 7.51-7.46 (m, 3H), 7.36 (d, 1H), 5.57 (s, 2H), 4.32 (m, 2H), 3.00 (m, 2H), 2.64 (m, 1H), 1.96-1.90 (m, 4H) ppm. LC-MS (MH+)=464.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH:10]([O:13][C:14]1[CH:15]=[C:16]([CH:28]=[C:29]([NH2:31])[CH:30]=1)[C:17]([NH:19][C:20]1[S:21][C:22]([C:25]([OH:27])=[O:26])=[CH:23][N:24]=1)=[O:18])([CH3:12])[CH3:11].C([BH3-])#N.[Na+]>CO>[CH:10]([O:13][C:14]1[CH:15]=[C:16]([CH:28]=[C:29]([NH:31][CH2:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=2[Cl:1])[CH:30]=1)[C:17]([NH:19][C:20]1[S:21][C:22]([C:25]([OH:27])=[O:26])=[CH:23][N:24]=1)=[O:18])([CH3:12])[CH3:11]
Reactant: O=Cc1ccccc1Cl
Reactant: CC(C)Oc1cc(N)cc(C(=O)Nc2ncc(C(=O)O)s2)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(C)Oc1cc(NCc2ccccc2Cl)cc(C(=O)Nc2ncc(C(=O)O)s2)c1
Reaction time: 16 h
Yield: 55 %

Procedure:
2-Chlorobenzaldehyde (0.012 ml, 0.11 mM) was added to 2-[(3-isopropoxy-5-aminobenzoyl)amino]-5-thiazolecarboxylic acid (29 mg 0.09 mM) and 4A molecular sieves (90 mg) in methanol under an inert atmosphere at room temperature. After 1 hr sodium cyanoborohydride (7 mg, 0.11 mM) was added and the reaction mixture stirred for 16 hrs. The reaction mixture was filtered, concentrated in vacuo, the residue stirred with water then extracted with ethyl acetate (3×10 ml). The organic extracts were washed with brine (20 ml), dried (MgSO4), filtered and concentrated in vacuo to give the title compound as a pale yellow solid (22 mg, 55%); 1H nmr (d6-DMSO, δ values): 1.22 (6H, d); 4.36 (2H, m); 4.58 (1H, m); 6.24 (1H, s); 6.47 (1H, m); 6.84 (2H, m); 7.26 (3H, m); 7.37 (2H, m); 7.45 (1H, m); 7.76 (1H, br s). MS [M-CO2H]− 400, 402.
Reaction SMILES: C(C1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[C:14]3=[N:15][C:16]([C:20]4[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=4)=[N:17][C:18](=[O:19])[C:13]3=[C:12]([CH3:26])[NH:11]2)=[CH:5][CH:4]=1)#N.[OH-:27].[Na+].[CH2:29]([OH:31])[CH3:30]>>[C:29]([C:30]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[C:14]3=[N:15][C:16]([C:20]4[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=4)=[N:17][C:18](=[O:19])[C:13]3=[C:12]([CH3:26])[NH:11]2)=[CH:5][CH:4]=1)([OH:27])=[O:31]
Reactant: CCO
Reactant: [OH-]
Reactant: Cc1[nH]n(Cc2ccc(C#N)cc2)c2nc(-c3ccncc3)nc(=O)c1-2
Agent: [Na+]
Product: Cc1[nH]n(Cc2ccc(C(=O)O)cc2)c2nc(-c3ccncc3)nc(=O)c1-2
Yield: 16 %

Procedure:
A mixture of 1-(4-cyanophenylmethyl)-3-methyl-6-(4-pyridyl)-pyrazolo[3,4-d]pyrimidin-4-one (1.6 g, 4.5 mmol), 10M NaOH (50 ml) and ethanol (50 ml) was refluxed for 4 hours. The mixture was filtered while hot, the filtrate was cooled and acidified with acetic acid (pH 6). The product was collected by filtration and washed with ethanol and ether. The product was recrystallized from DMF to afford 0.26 g (16%) of 1-(4-carboxyphenylmethyl)-3-methyl-6-(4-pyridyl)-pyrazolo[3,4-d]pyrimidin-4-one as an off-white powder, m.p. >300° C. when dried at 120° C. for 18 hours in high vacuum.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([OH:14])=O)[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH2:63]([N:65]([CH2:75][CH3:76])[CH2:66][CH2:67][CH2:68][CH:69]1[CH2:74][CH2:73][CH2:72][NH:71][CH2:70]1)[CH3:64]>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:71]1[CH2:72][CH2:73][CH2:74][CH:69]([CH2:68][CH2:67][CH2:66][N:65]([CH2:75][CH3:76])[CH2:63][CH3:64])[CH2:70]1)=[O:14])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: CCN(CC)CCCC1CCCNC1
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CCN(CC)CCCC1CCCN(C(=O)c2cc3ncnc(NC(C)c4nc5cc(Cl)ccc5[nH]4)c3cc2Cl)C1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and 3-(3-diethylamino-propyl)-piperidine in DMSO at ambient temperature.
Reaction SMILES: [F:1][C:2]([F:50])([F:49])[C:3]1[CH:48]=[CH:47][C:6]2[NH:7][C:8]([C:10]3[CH:15]=[CH:14][C:13]([S:16]([CH:19]4[CH2:25][CH2:24][CH2:23][CH2:22][N:21]([O:26]C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[C:20]4=[O:46])(=[O:18])=[O:17])=[CH:12][CH:11]=3)=[N:9][C:5]=2[CH:4]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:26][N:21]1[CH2:22][CH2:23][CH2:24][CH2:25][CH:19]([S:16]([C:13]2[CH:12]=[CH:11][C:10]([C:8]3[NH:7][C:6]4[CH:47]=[CH:48][C:3]([C:2]([F:50])([F:49])[F:1])=[CH:4][C:5]=4[N:9]=3)=[CH:15][CH:14]=2)(=[O:18])=[O:17])[C:20]1=[O:46]
Reactant: O=C1C(S(=O)(=O)c2ccc(-c3nc4cc(C(F)(F)F)ccc4[nH]3)cc2)CCCCN1OC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1C(S(=O)(=O)c2ccc(-c3nc4cc(C(F)(F)F)ccc4[nH]3)cc2)CCCCN1O
Reaction time: 0.5 h

Procedure:
3-[4-(5-trifluoromethyl-1H-benzoimidazol-2-yl)-benzenesulfonyl]-1-trityloxy-azepan-2-one prepared from step H (8.2 mg, 0.0117 mmol) in 0.75 ml of anhydrous CH2Cl2 was added 0.75 ml of TFA and the resulting solution was stirred for 30 min. After TLC indicated the completion of the reaction (<30 min), the reaction mixture was concentrated under reduced pressure to gave a crude material, which was then purified by a column chromatography (0˜5% MeOH in EtOAc and CH2Cl2 1:1). MS: 454.0 (M+H)+, 476.0 (M+Na)+.