Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:36])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:18]3[CH:23]=[CH:22][N:21]=[C:20]([NH:24][CH2:25][C:26]4[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:27]=4[O:34][CH3:35])[N:19]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)C.[OH-].[Li+]>C1COCC1.O>[CH3:35][O:34][C:27]1[CH:28]=[CH:29][C:30]([O:32][CH3:33])=[CH:31][C:26]=1[CH2:25][NH:24][C:20]1[N:19]=[C:18]([O:17][C:13]2[CH:14]=[C:15]([CH3:16])[C:7]3[CH:6]([CH2:5][C:4]([OH:36])=[O:3])[O:10][B:9]([OH:11])[C:8]=3[CH:12]=2)[CH:23]=[CH:22][N:21]=1
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3ccnc(NCc4cc(OC)ccc4OC)n3)cc(C)c21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(OC)c(CNc2nccc(Oc3cc(C)c4c(c3)B(O)OC4CC(=O)O)n2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 96.9 %

Procedure:
A solution of {6-[2-(2,5-dimethoxy-benzylamino)-pyrimidin-4-yloxy]-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl}-acetic acid ethyl ester (0.35 g, 0.71 mmol) in THF (5 mL) was treated with lithium hydroxide (0.081 g, 3.55 mmol) in water (5 mL) at 0° C. The mixture was stirred at 0° C. for 1 hour then at room temperature for 1 hour. The mixture was quenched with 2N HCl to pH 2 then concentrated to approximately ½ the entire volume, diluted with brine and extracted with ethyl acetate. The organic extracts were dried (Na2SO4), filtered and concentrated to give {6-[2-(2,5-dimethoxy-benzylamino)-pyrimidin-4-yloxy]-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl}-acetic acid as a yellow solid (0.32 g, 97%). 1H NMR (400 MHz, CD3OD) δ8.11 (d, J=6.64 Hz, 1H), 7.25 (s, 1H), 7.13 (s, 1H), 6.60-6.20 (m, 4H), 5.75-5.65 (m, 1H), 4.20-4.10 (m, 2H), 3.80 (s, 3H), 3.76 (s, 3H), 3.21-3.10 (m, 1H), 2.40 (s, 3H), 2.39-2.20 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[NH:12]1[CH:16]=[CH:15][CH:14]=[N:13]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[N:12]1[CH:16]=[CH:15][CH:14]=[N:13]1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(-n2cccn2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.2 %

Procedure:
A mixture of 3,4-difluoronitrobenzene (1.00 mL, 9.03 mmol), pyrazole (0.615 g, 9.04 mmol) and K2CO3 (2.50 g, 18.1 mmol) in DMF (10 mL) was stirred at room temperature overnight. Water (30 mL) was added to induce precipitation. The precipitate was collected, dried on vacuum to give 1-(2-fluoro-4-nitrophenyl)-1H-pyrazole as a solid (1.80 g). MS 208.3 (M+H)
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[N:5]=[C:6]([N:11]([CH3:32])[C:12]3[CH:13]=[C:14]([NH:18][C:19](=[O:31])[C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([C:29]#[N:30])([CH3:28])[CH3:27])[CH:21]=4)[CH:15]=[CH:16][CH:17]=3)[N:7]=[CH:8][C:9]=2[N:10]=1.[CH:33]1([C:36](Cl)=[O:37])[CH2:35][CH2:34]1.C(=O)([O-])O.[Na+]>CN(C)C(=O)C>[C:29]([C:26]([C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=1)[C:19]([NH:18][C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([N:11]([C:6]2[N:7]=[CH:8][C:9]3[N:10]=[C:2]([NH:1][C:36]([CH:33]4[CH2:35][CH2:34]4)=[O:37])[S:3][C:4]=3[N:5]=2)[CH3:32])[CH:13]=1)=[O:31])([CH3:27])[CH3:28])#[N:30]
Reactant: CN(c1cccc(NC(=O)c2cccc(C(C)(C)C#N)c2)c1)c1ncc2nc(N)sc2n1
Reactant: O=C(Cl)C1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CN(c1cccc(NC(=O)c2cccc(C(C)(C)C#N)c2)c1)c1ncc2nc(NC(=O)C3CC3)sc2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.4 %

Procedure:
To a solution of N-{3-[(2-amino[1,3]thiazolo[5,4-d]pyrimidin-5-yl)(methyl)amino]phenyl}-3-(1-cyano-1-methylethyl)benzamide (151 mg, 340 μmol) in N,N-dimethylacetamide (4 mL) was added cyclopropanecarbonyl chloride (389 μL, 4.32 mmol), and the mixture was stirred at room temperature for 3 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution (20 mL), and the mixture was extracted with ethyl acetate (20 mL, 5 mL). The solid which crystallized in the extract was collected by filtration to give the title compound (119 mg, 68%) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([N+]([O-])=O)[C:8]([F:14])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F-:15].[K+]>C1S(=O)(=O)CCC1>[Cl:1][C:2]1[CH:10]=[C:9]([F:15])[C:8]([F:14])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cc(F)c([N+](=O)[O-])cc1Cl
Reactant: [F-]
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Product: O=C(O)c1cc(F)c(F)cc1Cl
Temperature: 150 °C

Procedure:
The combined benzoic acids made in each of Examples 3, 11 and 12 (consisting of compounds 5 and 6 in a ratio of about 2:1) were converted to the corresponding acid chlorides as in Example 4. The acid chlorides (2 g, 8.4 mmol) were dissolved in 4 ml of tetramethylenesulfone and treated with spray-dried KF (2.0 g, 34.5 mmol). The mixture was heated at 150° C. under nitrogen for 3 hours and the product distilled at 70°-75° C./15 mm. The acid fluoride collected was hydrolyzed with water and the product was dried in vacuum to give pure compound 8 as the only product (0.4 g, 24%).
Reaction SMILES: FF.[NH2:3][C:4]1[N:9]=[C:8]([O:10]C)[CH:7]=[C:6]([O:12][CH3:13])[N:5]=1.Cl[CH:15]([F:17])[F:16]>>[NH2:3][C:4]1[N:9]=[C:8]([O:10][CH:15]([F:17])[F:16])[CH:7]=[C:6]([O:12][CH3:13])[N:5]=1
Reactant: FC(F)Cl
Reactant: COc1cc(OC)nc(N)n1
Agent: FF
Product: COc1cc(OC(F)F)nc(N)n1
Yield: 10 %

Procedure:
Because of the difficulty of handling fluorine, which is extremely reactive, non-selective and toxic, to date no methods for the direct fluorination of alkoxypyrimidines have been disclosed. Trifluoro- and chlorodifluoromethoxypyrimidines have not been disclosed either. Difluoromethoxypyrimidines have been obtained by a circuitous route, for example by ester cleavage of 2-amino-4,6-dimethoxypyrimidine to give the corresponding 4-hydroxy compound and subsequent reaction with chlorodifluoromethane to give 2-amino-4-difluoromethoxy-6-methoxypyrimidine in 10% yield (EP-A-70,804, Example 6). Since the starting material is prepared from trichloropyrimidine by reaction with ammonia and methanol, and then the methyl group has to be eliminated again, this is not an economic route. Direct reaction of 2-amino-4,6-dihydroxypyrimidine with chlorodifluoromethane yields the corresponding 4,6-bis(difluoromethoxy) compound in 6.4% yield (EP-A-70,804, Example 3). Finally, special safety measures are required when handling harmful chlorodifluoromethane in order to prevent escape into the atmosphere.
Reaction SMILES: [Br:1][C:2]1[C:10]2[NH:9][C:8](=[O:11])[NH:7][C:6]=2[CH:5]=[C:4]([Br:12])[C:3]=1[C:13]([O:15][CH3:16])=[O:14].[H-].[Na+].[CH2:19](Br)[CH2:20][CH:21]([CH3:23])[CH3:22].Cl>CN(C)C=O.O.C(OCC)(=O)C>[Br:1][C:2]1[C:10]2[N:9]([CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[C:8](=[O:11])[N:7]([CH2:10][CH2:2][CH:3]([CH3:13])[CH3:4])[C:6]=2[CH:5]=[C:4]([Br:12])[C:3]=1[C:13]([O:15][CH3:16])=[O:14]
Reactant: CC(C)CCBr
Reactant: COC(=O)c1c(Br)cc2[nH]c(=O)[nH]c2c1Br
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1c(Br)cc2c(c1Br)n(CCC(C)C)c(=O)n2CCC(C)C
Temperature: 55 °C
Reaction time: 3 h

Procedure:
In 10 ml of N,N-dimethylformamide are suspended 0.95 g of methyl 4,6-dibromo-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylate, 0.24 g of 60% sodium hydride and 0.7 ml of isopentyl bromide. The suspension is stirred at 50-60° C. for 3 hours. The reaction mixture is added to a mixture of ethyl acetate and water, pH is adjusted to 2 with 2 mol/L hydrochloric acid, and the organic layer is separated. The organic layer thus obtained is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. Thus, 0.71 g of methyl 4,6-dibromo-1,3-diisopentyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylate is obtained as a light brown-colored solid product.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].[OH:26][CH2:27][CH:28]([NH:31][S:32]([C:35]1[S:36][C:37](Cl)=[CH:38][CH:39]=1)(=[O:34])=[O:33])[CH2:29][OH:30]>>[OH:26][CH2:27][CH:28]([NH:31][S:32]([C:35]1[S:36][C:37]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)=[CH:38][CH:39]=1)(=[O:34])=[O:33])[CH2:29][OH:30]
Reactant: O=S(=O)(NC(CO)CO)c1ccc(Cl)s1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: O=S(=O)(NC(CO)CO)c1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)s1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (178 mg, 0.5 mmol) and 5-chloro-thiophene-2-sulfonic acid (2-hydroxy-1-hydroxymethyl-ethyl)-amide (example B.42) (138 mg, 0.5 mmol) according to general procedure II. Obtained as an orange solid (52 mg, 18%). MS (ISN) 589.1 [(M−H)−]; mp 247° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:5]2[S:10][C:9]([C:11]3[CH:12]=[N:13][O:14][CH:15]=3)=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:30]2[CH:38]=[CH:37][CH:36]=[C:35]3[C:31]=2[CH:32]=[N:33][NH:34]3)O1>>[NH:34]1[C:35]2[C:31](=[C:30]([C:2]3[N:3]=[C:4]([N:16]4[CH2:21][CH2:20][O:19][CH2:18][CH2:17]4)[C:5]4[S:10][C:9]([C:11]5[CH:12]=[N:13][O:14][CH:15]=5)=[CH:8][C:6]=4[N:7]=3)[CH:38]=[CH:37][CH:36]=2)[CH:32]=[N:33]1
Reactant: Clc1nc(N2CCOCC2)c2sc(-c3cnoc3)cc2n1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Product: c1cc(-c2nc(N3CCOCC3)c3sc(-c4cnoc4)cc3n2)c2cn[nH]c2c1

Procedure:
2-Chloro-6-(isoxazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine (85 mg) was coupled to 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 via General Procedure A to yield 4.3 mg of 328. MS (Q1) 405.1 (M)+
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].C1(C=CC(O)=CC=1)O.[O:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22][NH2:23])[CH2:16][CH2:15]1.[OH-].[Na+]>O.C(#N)C>[O:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22][NH:23][C:1](=[O:4])[CH:2]=[CH2:3])[CH2:16][CH2:15]1
Reactant: C=CC(=O)Cl
Reactant: NCCCN1CCOCC1
Agent: Oc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: C=CC(=O)NCCCN1CCOCC1
Reaction time: 3.5 h

Procedure:
In a 1 liter capacity round bottom flask equipped with a stirrer were put 90.5 g (1.0 mole) of acrylic acid chloride and 300 cc of acetonitrile and, as a polymerization inhibitor, 0.5 g of hydroquinone, and then, after the contents were cooled to 5°-10°C, 143 g (1.0 mole) of 3-morpholinopropylamine was added dropwise thereto over the course of 3.5 hours while stirring. Afterwards, the reaction mixture was stirred additionally for 2 hours at 40°-50°C. Next, a solution of 40 g of sodium hydroxide in 100 cc of water was added thereto and then the mixture was stirred for 30 minutes. After removal of the sodium chloride which separated, 152 g (77.0%) of a fraction of 144°-146°C/0.1 mmHg were obtained.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([C:16]2[CH:21]=[N:20][CH:19]=[C:18](I)[N:17]=2)=[N:13][C:12]=1[CH3:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].[F:30][C:31]([F:44])([F:43])[C:32]1[CH:37]=[CH:36][C:35](/[CH:38]=[CH:39]/B(O)O)=[CH:34][CH:33]=1.O>COC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([C:16]2[CH:21]=[N:20][CH:19]=[C:18](/[CH:39]=[CH:38]/[C:35]3[CH:34]=[CH:33][C:32]([C:31]([F:30])([F:43])[F:44])=[CH:37][CH:36]=3)[N:17]=2)=[N:13][C:12]=1[CH3:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)/C=C/c1ccc(C(F)(F)F)cc1
Reactant: Cc1nc(-c2cncc(I)n2)sc1C(=O)NCc1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: COC
Solvent: O
Product: Cc1nc(-c2cncc(/C=C/c3ccc(C(F)(F)F)cc3)n2)sc1C(=O)NCc1ccccc1
Reaction time: 2 h
Yield: 69.7 %

Procedure:
To a solution of 2-(6-iodo-pyrazin-2-yl)-4-methyl-thiazole-5-carboxylic acid benzylamide (100 mg, 0.23 mmol, 1.0 equiv) in dimethyl ether (1 mL) was added Na2CO3 (49 mg, 0.46 mmol, 2.0 equiv), trans-2-(4-trifluoromethylphenyl)vinyl boronic acid (123 mg, 0.57 mmol, 2.5 equiv.), PdCl2(dppf) (17 mg, 0.02 mmol, 0.1 equiv) and water (0.1 mL) in a sealed tube. The reaction vessel was immersed in an oil bath preheated to 100° C. After stirring for 2 hr, the reaction mixture was cooled and the solvent was removed in vacuo. The crude product was purified by column chromatography [SiO2, methanol/dichloromethane, 0:100 to 10:90, v/v] and recrystallization (methanol/pentane) to afford 4-methyl-2-{6-[(E)-2-(4-trifluoromethyl-phenyl)-vinyl]-pyrazin-2-yl}-thiazole-5-carboxylic acid benzylamide (77 mg, 70%). 1H NMR (400 MHz, CD2Cl2) δ 9.23 (s, 1H), 8.68 (s, 1H), 7.87 (d, J=16.0 Hz, 1H), 7.75 (d, J=8.0 Hz, 2H), 7.66 (d, J=12.0 Hz, 2H), 7.37 (d, J=4.0 Hz, 4H), 7.28-7.36 (m, 1H), 7.28 (d, J=16.0 Hz, 1H), 6.25 (bs, 1H), 4.62 (d, J=4.0 Hz, 2H), 2.74 (s, 3H); HRMS (M+H)+=481.13.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]([N:13]2[C:21]3[C:16](=[CH:17][C:18]([O:26][CH3:27])=[C:19]([C:22]([F:25])([F:24])[F:23])[CH:20]=3)[CH2:15][CH2:14]2)=[O:12])[CH:5]=[C:6](Br)[C:7]=1[CH3:8].[N:28]1[CH:33]=[CH:32][CH:31]=[C:30](B(O)O)[CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]([N:13]2[C:21]3[C:16](=[CH:17][C:18]([O:26][CH3:27])=[C:19]([C:22]([F:24])([F:25])[F:23])[CH:20]=3)[CH2:15][CH2:14]2)=[O:12])[CH:5]=[C:6]([C:30]2[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=2)[C:7]=1[CH3:8]
Reactant: COc1cc2c(cc1C(F)(F)F)N(C(=O)Nc1cc(Br)c(C)c(Br)c1)CC2
Reactant: OB(O)c1cccnc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1cc2c(cc1C(F)(F)F)N(C(=O)Nc1cc(Br)c(C)c(-c3cccnc3)c1)CC2
Yield: 27.7 %

Procedure:
A mixture of 1-(3,5-dibromo-4methylphenylcarbamoyl)-5-methoxy-6-trifluoromethylindoline (D25, 0.51 g, 1 mmol), 3-pyridylboronic acid (0.12 g, 1 mmol), tetrakis (triphenylphosphine)palladium (0) (35 mg, 0.03 mmol) and sodium carbonate (0.41 g, 4 mmol) in dimethoxyethane (30 mL) and water (3 mL) was heated under reflux, under argon, for 18 h. The mixture was cooled and poured into water. The precipitate was filtered off, washed with water and dried. The crude product was chromatographed on silica gel, eluted with ethyl acetate, and the eluted material was triturated with ether to give the title compound (0.14 g, 28%), m.p. 216-8° C.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[O:11][CH2:10][CH2:9][C@H:8]2[NH2:13].CCN(C(C)C)C(C)C.[Cl:23][C:24]1[N:29]=[C:28](Cl)[C:27]([N+:31]([O-:33])=[O:32])=[CH:26][N:25]=1>C(Cl)Cl>[Cl:23][C:24]1[N:29]=[C:28]([NH:13][C@H:8]2[C:7]3[C:12](=[C:3]([F:2])[CH:4]=[CH:5][CH:6]=3)[O:11][CH2:10][CH2:9]2)[C:27]([N+:31]([O-:33])=[O:32])=[CH:26][N:25]=1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: N[C@@H]1CCOc2c(F)cccc21
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cnc(Cl)nc1N[C@@H]1CCOc2c(F)cccc21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 88.1 %

Procedure:
A solution of (R)-8-fluorochroman-4-amine hydrochloride (1.02 g) and DIEA (2.6 mL) in DCM (10 mL) was slowly added to a solution of 2,4-dichloro-5-nitropyrimidine (0.97 g) THF (25 mL) at −78° C. The reaction mixture was stirred for 30 min at −78° C. then allowed to warm to RT overnight. The reaction was quenched with the addition of sat. NH4Cl (1 mL), the solvent volume was reduced in vacuo, and the resulting mixture partition between EtOAc and water then separated. The crude material was purified via column chromatography, elution with 30% EtOAc/Hex gave the titled product (1.43 g). 1H-NMR (300 MHz, CDCl3) δ 9.1 (s, 1H), 8.6 (br d, 1H), 7.1-6.8 (m, 3H), 5.6 (dd, 1H), 4.4 (m 1H), 4.3 (m, 1H), 2.4 (m, 1H), 2.2 (m, 1H).
Reaction SMILES: Cl.[NH:2]1[CH2:6][CH2:5][N:4]=[C:3]1[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([S:17](Cl)(=[O:19])=[O:18])=[CH:9]1.[CH3:21][NH:22][CH3:23]>C(=O)(O)[O-].[Na+]>[CH3:21][N:22]([CH3:23])[S:17]([C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]([CH2:7][C:3]2[NH:2][CH2:6][CH2:5][N:4]=2)[CH:9]=1)(=[O:19])=[O:18]
Reactant: O=S(=O)(Cl)c1cn(CC2=NCCN2)c2ccccc12
Reactant: CNC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CN(C)S(=O)(=O)c1cn(CC2=NCCN2)c2ccccc12
Reaction time: 0.25 h

Procedure:
1-(4,5-Dihydro-1H-imidazol-2-ylmethyl)-1H-indole-3-sulfonyl chloride hydrochloride (0.297 g, 1 mmol) was dissolved in 1-methylpyrrlolidinone (14 mL) and stirred. Excess dimethylamine in 1-methylpyrrlolidinone was added to the stirring solution, after which the mixture was allowed to stand at room temperature for 15 minutes. Saturated aqueous sodium bicarbonate (30 mL) was then added, and the mixture was evaporated to dryness. The residue was purified by preparative HPLC to provide 1-(4,5-dihydro-1H-imidazol-2-ylmethyl)-1H-indole-3-sulfonic acid dimethylamide as a crystalline solid.
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[N:8][N:9]([CH2:11][CH2:12][C@@:13]([CH3:21])([S:17]([CH3:20])(=[O:19])=[O:18])[C:14]([OH:16])=O)[CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN1CCOCC1.[O:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]1[O:35][NH2:36]>O>[CH:1]1([C:6]2[CH:7]=[N:8][N:9]([CH2:11][CH2:12][C@@:13]([CH3:21])([S:17]([CH3:20])(=[O:19])=[O:18])[C:14]([NH:36][O:35][CH:30]3[CH2:31][CH2:32][CH2:33][CH2:34][O:29]3)=[O:16])[CH:10]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C[C@@](CCn1cc(C2CCCC2)cn1)(C(=O)O)S(C)(=O)=O
Reactant: NOC1CCCCO1
Solvent: O
Solvent: CN1CCOCC1
Product: C[C@@](CCn1cc(C2CCCC2)cn1)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
(2R)-4-(4-cyclopentyl-1H-pyrazol-1-yl)-2-methyl-2-(methylsulfonyl)butanoic acid (100 mg, 0.318 mmol, 1 eq) and CDMT (73.2 mg, 0.413 mmol, 1.3 eq) were charged into a flask. The flask was flushed with nitrogen and then 2-MeTHF (5 mL) added. To this mixture was added N-methylmorpholine (50 uL, 0.445 mmol, 1.4 eq) and the reaction mixture was stirred at RT for one hour. O-Tetrahydro-2H-pyran-2-yl-hydroxylamine (49 mg, 0.413 mmol, 1.3 eq) was added and the reaction mixture was stirred overnight at RT. Water (25 mL) was added and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (50 mL). The organic phases were combined, dried over sodium sulfate, filtered and concentrated to give (2R)-4-(4-cyclopentyl-1H-pyrazol-1-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (100 mg, 76% yield) which was used without further purification. LC-MS M+H+414.1.
Reaction SMILES: Br.[NH2:2][C:3]1[S:4][C:5]2[C:11](=[O:12])[CH2:10][C:9]([CH3:14])([CH3:13])[CH2:8][C:6]=2[N:7]=1.[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([CH3:23])[C:17]=1[S:24](Cl)(=[O:26])=[O:25]>>[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([CH3:23])[C:17]=1[S:24]([NH:2][C:3]1[S:4][C:5]2[C:11](=[O:12])[CH2:10][C:9]([CH3:14])([CH3:13])[CH2:8][C:6]=2[N:7]=1)(=[O:26])=[O:25]
Reactant: CC1(C)CC(=O)c2sc(N)nc2C1
Reactant: Cc1cc(Cl)cc(Cl)c1S(=O)(=O)Cl
Agent: Br
Product: Cc1cc(Cl)cc(Cl)c1S(=O)(=O)Nc1nc2c(s1)C(=O)CC(C)(C)C2

Procedure:
The title compound was prepared from 2-amino-5,5-dimethyl-5,6-dihydro-1,3-benzothiazol-7(4H)-one hydrobromide and 2,4-dichloro-6-methylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a white-yellow solid (26 mg) with purity >90%: MS (pos) m/z 419.1, 421.1; HRMS m/z 417.9979 (calc. of monoisotopic mass for C16H16Cl2N2O3S2 gives 417.9979).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[CH2:6][CH2:7][N:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[C:9](=[O:12])[C:10]=2[CH:11]=1.[CH2:22]([OH:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.[Cu]I>[CH2:22]([O:29][C:2]1[CH:3]=[N:4][C:5]2[CH2:6][CH2:7][N:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[C:9](=[O:12])[C:10]=2[CH:11]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COc1ccc(CN2CCc3ncc(Br)cc3C2=O)cc1
Reactant: OCc1ccccc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: COc1ccc(CN2CCc3ncc(OCc4ccccc4)cc3C2=O)cc1
Temperature: 110 °C
Yield: 82.4 %

Procedure:
3-Bromo-6-(4-methoxybenzyl)-7,8-dihydro-1,6-naphthyridin-5(6H)-one (1.2 g, 3.5 mmol), benzyl alcohol (3.62 mL, 35.0 mmol), CuI (67.0 mg, 0.35 mmol), 1,10-phenanthroline (127.0 mg, 0.7 mmol) were mixed with Cs2CO3 (1.69 g, 5.2 mmol) in toluene (15.0 mL). The reaction was degassed, sealed in a microwave tube, heated to 110° C. for 1.5 day. The reaction mixture was passed through a Celite pad, diluted with H2O (50.0 mL), extracted with EtOAc (40.0×3 mL). The organic layers were combined, dried over MgSO4, concentrated in vacuo and purified by automated silica gel column chromatography (EtOAc/hexanes 0-60%). The compound was obtained as a sticky oil (1.08 g, 83%). 1HNMR (400 MHz, CDCl3) δ 8.39 (br s, 1H), 8.01 (d, J=3.2 Hz, 1H), 7.48-7.37 (overlapped, 5H), 7.30-7.27 (overlapped, 2H), 6.90 (d, J=8.8 Hz, 2H), 5.17 (s, 2H), 4.74 (s, 2H), 3.82 (s, 3H), 3.55 (t, J=6.8 Hz, 2H), 3.08 (t, J=6.8 Hz, 2H); LC-MS (M+H)=375.1.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH:8]([OH:9])[CH:7]([OH:10])[CH:6]([OH:11])[CH:5]([O:12][C:13]2[CH:17]=[CH:16][S:15][C:14]=2[CH:18]=[CH:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[O:4]1>CO.[Pd]>[OH:1][CH2:2][CH:3]1[CH:8]([OH:9])[CH:7]([OH:10])[CH:6]([OH:11])[CH:5]([O:12][C:13]2[CH:17]=[CH:16][S:15][C:14]=2[CH2:18][CH2:19][C:20]2[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=2)[O:4]1
Reactant: COc1ccc(C=Cc2sccc2OC2OC(CO)C(O)C(O)C2O)cc1
Agent: [Pd]
Solvent: CO
Product: COc1ccc(CCc2sccc2OC2OC(CO)C(O)C(O)C2O)cc1
Reaction time: 18 h

Procedure:
50 mg 2-hydroxymethyl-6-{2-[2-(4-methoxy-phenyl)-vinyl]-thiophen-3-yloxy}-tetrahydro-pyran-3,4,5-triol were dissolved in 10 of methanol. 20 mg of palladium on activated carbon were added and the solution was stirred under a hydrogen atmosphere for 18 h. The catalyst was filtered off and washed with 60 ml of methanol, and the organic phase was concentrated. The residue was chromatographed on silica gel (ethyl acetate). 18 mg of the product with the molecular weight of 396.46 (C19H24)7S); MS (ESI): 419.05 (M+Na+), 414.10 (M+NH4+).
Reaction SMILES: CS(Cl)(=O)=O.[Cl:6][C:7]1[C:15]2[N:14]=[C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[Cl:24])[N:12]([CH2:25][CH2:26][CH2:27]O)[C:11]=2[C:10]([C:29]([O:31][CH3:32])=[O:30])=[CH:9][CH:8]=1.S([O-])(=O)(=O)C.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.C(=O)([O-])O.[Na+].CN(C)C=O.C(N(CC)CC)C.N1C=CC=CC=1>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([C:29]([O:31][CH3:32])=[O:30])=[C:11]2[C:15]=1[N:14]=[C:13]1[N:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[Cl:24])[CH2:27][CH2:26][CH2:25][N:12]21
Reactant: COC(=O)c1ccc(Cl)c2nc(Nc3ccc(Cl)cc3Cl)n(CCCO)c12
Agent: CS(=O)(=O)Cl
Agent: CS(=O)(=O)[O-]
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 13 h
Yield: 87.4 %

Procedure:
Methanesulfonyl chloride (11.3 mL, 143 mmol) was added to a stirred solution of methyl 4-chloro-2-[(2,4-dichlorophenyl)amino]-1-(3-hydroxypropyl)-1H-benzimidazole-7-carboxylate (Reference example 117, 15.3 g, 35.7 mmol), pyridine (50 mL) and triethylamine (25 mL) in tetrahydrofuran (100 mL) at 0° C. The mixture was stirred at 0° C. for 13 hr, and diluted with aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. A mixture of the resulting mesylate and potassium carbonate (14.7 g, 106 mmol) in N,N-dimethylformamide (60 mL) was stirred at 70° C. for 4 hr. The mixture was diluted with aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was washed with diisopropyl ether to give the title compound as a colorless powder (12.8 g, 31.2 mmol, 87% in 2 steps).