Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2[CH2:14][O:15][C:16]2[N:21]=[N:20][C:19]([C:22]([OH:24])=O)=[CH:18][CH:17]=2)=[N:6][CH:7]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:56][C:57]([CH3:61])([CH3:60])[CH2:58][OH:59]>CN(C=O)C>[OH:59][CH2:58][C:57]([NH:56][C:22]([C:19]1[N:20]=[N:21][C:16]([O:15][CH2:14][C:9]2[N:10]([CH3:13])[N:11]=[N:12][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=2)=[CH:17][CH:18]=1)=[O:24])([CH3:61])[CH3:60]
Reactant: Cn1nnc(-c2ccc(F)cn2)c1COc1ccc(C(=O)O)nn1
Reactant: CC(C)(N)CO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nnc(-c2ccc(F)cn2)c1COc1ccc(C(=O)NC(C)(C)CO)nn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
To a solution of 6-[5-(5-fluoro-pyridin-2-yl)-3-methyl-3H-[1,2,3]triazol-4-ylmethoxy]-pyridazine-3-carboxylic acid (50 mg, 0.15 mmol) and TBTU (54 mg, 0.17 mmol) in DMF (2 mL) was added DIPEA (130 μL, 0.76 mmol). Then 2-amino-2-methyl-1-propanol (16 μL, 0.167 mmol) was added and the mixture was stirred at room temperature under Ar for 1 h. The mixture was then evaporated and purification by chromatography (silica, 50 to 100% ethyl acetate in heptane) afforded the title compound (56 mg, 92%) as a white foam. MS: m/e=402.4 [M+H]+.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1[CH:10]=[C:11]([NH:16][C:17]([C:19]2[C:20](=[S:25])[NH:21][CH:22]=[CH:23][CH:24]=2)=[O:18])[CH:12]=[C:13]([CH3:15])[CH:14]=1.[C:26]([NH:29][C:30]1[N:35]=[C:34]([CH2:36]Cl)[CH:33]=[CH:32][N:31]=1)(=[O:28])[CH3:27].C(OCC)(=O)C>CN(C)C=O>[C:26]([NH:29][C:30]1[N:35]=[C:34]([CH2:36][S:25][C:20]2[C:19]([C:17]([NH:16][C:11]3[CH:12]=[C:13]([CH3:15])[CH:14]=[C:9]([CH3:8])[CH:10]=3)=[O:18])=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:33]=[CH:32][N:31]=1)(=[O:28])[CH3:27]
Reactant: CC(=O)Nc1nccc(CCl)n1
Reactant: Cc1cc(C)cc(NC(=O)c2ccc[nH]c2=S)c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(=O)Nc1nccc(CSc2ncccc2C(=O)Nc2cc(C)cc(C)c2)n1
Yield: 52 %

Procedure:
Triethylamine (45 μL, 0.32 mmol) was added to a solution of N-(3,5-dimethylphenyl)-2-thioxo-1,2-dihydropyridine-3-carboxamide (28 mg, 0.11 mmol, Reference Compound No. 13-1) and 2-acetylamino-4-(chloromethyl)pyrimidine (18 mg, 0.10 mmol, Reference Compound No. 11-1) in anhydrous N,N-dimethylformamide (1.0 mL) at room temperature, and the mixture was stirred for 16 hours. Ethyl acetate (30 mL) was added thereto, then the whole was washed with saturated aqueous sodium hydrogen carbonate solution (30 mL) and brine (30 mL), and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and then the precipitated solid was filtered off with diethyl ether and washed. The solid was dried at 50° C. under reduced pressure to give 21 mg of the target compound as a light orange solid (Yield: 52%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][C:18](I)=[CH:17][C:16]=3[F:24])=[O:11])=[CH:4][CH:3]=1.[C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)#[CH:26].CCN(CC)CC>CN(C=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][C:18]([C:26]#[C:25][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)=[CH:17][C:16]=3[F:24])=[O:11])=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)cc(I)cc2c1O
Reactant: C#Cc1ccccn1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)cc(C#Cc3ccccn3)cc2c1O
Temperature: 25 °C
Yield: 59.1 %

Procedure:
A solution of the title compound of Example 5 (540.3 mg), 2-ethynyl pyridine (0.172 g), PdCl2 (PPh3)2 (21.1 mg), and 0.75 mL Et3N in 3 mL DMF is heated at 90° C. for 1 hr. The reaction mixture is cooled to room temperature and diluted with H2O. A tan solid precipitates, which is collected, dissolved in a mixture of CH2Cl2 and MeOH, and adsorbed onto silica. The crude product is chromatographed eluting with 2% MeOH in CH2Cl2. Fractions homogenous by TLC are combined, condensed and recrystallized from hot MeOH/CH2Cl2 and hexanes to yield 0.302 g of the desired product as a white solid.
Reaction SMILES: [CH2:1]([C:5]1[N:10]=[C:9]([CH3:11])[N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]([O:20][Si](C(C)(C)C)(C)C)[CH3:19])[CH:13]=2)[C:7](=[O:28])[C:6]=1[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[C:42]2[NH:46][C:45](=[O:47])[O:44][N:43]=2)=[CH:32][CH:31]=1)[CH2:2][CH2:3][CH3:4].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C.O>O1CCCC1>[CH2:1]([C:5]1[N:10]=[C:9]([CH3:11])[N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]([OH:20])[CH3:19])[CH:13]=2)[C:7](=[O:28])[C:6]=1[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[C:42]2[NH:46][C:45](=[O:47])[O:44][N:43]=2)=[CH:32][CH:31]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)n(-c2cccc(C(C)O[Si](C)(C)C(C)(C)C)c2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCc1nc(C)n(-c2cccc(C(C)O)c2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 50 °C
Reaction time: 12 h
Yield: 62.8 %

Procedure:
To a solution of 6-butyl-3-[3-(1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one (1.70 g) in tetrahydrofuran (10 mL) was added tetrabutylammonium fluoride (1.0 g), and the mixture was stirred at 50° C. for 12 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.88 g, 63%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:20])[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[S:21]([NH2:24])(=[O:23])=[O:22].CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:20])[C:9]2[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:13][CH:14]=2)=[CH:4][C:3]=1[S:21]([NH2:24])(=[O:23])=[O:22]
Reactant: CCCCOc1ccc(C(O)c2ccc(Cl)c(S(N)(=O)=O)c2)cc1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)=O
Product: CCCCOc1ccc(C(=O)c2ccc(Cl)c(S(N)(=O)=O)c2)cc1
Reaction time: 0.5 h

Procedure:
2-Chloro-5-[hydroxy-(4-butoxy-phenyl)-methyl]-benzenesulfonamide is dissolved in acetone (10 mL), and treated with a solution of Jones reagent (3 M in water, 0.91 mmol). The reaction is allowed to stir for 30 minutes. The reaction is diluted with water and extracted with dichloromethane. The organic phase is separated and concentrated in vacuo. The residue is purified by silica gel chromatography (gradient of ethyl acetate in hexanes 10-50%) affording 74 mg of the title compound. 1H NMR (CDCl3) δ 0.95 (t, 3H, J=7.31 Hz), 1.50 (m, 2H), 1.80 (m, 2H), 4.05 (t, 2H, J=6.48 Hz), 5.15 (s, 2H), 6.95 (d, 2H, J=9.04 Hz), 7.65 (d, 1H, J=8.22), 7.80 (d, 2H, J=9.04 Hz), 7.90 (dd, 1 h, J=1.88, 7.91), 8.45 (d, 1H, J=1.88). MS (m/z): 368 (M+1). CHN Calc C, 55.51; H, 4.93; N, 3.81. Found C, 55.47; H, 4.84; N, 3.63.
Reaction SMILES: [OH:1][CH:2]([CH2:14][CH2:15][O:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][O:18]1)[CH2:3][CH:4]([CH2:12]O)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].C(N(CC)CC)C.[S:30](Cl)([CH3:33])(=[O:32])=[O:31]>C(Cl)Cl>[S:30]([O:1][CH:2]([CH2:14][CH2:15][O:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][O:18]1)[CH2:3][C:4](=[CH2:12])[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])([CH3:33])(=[O:32])=[O:31]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)C(CO)CC(O)CCOC1CCCCO1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(CC(CCOC1CCCCO1)OS(C)(=O)=O)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.1 %

Procedure:
To a stirred solution of tert-butyl 4-hydroxy-2-hydroxymethyl-6-tetrahydropyranyloxyhexanoate (0.28 g) and triethylamine (0.56 g) in methylene chloride (20 ml), mesylchloride (0.56 g) dissolved in methylene chloride (10 ml) was added dropwise under nitrogen atmosphere and ice-cooling. The mixture was stirred for 2 hours at room temperature and concentrated in vacuo. Saturated aqueous sodium bicarbonate solution was added to the oily residue and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate solution, 1N hydrochloric acid, water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. The oily residue was dissolved in benzene (20 ml), and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.2 g) was added to the solution. The mixture was stirred for 3 hours. Aqueous citric acid solution was added to the mixture and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate solution, water and saturated sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. The oily residue was purified by a silica gel column chromatography to give 0.22 g (31%) of tert-butyl 4-mesyloxy-2-methylene-6-tetrahydropyranyloxyhexanoate.
Reaction SMILES: CS(C)=O.[Cl:5][C:6]1[CH:7]=[C:8]([C:13]([F:16])([F:15])[F:14])[CH:9]=[CH:10][C:11]=1Cl.[C:17](=[O:20])([O-])[O-:18].[K+].[K+].[OH2:23]>>[Cl:5][C:6]1[CH:7]=[C:8]([C:13]([F:16])([F:15])[F:14])[CH:9]=[CH:10][C:11]=1[O:23][C:6]1[CH:11]=[C:10]([CH:9]=[CH:8][CH:7]=1)[C:17]([OH:18])=[O:20]
Reactant: O=C([O-])[O-]
Reactant: O
Reactant: FC(F)(F)c1ccc(Cl)c(Cl)c1
Agent: [K+]
Solvent: CS(C)=O
Product: O=C(O)c1cccc(Oc2ccc(C(F)(F)F)cc2Cl)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 85 %

Procedure:
To a 300 ml. 3-necked flask fitted with a magnetic stirring bar, condenser, drying tube and thermometer is charged the solid from above dimethylsulfoxide (100 ml), 3,4-dichlorobenzotrifluoride (21.5 g. 0.10 mole) and anhydrous potassium carbonate (5.0 g) to asure an alkaline pH. The reaction temperature is taken rapidly to 138°-44° C. while vigorous stirring is maintained. After 4 hours a significant conversion is realized and heating is continued overnight (total 22 hrs. ). The reaction mixture is then cooled to room temperature and poured into water (1000 ml) and the aqueous reaction mixture extracted with CCl4 (200 ml). The aqueous layer is then decanted and acidified to pH1 with concentrated hydrochloric acid. The white solid that precipitated is collected by filtration and vacuum dried at 60° C. overnight to give 27 g of an off-white solid 3-(2-chloro-4-trifluoromethylphenoxy)benzoic acid (85% yield, mp 124°-5° C.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][CH:11]2[C:14]([O:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[O:15])=[CH:6][CH:5]=1)([O-])=O>C(O)(=O)C.[Zn]>[ClH:23].[NH2:1][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][CH:11]2[C:14]([O:16][C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)=[O:15])=[CH:6][CH:5]=1
Reactant: O=C(Oc1ccc(Cl)cc1)C1CCCc2ccc([N+](=O)[O-])cc21
Agent: [Zn]
Solvent: CC(=O)O
Product: Cl
Product: Nc1ccc2c(c1)C(C(=O)Oc1ccc(Cl)cc1)CCC2

Procedure:
A 330-mg portion of the p-chlorophenyl 7-nitro-1,2,3,4-tetrahydro-1-naphthoate obtained above was dissolved in 10 ml of acetic acid and the resulting solution was slowly added dropwise at room temperature to 10 ml of acetic acid containing 2 g of zinc dust. After 30 minutes the precipitates were removed by filtration and the filtrate was concentrated under reduce pressure. The residue was dissolved in ethyl acetate and washed with a 5% aqueous sodium hydrogen carbonate solution. The ethyl acetate layer was concentrated under reduced pressure. The residue was dissolved in diethyl ether and dry gaseous hydrogen chloride was introduced thereinto to obtain 290 mg of p-chlorophenyl 7-amino-1,2,3,4-tetrahydro-1-naphthoate hydrochloride having a melting point of 175°-177° C.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[C@@H:5]([NH2:7])[CH3:6])[CH3:2].[N:11]1[S:12][N:13]=[C:14]2[C:19]([CH:20]=O)=[CH:18][CH:17]=[CH:16][C:15]=12>>[N:11]1[S:12][N:13]=[C:14]2[C:19]([CH2:20][NH:7][C@@H:5]([CH3:6])[CH:4]([O:8][CH2:9][CH3:10])[O:3][CH2:1][CH3:2])=[CH:18][CH:17]=[CH:16][C:15]=12
Reactant: CCOC(OCC)[C@H](C)N
Reactant: O=Cc1cccc2nsnc12
Product: CCOC(OCC)[C@H](C)NCc1cccc2nsnc12
Yield: 93.6 %

Procedure:
According to the procedure described in the synthesis method of Compound IX-5, (S)-1,1-diethoxypropan-2-amine (Compound XVIII-1) (883 mg, 6.0 mmol) was reacted with benzo[c][1,2,5]thiadiazole-4-carbaldehyde (837 mg, 5.1 mmol) to obtain the title compound (1.41 g, 95%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:3]=1.[Li]CCCC.[CH3:17][O:18]C=O>C1COCC1.CCCCCC>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:9])([F:10])[F:11])[C:3]=1[CH:17]=[O:18]
Reactant: FC(F)(F)c1cccc(Cl)c1
Reactant: COC=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=Cc1c(Cl)cccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-chloro-3-trifluoromethylbenzene (1.0 g, 5.54 mmol) in THF (15 mL) cooled to −78° C., under N2 protection was added dropwise n-BuLi (3.81 mL of a 1.6 M solution in hexane, 6.1 mmol). After an hour, formic acid methyl ester (664.8 mg, 11.08 mmol) was added slowly to the solution. After the addition, the solution was warmed to ambient temperature slowly and stirred for 30 min. The reaction mixture was quenched with water and the aqueous layer was extracted with EtOAc. The organic layer was washed with water, brine, dried with MgSO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by flash chromatography using heptane/EtOAc (15:1) as eluent to give 2-chloro-6-trifluoromethylbenzaldehyde as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[C:17]([O:21][C:22]([N:24]1[CH2:28][CH2:27][CH2:26][C@H:25]1[CH2:29]OS(C)(=O)=O)=[O:23])([CH3:20])([CH3:19])[CH3:18].C(=O)([O-])[O-].[Cs+].[Cs+]>CN1CCCN(C)C1=O.O>[C:17]([O:21][C:22]([N:24]1[CH2:28][CH2:27][CH2:26][C@H:25]1[CH2:29][N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)[C:6]([C:11](=[O:16])[C:12]([F:13])([F:14])[F:15])=[CH:7]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN1CCCN(C)C1=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1Cn1cc(C(=O)C(F)(F)F)c2ccc(Cl)cc21
Temperature: 80 °C
Reaction time: 48 h
Yield: 45.4 %

Procedure:
A mixture of 2.2 g (8.7 mmol) 1-(6-chloro-1H-indol-3-yl)-2,2,2-trifluoro-ethanone, 3.7 g (13 mmol) (S)-2-methanesulfonyloxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (preparation described in Tetrahedron 2006, 62, 4584-4589) and 5.7 g (18 mmol) cesium carbonate in 44 ml dry 1,3-dimethyl-3,4,5,6-tetrahydropyrimidinone (DMPU) was stirred for 48 h at 80° C. The reaction mixture was diluted with 100 ml water and extracted with ethyl acetate (3×100 ml). The combined organic layers were dried over sodium sulfate and concentrated to dryness. Residual DMPU was removed by kugelrohrdistillation in high vacuo (ca. 1 mbar) at 120° C. Flash chromatography gave the title compound (1.7 g, 46%) as a light yellow solid.
Reaction SMILES: [NH:1]1[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.CC(C)([O-])C.[K+].[NH2:16]Cl>CN(C=O)C.CCOCC>[N:1]1([NH2:16])[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1
Reactant: NCl
Reactant: c1cc2cc[nH]c2cn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Nn1ccc2ccncc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 11 %

Procedure:
A solution of pyrrolo[2,3-c]pyridine (8.47 mmol) and potassium tert-butoxide (16.9 mmol) in DMF (38 mL) is stirred at rt under N2 for 2 h. 0.15 M NH2Cl in ether (84.6 mL) is added drop-wise at rt, and the reaction mixture is stirring at rt for 2 h., quenched with 5% Na2S2O3 aqueous solution (10 mL), and extracted with ether. The organic layer is separated, washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 0-10% MeOH in DCM to afford pyrrolo [2,3-c]pyridin-1-ylamine (226 mg, 11%) as a solid. MS: 134 (M+H); 1H NMR (300 MHz, CDCl3): δ 4.96 (br, 2N—H), 6.43 (d, H), 7.29 (m, H), 7.50 (d, H), 8.29 (d, H), 8.89 (s, H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[C:16]([CH3:18])[NH:15][C:14](=O)[N:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].O=P(Cl)(Cl)[Cl:22]>>[Cl:22][C:14]1[N:13]=[C:12]([C:4]2[CH:5]=[CH:6][C:7]([C:8]([F:11])([F:10])[F:9])=[C:2]([CH3:1])[CH:3]=2)[CH:17]=[C:16]([CH3:18])[N:15]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)c(C)c2)nc(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cc(-c2ccc(C(F)(F)F)c(C)c2)nc(Cl)n1

Procedure:
The title compound was prepared from 4-(3-methyl-4-trifluoromethyl-phenyl)-6-methyl-1H-pyrimidin-2-one (1.73 g, 6.45 mmol) and phosphoroxychloride (20 mL) according to the general procedure I. Obtained as a brown solid (1.4 g, 76%). MS (EI) 286.1 [(M)+]; mp 101° C.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([C:15]([OH:18])([CH3:17])[CH3:16])=[CH:11][CH:10]=2)O1.Br[C:21]1[CH:26]=[CH:25][C:24]([C:27]2[N:32]=[C:31]3[N:33]=[C:34]([O:36][C@H:37]4[CH2:42][O:41][C@H:40]([CH2:43][OH:44])[C@@H:39]([OH:45])[CH2:38]4)[NH:35][C:30]3=[CH:29][C:28]=2[Cl:46])=[CH:23][CH:22]=1>O1CCOCC1.O.CCOC(C)=O.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]>[Cl:46][C:28]1[CH:29]=[C:30]2[NH:35][C:34]([O:36][C@H:37]3[CH2:42][O:41][C@H:40]([CH2:43][OH:44])[C@@H:39]([OH:45])[CH2:38]3)=[N:33][C:31]2=[N:32][C:27]=1[C:24]1[CH:25]=[CH:26][C:21]([C:9]2[CH:10]=[CH:11][C:12]([C:15]([OH:18])([CH3:16])[CH3:17])=[CH:13][CH:14]=2)=[CH:22][CH:23]=1
Reactant: CC(C)(O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: OC[C@H]1OC[C@H](Oc2nc3nc(-c4ccc(Br)cc4)c(Cl)cc3[nH]2)C[C@@H]1O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(O)c1ccc(-c2ccc(-c3nc4nc(O[C@H]5CO[C@H](CO)[C@@H](O)C5)[nH]c4cc3Cl)cc2)cc1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-ol (50.4 mg, 0.192 mmol) and (2R,3 S,5R)-5-((5-(4-bromophenyl)-6-chloro-1H-imidazo[4,5-b]pyridin-2-yl)oxy)-2-(hydroxymethyl)-tetrahydro-2H-pyran-3-ol (70 mg, 0.154 mmol) were dissolved in dioxane (600 μl) and water (600 μl). The reaction mixture was sparged with N2 with 15 min and then [1,1′-Bis(Diphenylphosphino)-Ferrocene]Dichloropalladium (II) (22.53 mg, 0.031 mmol) was added. After stirring 3 h at 80° C., the reaction mixture was diluted with water and EtOAc. The aqueous phase was extracted with EtOAc (×2); and the combined extracts were washed with brine, dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by mass directed reverse phase HPLC eluted with acetonitrile in water containing 0.1% formic acid. The desired fractions were combined and lyophilized to give the title compound as a white solid. LC-MS: calculated for C27H28ClN3O5 509.17 observed m/e: 509.87 (M+H)+ (Rt 1.12/2 min); 1H NMR δ (ppm) (CD3OD): 7.82 (s, 1H), 7.72 (s, 4H), 7.66 (d, 2H), 7.59 (d, 2H), 5.11 (septet, 1H), 4.34 (dd, 1H), 3.88 (dd, 1H), 3.66-3.59 (m, 2H), 3.37 (t, 1H), 3.18-3.15 (m, 1H), 2.76-2.74 (m, 1H), 1.68 (q, 1H), 1.58 (s, 6H).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][C@H:14]([C:18]2[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=2)[CH2:13]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:32][CH2:33][CH2:34][OH:35]>CC#N>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][C@H:14]([C:18]2[CH:19]=[C:20]([CH:21]=[CH:22][CH:23]=2)[O:24][CH2:32][CH2:33][CH2:34][OH:35])[CH2:13]1
Reactant: OCCCBr
Reactant: Oc1cccc([C@H]2CCCN(C[C@H]3COc4ccccc4O3)C2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: OCCCOc1cccc([C@H]2CCCN(C[C@H]3COc4ccccc4O3)C2)c1
Reaction time: 2 h
Yield: 32 %

Procedure:
(R*)-3-{1-[(S)-1-(2,3-Dihydrobenzo[1,4]dioxin-2-yl)methyl]piperidin-3-yl}phenol (208 mg, 0.64 mmol), K2CO3 (103 mg, 0.74 mmol), 3-bromo-1-propanol (86 mg, 0.62 mmol) and MeCN (5 ml) were heated under microwaves at 105° C. for 6 h. More K2CO3 (103 mg) and 3-bromo-1-propanol (86 mg) were added and the heating was continued for 2 h. The solvent was removed and the residue was taken up in DCM. This solution was washed with water and 1 M NaOH and evaporated to dryness. Flash chromatography (heptane/EtOAc) gave 76 mg of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([OH:13])[CH:10]2[N:14]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:15][CH2:16][CH:9]12)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:27]1(O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:10]2[N:14]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:15][CH2:16][CH:9]12)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(O)C2C1CCN2C(=O)OCc1ccccc1
Reactant: Oc1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(Oc2ccccc2)C2C1CCN2C(=O)OCc1ccccc1
Reaction time: 16 h
Yield: 47 %

Procedure:
To a solution of 11 (600 mg, 1.65 mmol) in THF (10 mL) was added phenol (186 mg, 1.98 mmol) and Ph3P (520 mg, 1.98 mmol). DIAD (459 mg, 2.31 mmol) was then added and the reaction mixture was immersed into a preheated (75° C.) oil bath. After 16 h, the reaction mixture was concentrated in vacuo and the residue was passed through a short column of silica gel (4:1 hexanes/EtOAc). The crude product was then purified by reverse-phase HPLC (2″ Dynamax® C18, 10-70% ACN/water containing 0.1% HOAc over 30 min; Flow: 40 mL/min) to afford 340 mg (46%) of 12 as a white solid. 1H NMR (CDCl3, 300 MHz), mixture of rotomers: δ7.37-7.27 (m, 6H), 7.22 (m, 1H), 7.04 (m, 1H), 6.96-6.88 (m, 1H), 6.81 (d, J=8.4 Hz, 1H), 5.27-5.13 (m, 2H), 5.01 (dd, J=3.3, 6.3 Hz, 0.5H), 4.77 (d, J=2.7 Hz, 0.5H), 4.57-4.45 (m, 1H), 4.43-4.32 (m, 1H), 3.99-3.89 (m, 1H), 3.85-3.73 (m, 1H), 3.37 (m, 1H), 3.21 (dt, J=5.7, 11.7 Hz, 1H), 2.38 (m, 0.5H), 2.23 (dd, J=5.7, 13.2 Hz, 0.5H), 1.91-1.83 (m, 1H), 1.47 (m, 9H) ppm. Mass spectrum, m/z [339.2] (M−Boc)+.
Reaction SMILES: [CH3:1][S:2]([N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7](C=O)=[CH:6]1)(=[O:4])=[O:3].ClC1C=CC=C(C(OO)=[O:24])C=1>ClCCl>[CH3:1][S:2]([N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7](=[O:24])[CH2:6]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)n1cc(C=O)c2cccnc21
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)(=O)N1CC(=O)c2cccnc21
Temperature: 0 °C
Reaction time: 8 h
Yield: 26 %

Procedure:
1-Methanesulfonyl-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (2.84 g, 12.7 mmol) from step 2 was dissolved in dichloromethane (150 ml) and cooled to 0° C. Meta-chloroperbenzoic acid (3.4 g, 15 mmol) was added in several portions. The reaction mixture was stirred under a nitrogen atmosphere overnight, while slowly warming to room temperature. The reaction mixture was filtered through a plug of basic alumina and concentrated under reduced pressure to a yellow solid. The crude product was chromatographed over silica gel eluting with 50% ethyl acetate in hexane to yield 1-methanesulfonyl-1,2-dihydro-pyrrolo[2,3-b]pyridin-3-one (700 mg, 26%). 1H NMR (DMSO-d6) δ: 3.59 (3H, s), 4.60 (2H, s), 7.45 (1H, dd, J=4.9 Hz, 7.7 Hz), 8.31 (1H, dd, J=1.8 Hz, 7.7 Hz), 8.84 (1H, dd, J=1.8 Hz, 4.9 Hz).