Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:3]1.[C:14](OC(=O)C)(=[O:16])[CH3:15].[OH-].[Na+]>C(Cl)Cl>[C:14]([NH:1][CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:3]1)(=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: NC1CCN(Cc2ccccc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(=O)NC1CCN(Cc2ccccc2)C1
Temperature: 0 °C

Procedure:
3-Amino-1-benzylpyrrolidine [8.3 g, prepared by a method of G. C. Helsley et al., J. Med. Chem., 11, 1034 (1968)] was dissolved in methylene chloride (40 ml) and thereto acetic anhydride (5.3 g) was added dropwise with stirring under cooling with ice-water and the mixture was stirred for 1.5 hours. After addition of 2N sodium hydroxide (40 ml), the mixture was extracted with methylene chloride. The extract was washed with water and dried over anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure to give 3-acetylamino-1benzylpyrrolidine (9.0 g) as oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH2:12][N:13]([CH:26]1[CH2:31][CH2:30][CH:29]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:28][CH2:27]1)[C:14]1[N:18]([CH3:19])[C:17]2[CH:20]=[CH:21][C:22]([O:24]C)=[CH:23][C:16]=2[N:15]=1)[C:5]([O:7][CH3:8])=[O:6].B(Br)(Br)Br>C(Cl)Cl.CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH2:12][N:13]([CH:26]1[CH2:27][CH2:28][CH:29]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:30][CH2:31]1)[C:14]1[N:18]([CH3:19])[C:17]2[CH:20]=[CH:21][C:22]([OH:24])=[CH:23][C:16]=2[N:15]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1ccc(CN(c2nc3cc(OC)ccc3n2C)C2CCC(C(C)(C)C)CC2)c(Br)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1ccc(CN(c2nc3cc(O)ccc3n2C)C2CCC(C(C)(C)C)CC2)c(Br)c1
Temperature: 25 °C

Procedure:
To a stirring solution of the title compound of Example 224 Step D (0.1 mmol, 54 mg) in 1 mL of DCM cooled to −78° C. under N2 was added dropwise BBr3 (0.3 mmol, 0.3 mL of a 1M solution in DCM). The reaction was allowed to warm to ambient temperature. After 1 h the reaction was taken up in 10 mL of MeOH and then concentrated under reduced pressure. The residue was purified by flash chromatography on silica eluting with 50% EtOAc/hexanes, affording the product as a white solid. HPLC A: 2.54 min.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8].[CH2:10]([OH:12])[CH3:11].[H-].[Na+]>CN(C=O)C>[Br:1][C:2]1[C:3]([O:12][CH2:10][CH3:11])=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: CCO
Reactant: Cc1ccnc(Cl)c1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1nccc(C)c1Br
Temperature: 100 °C
Reaction time: 5 h
Yield: 40 %

Procedure:
3-bromo-2-chloro-4-methylpyridine obtained in Preparation Example 37(1) (1 g) was added to a mixed solvent of ethanol (2 mL) and DMF (5.6 mL). Sodium hydride (60% oil dispersion, 58 mg) was added to the solution, and the mixture was stirred at 100° C. for five hours. The reaction mixture was partitioned by adding ethyl acetate and water. The organic layer was dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/n-heptane, 5% to 30%) to give the title compound (40% solution in n-heptane, 250 mg).
Reaction SMILES: [N:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)=[C:2]=[S:3].[OH:10][CH2:11][CH:12]1[NH:17][CH2:16][C:15]2[CH:18]=[CH:19][S:20][C:14]=2[CH2:13]1.C(O)(C)C.C(OC(C)C)(C)C>C(O)C>[OH:10][CH2:11][CH:12]1[N:17]([C:2](=[S:3])[NH:1][C:4]2[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=2)[CH2:16][C:15]2[CH:18]=[CH:19][S:20][C:14]=2[CH2:13]1
Reactant: S=C=Nc1cccnc1
Reactant: OCC1Cc2sccc2CN1
Solvent: CC(C)OC(C)C
Solvent: CC(C)O
Solvent: CCO
Product: OCC1Cc2sccc2CN1C(=S)Nc1cccnc1
Temperature: 20 °C
Reaction time: 20 h
Yield: 75.4 %

Procedure:
A solution of 3-isothiocyanatopyridine (1.36 g) in absolute ethanol (40 cc) is added dropwise, at a temperature of about 0° C., to a solution of (RS)-6-hydroxymethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (1.69 g) in absolute ethanol (60 cc). The resulting solution is stirred for 20 hours at a temperature of about 20° C. and the solid formed is then filtered off. The filtrate is evaporated to dryness under reduced pressure (25 mm Hg; 3.3 kPa) at 40° C. and a white solid is obtained which is combined with the solid isolated by filtration. These solids are dissolved in a mixture, heated under reflux, of isopropanol and diisopropyl ether (1:2 by volume; 130 cc) and the solution, after cooling, is kept at +5° C. for 20 hours. The resulting crystals are filtered off, washed with diisopropyl ether (50 cc) and dried at 20° C. under reduced pressure (0.1 mm Hg; 0.013 kPa). (RS)- 6-Hydroxymethyl-5-[(pyrid-3-yl)thiocarbamoyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (2.3 g) is thus obtained in the form of white crystals melting at 186° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9]COC)=[CH:7][C:6]([O:13][CH3:14])=[C:5]([O:15]COC)[C:4]=1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][S:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]1[C:35]([O:36][CH2:37]OC)=[C:34]([O:40]C)[CH:33]=[C:32]([O:42][CH2:43]OC)[C:31]=1[O:46]C.O1CCCC1.C(O)(C)C.Cl.C(OCC)(=O)C.CCCCCC>O1CCCC1.C(O)(C)C.CO>[CH3:37][O:36][C:35]1[C:34](=[O:40])[CH:33]=[C:32]([O:42][CH3:43])[C:31](=[O:46])[C:30]=1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][S:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][C:4]1[C:5](=[O:15])[C:6]([O:13][CH3:14])=[CH:7][C:8](=[O:9])[C:3]=1[O:2][CH3:1]
Reactant: COCOc1cc(OC)c(OCOC)c(CCCCCSCCCCCc2c(OC)c(OCOC)cc(OC)c2OCOC)c1OC
Agent: Cl
Solvent: C1CCOC1
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: COC1=CC(=O)C(OC)=C(CCCCCSCCCCCC2=C(OC)C(=O)C=C(OC)C2=O)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.2 %

Procedure:
118.0 Milligrams (0.17 mmole) of bis{5-[2,5-dimethoxy-3,6-bis(methoxymethoxy)phenyl]pentyl} sulfide was dissolved in a mixed solvent of 1 ml of tetrahydrofuran--1 ml of isopropanol. The gas phase in the reaction vessel was replaced three times with argon gas under reduced pressure deaeration. 0.2 Milliliters of tetrahydrofuran-isopropanol solution containing 20% (by weight) of hydrogen chloride was added to the reaction vessel, and the reaction mixture was stirred at room temperature for 1 hour, then the temperature was elevated to 70° C., and the reaction was completed in an hour. The solvent was removed by evaporation under reduced pressure, then 2 ml of benzene was added to the residue, this mixture was further treated under reduced pressure to obtain light brawn oily product. This product was dissolved in 5 ml of methanol without purified, then this solution was heated to 40° C., a small amount of sodium hydrogen carbonate was added thereto, and oxygen gas was bubbled therein, and the reaction was completed in about 1 hour. The solvent was removed under reduced pressure, and the residue obtained was treated by means of a silica gel preparative thin layer chromatography (thickness: 1 mm, developing solvent: 50% ethyl acetate-n-hexane) to obtain 60.5 mg of bis[5-(3,6-dimethoxy-1,4-benzoquinon-2-yl)pentyl] sulfide. Yellow oily substance.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([NH:16][C:17]([C:19]2[CH:20]=[N:21][N:22]3[CH:27]=[CH:26][CH:25]=[N:24][C:23]=23)=[O:18])=[C:5]([C:7]2[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=2[O:14]C)[N:6]=1.B(Br)(Br)Br.C(=O)([O-])O.[Na+]>C(Cl)Cl>[Br:1][C:2]1[S:3][C:4]([NH:16][C:17]([C:19]2[CH:20]=[N:21][N:22]3[CH:27]=[CH:26][CH:25]=[N:24][C:23]=23)=[O:18])=[C:5]([C:7]2[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=2[OH:14])[N:6]=1
Reactant: COc1ccc(Cl)cc1-c1nc(Br)sc1NC(=O)c1cnn2cccnc12
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(Nc1sc(Br)nc1-c1cc(Cl)ccc1O)c1cnn2cccnc12
Temperature: -78 °C
Reaction time: 1 h
Yield: 143.1 %

Procedure:
To a solution of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid [2-bromo-4-(5-chloro-2-methoxy-phenyl)-thiazol-5-yl]-amide (4.3 g, 9.3 mmol) in DCM (90 mL) at −78° C. under an atmosphere of N2 was added boron tribromide (1M in DCM, 45 mL, 45 mmol) dropwise. The mixture was stirred at −78° C. for 1 hour and then allowed slowly to room temperature and stirred for a further 16 hours. The mixture was poured cautiously onto an aqueous solution of sodium hydrogen carbonate, stirred for 15 mins, filtered and the solid collected and dried to afford pyrazolo[1,5-a]pyrimidine-3-carboxylic acid [2-bromo-4-(5-chloro-2-hydroxy-phenyl)-thiazol-5-yl]-amide as a beige solid (6 g, >100%). LCMS (Method 3) [M+H]+=450.1, RT=3.71 min. 1H NMR (400 MHz, DMSO-d6) δ: 15.96 (s, 1H), 9.18 (dd, 1H, J=1.6, 6.9 Hz), 8.70 (dd, 1H, J=1.8, 4.0 Hz), 8.59 (s, 1H), 7.80 (d, 1H, J=2.8 Hz), 7.15 (dd, 1H, J=4.0, 7.1 Hz), 7.05 (dd, 1H, J=2.8, 8.6 Hz), 6.77 (d, 1H, J=8.6 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].[OH-].[Na+].Cl[C:13]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:14]=1[C:15]#[N:16].O>CS(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9][C:13]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:14]=1[C:15]#[N:16]
Reactant: Oc1ccc(Cl)cc1Cl
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1cc([N+](=O)[O-])ccc1Oc1ccc(Cl)cc1Cl
Temperature: 60 °C
Yield: 94.9 %

Procedure:
To a solution of 5.0 g (0.0307 moles) of 2,4-dichlorophenol dissolved in 150 ml of DMSO was added 1.23 g (0.0307 moles) of NaOH. The slurry was heated at 60° C. for 15 minutes and 5.04 g (0.0276 moles) of 2-chloro-5-nitrobenzonitrile was added. The mixture was heated at 75° C. for 3.25 hrs. The reaction mixture was cooled and poured into water. The product was collected by filtration, washed well with water and dried, yielding 8.1 g of product (95.3% yield). Recrystallization from ethanol afforded purified 2-(2,4-dichlorophenoxy)-5-nitrobenzonitrile, mp 153.5°-154.5° C.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[N:19]=[CH:18][NH:17][C:16](=O)[CH:15]=1.CN(C=O)C.C(Cl)(=O)C([Cl:29])=O>ClCCl.O1CCOCC1>[Cl:29][C:16]1[CH:15]=[C:14]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][CH2:6][CH:2]2[CH2:3][CH2:4][CH2:5][O:1]2)[N:19]=[CH:18][N:17]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=c1cc(-c2ccccc2OCC2CCCO2)nc[nH]1
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: Clc1cc(-c2ccccc2OCC2CCCO2)ncn1
Reaction time: 1 h
Yield: 100.4 %

Procedure:
To a stirred suspension of 6-[2-(tetrahydro-furan-2-ylmethoxy)-phenyl]-3H-pyrimidin-4-one (0.375 g, 1.37 mmol) in dichloromethane (5 mL) and dioxane (5 mL) was added DMF (0.05 mL) followed by a solution of oxalyl chloride (0.5 mL, 4 mmol). After stirring for 1 h, the mixture was concentrated under vacuum. The residue was partitioned between ethyl acetate (25 mL) and saturated aqueous sodium bicarbonate solution (10 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum to give 0.4 g (99%) 4-chloro-6-[2-(tetrahydro-furan-2-ylmethoxy)-phenyl]-pyrimidine as colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:9][C:10](=[O:20])[N:11]([C@H:13]2[CH2:18][CH2:17][C@H:16]([OH:19])[CH2:15][CH2:14]2)[CH3:12])[CH:5]=[CH:6][C:7]=1[F:8].[OH-].[Na+].[Br:23][CH2:24][CH2:25][CH2:26][CH2:27]Br>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[F:1][C:2]1[CH:3]=[C:4]([O:9][C:10](=[O:20])[N:11]([C@H:13]2[CH2:18][CH2:17][C@H:16]([O:19][CH2:27][CH2:26][CH2:25][CH2:24][Br:23])[CH2:15][CH2:14]2)[CH3:12])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: BrCCCCBr
Reactant: CN(C(=O)Oc1ccc(F)c(F)c1)[C@H]1CC[C@H](O)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Product: CN(C(=O)Oc1ccc(F)c(F)c1)[C@H]1CC[C@H](OCCCCBr)CC1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
A solution of 11.6 g (containing 31 mmol) of crude trans-(4-Hydroxy-cyclohexyl)-methyl-carbamic acid 3,4-difluoro-phenyl ester in 110 ml of 1,4-dibromobutane was treated with 3.16 g (9.3 mmol) tetrabutylammonium hydrogen sulfate and 200 ml of aqueous 50% NaOH and stirred for 2.5 days at RT. The reaction was extracted (CH2Cl2 2×). The organic phase was dried over Na2SO4, evaporated and purified by flash silica gel column (first with hexane to remove the dibromobutane and then hexane/EtOAc 1:1) to yield 4.06 g (31%) of trans-[4-(4-bromo-butoxy)-cyclohexyl]-methyl-carbamic acid 3,4-difluoro-phenyl ester, MS: 420 (M, 1Br).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[N:9][CH:10]=1)=[O:4].[Cl:17][C:18]1[N:19]=[N:20][C:21](Cl)=[C:22]([CH3:25])[C:23]=1[CH3:24].O>CN1C(=O)CCC1>[CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]([N:11]2[CH2:12][CH2:13][N:14]([C:21]3[N:20]=[N:19][C:18]([Cl:17])=[C:23]([CH3:24])[C:22]=3[CH3:25])[CH2:15][CH2:16]2)=[N:9][CH:10]=1)=[O:4]
Reactant: Cc1c(Cl)nnc(Cl)c1C
Reactant: COC(=O)c1cnc(N2CCNCC2)cn1
Solvent: CN1CCCC1=O
Solvent: O
Product: COC(=O)c1cnc(N2CCN(c3nnc(Cl)c(C)c3C)CC2)cn1
Temperature: 190 °C
Reaction time: 1 h
Yield: 42.5 %

Procedure:
To the solution of 3,4,5,6-tetrahydro-2H-[1,2]bipyrazinyl-5′-carboxylic acid methyl ester (250 mg, 1.07 mmol) in NMP (5 mL) is added 3,6-dichloro-4,5-dimethyl-pyridazine (237 mg, 1.33 mmol) and TEA (446 μl, 3.21 mmol), the reaction mixture is stirred at 190° C. for 60 min. Water is added to the mixture and extracted with EtOAc. The combined organic layers are washed with water, brine, dried over Na2SO4, filtered and concentrated. The crude product is purified by HPLC, (acetonitrile/water: 10%˜95% with 3% 1-propanol) to give white powder (165 mg, 43%).
Reaction SMILES: [NH2:1][C:2]1[N:34]=[C:5]2[C:6]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)=[C:7]([CH3:23])[C:8]([C:10]3[N:14]([C:15]4[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=4)[N:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1.[CH3:35][S:36](Cl)(=[O:38])=[O:37].O>N1C=CC=CC=1>[C:19]([C:18]1[CH:17]=[CH:16][C:15]([N:14]2[C:10]([C:8]3[C:7]([CH3:23])=[C:6]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:32])([F:33])[F:31])[CH:25]=4)[C:5]4[N:4]([N:3]=[C:2]([NH:1][S:36]([CH3:35])(=[O:38])=[O:37])[N:34]=4)[CH:9]=3)=[CH:11][CH:12]=[N:13]2)=[CH:22][CH:21]=1)#[N:20]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(N)nc2c1-c1cccc(C(F)(F)F)c1
Solvent: O
Solvent: c1ccncc1
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(NS(C)(=O)=O)nc2c1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 48.5 %

Procedure:
4-{5-[2-Amino-7-methyl-8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl]-pyrazol-1-yl}-benzonitrile (Ex. 1, 150 mg, 0.326 mmol) was dissolved in pyridine (4 mL) and methanesulfonyl chloride (50 μL, 0.652 mmol) was added. The reaction mixture was stirred at RT for 18 hrs then at 60° C. for 3 hrs. A further quantity of methanesulfonyl chloride (50 μL) was added and the mixture was heated at 60° C. overnight. The reaction mixture was allowed to cool then water was added and the mixture was extracted with EtOAc. The organic extract was washed with 1 M HCl followed by water and then saturated brine, before being dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was purified by flash chromatography eluting with a gradient of 0-50% EtOAc in cyclohexane to give the title compound as a tan solid (85 mg).
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C:11]1[C:19]2[C:14](=[CH:15][N:16]=[CH:17][CH:18]=2)[N:13]([CH2:20][C:21]([OH:23])=O)[N:12]=1)(=[O:10])[NH2:9].FC(F)(F)C(O)=O.[Cl:31][C:32]1[C:33]([F:48])=[C:34]([CH:45]=[CH:46][CH:47]=1)[CH2:35][NH:36][C:37]([C@@H:39]1[CH2:44][C@@H:43]2[C@@H:41]([CH2:42]2)[NH:40]1)=[O:38].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:31][C:32]1[C:33]([F:48])=[C:34]([CH:45]=[CH:46][CH:47]=1)[CH2:35][NH:36][C:37]([C@@H:39]1[CH2:44][C@@H:43]2[C@@H:41]([CH2:42]2)[N:40]1[C:21](=[O:23])[CH2:20][N:13]1[C:14]2=[CH:15][N:16]=[CH:17][CH:18]=[C:19]2[C:11]([C:8]([NH2:9])=[O:10])=[N:12]1)=[O:38]
Reactant: O=C(NCc1cccc(Cl)c1F)[C@@H]1C[C@H]2C[C@H]2N1
Reactant: NC(=O)c1nn(CC(=O)O)c2cnccc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: NC(=O)c1nn(CC(=O)N2[C@@H]3C[C@@H]3C[C@H]2C(=O)NCc2cccc(Cl)c2F)c2cnccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (3-carbamoyl-pyrazolo[3,4-c]pyridin-1-yl)-acetic acid trifluoroacetate salt (2.12 g, 6.35 mmol, prepared as described in Scheme A26) in DMF (32 mL) were successively added (1R,3S,5R)—N-(3-chloro-2-fluorobenzyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide trifluoroacetate salt (2.70 g, 6.35 mmol), HBTU (3.37 g, 8.89 mmol) and DIPEA (4.44 mL, 25.4 mmol). The reaction mixture was stirred at RT for 16 h, and then was concentrated under vacuum. The residual oil was partitioned between CH2Cl2 and a sat. aq. NaHCO3 solution. A solid precipitated from the resulting emulsion and was filtered off, washed with water and dried under vacuum. The solid was suspended in a mixture of water (150 mL) and MeOH (3 mL), stirred for 1 h at RT, filtered, washed with water and finally dried under vacuum to give the title material as a white powder. MS (LC/MS): 471 [M+H]+; tR (HPLC conditions c): 3.41 min.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=O)(=[O:3])[CH3:2].CCN=C=NCCCN(C)C.C1C=C2N=NN(O)C2=CC=1.O.[C:36]([NH2:45])([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([CH3:38])[CH3:37]>CN(C=O)C>[C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([NH:45][C:36]([CH3:38])([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH3:37])=[O:10])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cccc(C(=O)O)c1
Reactant: CC(C)(N)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Oc1cccc(C(=O)NC(C)(C)c2ccccc2)c1
Yield: 73.1 %

Procedure:
In a similar manner to Step 1 of Example 137, 3-acetoxybenzoic acid (7.92 g, 44.0 mmol) was dissolved in DMF (45 mL), and the solution was treated with EDCI (12.7 g, 66.0 mmol), HOBT monohydrate (3.37 g, 22.0 mmol) and cumylamine (14.2 mL, 96.8 mmol), followed by purification by slurry using diisopropylether to obtain 3-acetoxy-N-(1-methyl-1-phenylethyl)benzamide (9.57 g, yield 73%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([OH:15])[C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:14].C(=O)([O-])[O-].[K+].[K+].[CH2:22](Br)[CH:23]=[CH2:24]>CN(C=O)C>[CH2:24]([O:15][C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([Cl:1])[C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:14])[CH:23]=[CH2:22]
Reactant: Cc1ccccc1-c1c(O)cccc1Cl
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOc1cccc(Cl)c1-c1ccccc1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.7 %

Procedure:
To a solution of 6-chloro-2′-methyl-biphenyl-2-ol (4.75 g, 21.7 mmol) in DMF (30 mL) was added potassium carbonate (4.5 g, 32.6 mmol) and allyl bromide (3.0 mL, 32.6 mmol) at room temperature. The resulting mixture was stirred at room temperature for 4 h. The mixture was extracted with ethyl acetate, washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by ISCO using a solvent gradient of O to 30% ethyl acetate in hexanes provided 5.6 g (100%) of 2-allyloxy-6-chloro-2′-methylbiphenyl as a light yellow oil.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([C:14]3[CH:15]=[C:16]([CH2:20][CH:21]([C:24]4[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=4)[C:22]#[N:23])[CH:17]=[CH:18][CH:19]=3)[CH:13]=1)[N:10]=[CH:9][CH:8]=[CH:7]2)([CH3:3])[CH3:2].C([Sn](Cl)(CCCC)CCCC)CCC.[N-:48]=[N+:49]=[N-:50].[Na+]>C1(C)C(C)=CC=CC=1>[CH:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][CH:21]([C:24]4[CH:25]=[CH:26][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:28][CH:29]=4)[C:22]4[NH:50][N:49]=[N:48][N:23]=4)[CH:15]=3)[CH:13]=1)[N:10]=[CH:9][CH:8]=[CH:7]2)([CH3:3])[CH3:2]
Reactant: CC(C)c1cc(-c2cccc(CC(C#N)c3ccc(S(C)(=O)=O)cc3)c2)c2ncccc2c1
Reactant: [N-]=[N+]=[N-]
Agent: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: CC(C)c1cc(-c2cccc(CC(c3ccc(S(C)(=O)=O)cc3)c3nnn[nH]3)c2)c2ncccc2c1
Temperature: 21 °C
Reaction time: 1 h

Procedure:
A solution of Example 78 (160 mg, 0.35 mmol), tri-n-butyltin chloride (0.478 mL, 1.76 mmol) and sodium azide (115 mg, 1.76 mmol) in xylene (5 mL) was heated at 150° C. for 18 h. Cooling to 21° C., then purification by flash chromatography (eluting with CH2Cl2/MeOH, NH4OH, 50:5:1) followed by stirring vigorously in ether for 1 h, then filtered, afforded the title compound as a white powder.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][OH:12])[C:5](I)=[CH:4][N:3]=1.[S:14]1[CH:18]=[CH:17][CH:16]=[C:15]1B(O)O.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>C(COC)OC>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][OH:12])[C:5]([C:15]2[S:14][CH:18]=[CH:17][CH:16]=2)=[CH:4][N:3]=1
Reactant: OB(O)c1cccs1
Reactant: OCCCNc1nc(Cl)ncc1I
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: COCCOC
Product: OCCCNc1nc(Cl)ncc1-c1cccs1
Temperature: 75 °C
Reaction time: 18 h

Procedure:
In accordance with procedure 3, 3-(2-chloro-5-iodopyrimidine-4-ylamino)propan-1-ol (1.38 g, 4.4 mmol) and 2-thiophenboronic acid (0.62 g, 4.87 mmol) are dissolved in 15 ml dimethoxyethane under argon, and tri(2-furyl)phosphine (104 mg, 0.45 mmol) and 1 molar Na2CO3 soln. (7.1 ml, 7.1 mmol) are added (the previously light yellow reaction mixture becomes almost colourless and turbid after the Na2CO3 addition). Argon is passed in for 15 mins. Tetrakis(triphenyl-phosphine)palladium (511 mg, 0.44 mmol) is then added and the reaction mixture is stirred for 18 hrs at 75° C. under argon (suspension). Dimethoxyethane is distilled off on the rotary evaporator, the residue treated with 250 ml ethyl acetate and 30 ml H2O, stirred vigorously for 30 mins, and the undissolved substance filtered off at the pump on a G4 frit, and washed with H2O and ethyl acetate: 372 mg residue.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]([O:9][C:10]1[C:11]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:12][C:13]2[O:17][CH:16]=[CH:15][C:14]=2[C:18]=1[C:19]([CH3:22])([CH3:21])[CH3:20])(=[O:8])[CH3:7].O.CN(C)[CH:30]=[O:31]>>[C:6]([O:9][C:10]1[C:11]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:12][C:13]2[O:17][C:16]([CH:30]=[O:31])=[CH:15][C:14]=2[C:18]=1[C:19]([CH3:22])([CH3:21])[CH3:20])(=[O:8])[CH3:7]
Reactant: CC(=O)Oc1c(C(C)(C)C)cc2occc2c1C(C)(C)C
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CC(=O)Oc1c(C(C)(C)C)cc2oc(C=O)cc2c1C(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 86 %

Procedure:
Phosphorus oxychloride (1.1 g) was added dropwise to N,N-dimethylformamide (0.4 g) under cooling with ice and, subsequently, a solution of 5-acetoxy-4,6-di-tert-butylbenzofuran (1.0 g) in N,N-dimethylformamide (2 ml) was added dropwise. The mixture was stirred first at room temperature for 20 min, then under heating at 80° C. for 75 min. After cooling, the reaction mixture was poured into water and subjected to extraction ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The concentrate was purified by silica gel chromatography (10% ethyl acetate in n-hexane) to afford 5-acetoxy-4,6-di-tert-butyl-2-formylbenzofuran [0.95 g (yield, 86%)] as a colorless, fine-grained crystal.