Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:13])[C:3]1[S:4][CH:5]=[C:6]([C:8](OCC)=[O:9])[N:7]=1.[BH4-].[Na+]>CO>[F:1][CH:2]([F:13])[C:3]1[S:4][CH:5]=[C:6]([CH2:8][OH:9])[N:7]=1
Reactant: CCOC(=O)c1csc(C(F)F)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1csc(C(F)F)n1
Temperature: 0 °C
Reaction time: 3 h
Yield: 55.2 %

Procedure:
To a solution of ethyl 2-(difluoromethyl)thiazole-4-carboxylate (100 mg) in MeOH (1 ml) was added NaBH4 (36.5 mg) at 0° C., and the mixture was stirred at 0° C. for 3 h. The mixture was quenched with saturated NH4Cl solution, and extracted with EtOAc. The organic layer was separated, washed with water and brine successively, dried over MgSO4 and concentrated in vacuo. The residue was purified by NH silica gel column chromatography (hexane/EtOAc) to give the title compound (44.0 mg) as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:12][O:11]2)=[CH:4][CH:3]=1.[NH:18]1[CH:22]=[N:21][CH:20]=[N:19]1.[OH-].[Na+].O>CN1CCCC1=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([CH2:12][N:18]2[CH:22]=[N:21][CH:20]=[N:19]2)([OH:11])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:4][CH:3]=1
Reactant: c1nc[nH]n1
Reactant: CCCCCC1(CCc2ccc(Cl)cc2)CO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCCCCC(O)(CCc1ccc(Cl)cc1)Cn1cncn1
Temperature: 25 °C
Yield: 47 %

Procedure:
A solution of 89 g (0.352 mol) of 2-(4-chlorophenylethyl)-2-pentyl-oxirane, 26.5 g (0.384 mol) of 1,2,4-triazole, 3.5 g (0.0875 mol) of sodium hydroxide, 1.2 ml of water and a spatula tipful of α,α'-azoisobutyronitrile in 175 ml of N-methylpyrrolidone is heated at 120° C. for 4 hours. After this the mixture is cooled to room temperature and concentrated by stripping off the solvent under reduced pressure, the remaining residue is dissolved in ethyl acetate and washed three times with water, the organic phase is dried over sodium sulphate and the solvent is removed under reduced pressure. The residue is purified by column chromatography (silica gel; dichloromethane:ethyl acetate=1:1). In this manner 53.2 g (47.0% of theory) of 1-(4-chlorophenyl)-3-(1,2,4-triazol-1-yl-methyl)-3-octanol are obtained in the form of a yellow oil.
Reaction SMILES: [Br:1][C:2]1[S:10][C:9]2[CH2:8][CH2:7][NH:6][CH2:5][C:4]=2[CH:3]=1.[C:11](O)(=O)[CH3:12].[BH4-].[Na+]>C1COCC1>[Br:1][C:2]1[S:10][C:9]2[CH2:8][CH2:7][N:6]([CH2:11][CH3:12])[CH2:5][C:4]=2[CH:3]=1
Reactant: CC(=O)O
Reactant: Brc1cc2c(s1)CCNC2
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN1CCc2sc(Br)cc2C1
Temperature: 60 °C
Yield: 89 %

Procedure:
To a suspension of 2-bromo-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (1.86 g, 8.50 mmol) in THF (30.6 mL) was added acetic acid (17 mL) then the reaction temperature was reduced to 0° C. and sodium borohydride (2.55 g, 42.5 mmol) was added in portions. After the addition was complete, the reaction mixture was heated at 60° C. for 1 h then the reaction mixture was cooled to ambient temperature and quenched by the addition of water. The resultant solution was partitioned between ethyl acetate (75 mL) and 1N sodium hydroxide solution (50 mL) and the layers separated. The organic phase was collected then dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to give the title compound (1.87 g, 89%). 1H NMR (MeOD, 300 MHz): 6.78 (s, 1H), 3.50 (s, 2H), 2.81 (s, 4H), 2.62 (q, J=7.2 Hz, 2H), 1.17 (t, J=7.2 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH2:11](OC1C=CC=CC=1CO)[CH2:12][CH:13]=[CH2:14]>>[CH2:14]([O:10][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:9][C:6]=1[CH2:7][OH:8])[CH2:13][CH:12]=[CH2:11]
Reactant: O=Cc1cc(F)ccc1O
Reactant: C=CCCOc1ccccc1CO
Product: C=CCCOc1ccc(F)cc1CO
Yield: 39 %

Procedure:
Prepared from 5-fluoro-2-hydroxybenzaldehyde in 39% yield following the same procedure as (2-(but-3-en-1-yloxy)phenyl)methanol. 1H NMR (400 MHz, CDCl3) δ 7.03 (dd, J=8.7, 3.1 Hz, 1H), 6.94 (td, J=8.5, 3.0 Hz, 1H), 6.80 (dd, J=9.0, 4.3 Hz, 1H), 5.90 (ddt, J=17.1, 10.3, 6.8 Hz, 1H), 5.26-5.09 (m, 2H), 4.65 (d, J=6.8 Hz, 2H), 4.06 (t, J=6.3 Hz, 2H), 2.66-2.53 (m, 2H), 2.40 (t, J=6.8 Hz, 1H).
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].[Cl:5][CH2:6][CH2:7][CH2:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)=O>N1C=CC=CC=1>[CH3:2][O:3][N:4]=[C:9]([C:11]1[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=1)[CH2:8][CH2:7][CH2:6][Cl:5]
Reactant: CON
Reactant: O=C(CCCCl)c1ccc(F)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CON=C(CCCCl)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
Methoxyamine hydrochloride (0.833 g, 9.97 mmol) was added portionwise to 4-chloro-4′-fluorobutyrophenone (2.00 g, 9.97 mmol) in pyridine (10 mL) and the mixture stirred at room temperature overnight and evaporated under vacuum. The residue was diluted with ethyl acetate, washed with 2N aqueous hydrochloric acid and brine, dried (MgSO4) and evaporated to give product as an oil (2.29 g, quant.); MS for C11H13ClFNO m/z 230 (M+H)+.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:6]=[N:5]2.F[B-](F)(F)F.[H+].N([O-])=O.[Na+].[I-:27].[K+].C(=O)([O-])[O-].[Na+].[Na+]>O>[I:27][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:6]=[N:5]2
Reactant: CCOC(=O)c1cnc2cc(N)ccc2n1
Reactant: [I-]
Agent: F[B-](F)(F)F
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Solvent: O
Product: CCOC(=O)c1cnc2cc(I)ccc2n1
Temperature: 0 °C
Yield: 32.8 %

Procedure:
To a mixture of compound 8 (1.37 g, 6.31 mmol) in a 50% aqueous fluoroboric acid solution (10 mL), at 0° C., was added dropwise, a solution of sodium nitrite (480 mg, 6.96 mmol) in water (3 mL). The reaction mixture was stirred for an additional hour at 0° C. and a solution of potassium iodide (1.57 g, 9.46 mmol) in water (5 mL) was added. The reaction was stirred at 0° C. for 1 h and then warmed at 50° C. until no more gas evolution was observed (1 h). After cooling to room temperature, the mixture was basified with a saturated aqueous sodium carbonate solution (60 mL) and extracted with dichloromethane (3×40 mL). The combined organic layers were washed with a 5% aqueous sodium bisulfite solution (2×30 mL), dried on magnesium sulfate, filtered and concentrated under vacuum. The crude product was purified by chromatography (Al2O3, CH2Cl2) to give compound 9 (0.68 g, 2.07 mmol) as a yellow solid. Yield 33%; Rf (Al2O3, CH2Cl2) 0.80; mp 160-162° C.; IR (KBr) ν 1103, 1151, 1230, 1237, 1717 cm−1; 1H NMR (400 MHz, CDCl3) δ 1.51 (t, 3H, J=7 Hz), 4.59 (q, 2H, J=7 Hz), 7.99 (d, 1H, J=9 Hz), 8.10 (dd, 1H, J=2.9 Hz), 8.62 (d, 1H, J=2 Hz), 9.51 (s, 1H); MS m/z 328 (M+, 19), 284 (43), 256 (100), 128 (29), 101 (50), 75 (30).
Reaction SMILES: [CH3:1][C@:2]12[CH2:19][CH2:18][C@H:17]3[C@@H:7]([CH2:8][CH:9]=[C:10]4[C@:15]3([CH3:16])[CH2:14][CH2:13][C:12](=[O:20])[NH:11]4)[C@@H:6]1[CH2:5][CH2:4][C:3]2=O.[CH:22]1([NH2:25])[CH2:24][CH2:23]1.[BH4-].[Na+]>C(Cl)(Cl)Cl.C(O)C.CCOC(C)=O>[CH:22]1([NH:25][C@H:3]2[CH2:4][CH2:5][C@H:6]3[C@H:7]4[C@H:17]([CH2:18][CH2:19][C@:2]23[CH3:1])[C@:15]2([CH3:16])[C:10]([NH:11][C:12](=[O:20])[CH2:13][CH2:14]2)=[CH:9][CH2:8]4)[CH2:24][CH2:23]1
Reactant: C[C@]12CCC(=O)NC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: NC1CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: C[C@]12CC[C@H]3[C@@H](CC=C4NC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2NC1CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
4-Aza-androst-5(6)-ene-3,17-dione (0.53 g, 1.844 mmol) dissolved in chloroform (CHCl3, 10.0 mL) and cyclopropylamine ((CH2)2CHNH2, ALDRICH, 4.12 g, 72.15 mmol) is added, and the reaction mixture is heated to reflux under nitrogen. After 15 hours, the reaction is cooled to room temperature and analysis indicates the stoichiometric conversion to the cyclopropylimine. Sodium borohydride (NaBH4, ALPHA, 0.3574 g, 0.4475 mmol) in ethanol (21 mL) is added and the reaction is stirred at room temperature under nitrogen. After 21 hours, the reaction is worked-up by diluting with EtOAc (50 mL), washing in water (2×40 mL), in brine (40 mL) and drying over MgSO4, filtering and evaporating the solvent to obtain the crude product of the title compound. The crude product is further purified by flash chromatography (10.5″, 5.25 g, SiO2; elute first with 25% EtOAc/×25% CH2Cl2/50% hexane then with 15% iPrOH/×85%×CH2Cl2) to give 17β-cyclopropylamino-4-aza-androst-5(6)-en-3-one in excellent purity (0.4948 g, 1.5063 mmol). Yield: 82%.
Reaction SMILES: C[O:2][C:3]([C:5]1([NH:14][C:15](=[O:26])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([CH2:24][OH:25])[CH:17]=2)[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)=[O:4].[H-].[Na+].Br[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[CH:32]=1.[OH-].[Li+]>CN(C=O)C.O1CCOCC1>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([C:15]([NH:14][C:5]2([C:3]([OH:2])=[O:4])[CH2:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:13]2)=[O:26])=[CH:17][C:18]=1[CH2:24][O:25][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[CH:32]=1
Reactant: COC(=O)C1(NC(=O)c2ccc(OC)c(CO)c2)Cc2ccccc2C1
Reactant: Cc1cccc(CBr)c1
Agent: [H-]
Agent: [Li+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: COc1ccc(C(=O)NC2(C(=O)O)Cc3ccccc3C2)cc1COCc1cccc(C)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 8 %

Procedure:
The compound of step 2 (50 mg, 0.14 mmol)) was dissolved in DMF (3 ml) and sodium hydride (60% dispersion in mineral oil, 6.2 mg, 0.15 mmol) was added followed by 1-bromomethyl-3-methyl-benzene (27 mg, 0.14 mmol). The mixture was stirred overnight. Then lithium hydroxide (1 M solution in water, 0.42 ml) and dioxane (1 ml) were added and the mixture heated to 60° C. for 1 h. The residue was partitioned between 2 N hydrochloric acid and EA and the aqueous phase was extracted with EA. The combined organic phases were dried over sodium sulfate and evaporated to dryness. The residue was purified by RP HPLC (water/ACN gradient) to yield 5 mg of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][C:11](I)=[C:10]([Cl:15])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:17][N:18]([CH3:22])[CH2:19][C:20]#[CH:21]>C(N(CC)CC)C>[C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:21]#[C:20][CH2:19][N:18]([CH3:22])[CH3:17])=[C:10]([Cl:15])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C#CCN(C)C
Reactant: CC(C)(C)OC(=O)Nc1ccc(I)c(Cl)c1
Solvent: CCN(CC)CC
Product: CN(C)CC#Cc1ccc(NC(=O)OC(C)(C)C)cc1Cl
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a deoxygenated solution of (3-chloro-4-iodo-phenyl)-carbamic acid tert-butyl ester (10.0 g) in triethylamine (120 ml) is added 1-dimethylamino-2-propyne (2.82 g), bis(triphenyl-phosphine)palladium(ll) chloride (0.4 g), and cuprous iodide (0.054 g). The mixture is stirred at room temperature under an atmosphere of argon for approximately 6 hours and is then heated briefly (ca. 10 minutes) to 60° C. The reaction mixture is then cooled, filtered through diatomaceous earth, and the solvent is removed by evaporation under reduced pressure. The residue is dissolved in ethyl acetate, washed three times with water, once with saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. The solvent is removed by evaporation under reduced pressure, and the residue is chromatographed over silica gel (80% ethyl acetate in hexanes is used as the eluant) to give the purified product as an amber oil that solidified on standing.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13](=[O:20])[CH2:14][CH2:15][C:16]([O:18]C)=[O:17])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[OH-].[Na+].O1CCCC1>CO>[Cl:1][C:2]1[S:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]([C:13](=[O:20])[CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)CCC(=O)c1ccc(-c2ccc(Cl)s2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CCC(=O)c1ccc(-c2ccc(Cl)s2)cc1
Temperature: 25 °C
Reaction time: 26 h
Yield: 52.3 %

Procedure:
A mixture of 4-[4-(5-chloro-thiophen-2-yl)-phenyl]-4-oxo-butyric acid, methyl ester (5.99 g, 0.0194 mol), 1.0 M aqueous sodium hydroxide (23 mL, 0.023 mol), tetrahydrofuran (50 mL), and methanol (50 mL) was stirred at room temperature for 26 hours. The resulting suspension was filtered, and the filtercake was washed with methanol. The filtercake was partitioned between dichloromethane-tetrahydrofuran-ethyl acetate (100 mL each) and 0.5 M aqueous hydrochloric acid (50 mL). The organics were washed with brine, dried (Na2SO4), and rotary evaporated to give 2.99 g of 4-[4-(5-chloro-thiophen-2-yl)-phenyl]-4-oxo-butyric acid as a bright yellow solid; mp 212-213° C.
Reaction SMILES: Cl[C:2]1[C:10]2[C:5](=[N:6][C:7]([NH:11][CH2:12][CH2:13][N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])=[N:8][CH:9]=2)[N:4]([CH3:19])[N:3]=1.CC1(C)C(C)(C)OB([C:28]2[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=2)O1>>[NH2:32][C:31]1[CH:33]=[CH:34][C:28]([C:2]2[C:10]3[C:5](=[N:6][C:7]([NH:11][CH2:12][CH2:13][N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])=[N:8][CH:9]=3)[N:4]([CH3:19])[N:3]=2)=[CH:29][CH:30]=1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: CCN(CC)CCNc1ncc2c(Cl)nn(C)c2n1
Product: CCN(CC)CCNc1ncc2c(-c3ccc(N)cc3)nn(C)c2n1

Procedure:
Prepared as described above in Example 15 starting from N′-(3-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-N,N-diethyl-ethane-1,2-diamine and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline to give the title compound N-[3-(4-amino-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-N′,N′-diethyl-ethane-1,2-diamine; 1H-NMR (MeOH): δ 1.38 (m, 6H), 3.36 (m, 4H), 3.82 (m, 2H), 3.92 (m, 2H), 3.98 (s, 3H), 7.46 (d, 2H, J=8.4 Hz), 8.09 (d, 2H, J=8.4 Hz), 9.18 (s, 1H), LC/MS (m/e)=340.2 (MH+), Rt=0.98 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30]([OH:32])=O)[C:25]=1[CH3:33])(=[O:12])=[O:11].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:56][CH2:57][CH2:58][O:59][CH2:60][CH2:61][OH:62]>CN(C=O)C>[OH:62][CH2:61][CH2:60][O:59][CH2:58][CH2:57][NH:56][C:30]([C:26]1[C:25]([CH3:33])=[C:24](/[CH:23]=[C:16]2\[C:17](=[O:22])[NH:18][C:19]3[C:15]\2=[CH:14][C:13]([S:10]([CH2:9][C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=2[Cl:8])(=[O:11])=[O:12])=[CH:21][CH:20]=3)[NH:28][C:27]=1[CH3:29])=[O:32]
Reactant: NCCOCCO
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)NCCOCCO
Temperature: 25 °C
Reaction time: 168 h

Procedure:
To a mixture of 5-[5-(2,6-Dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (100 mg, 0.19 mmol), HOBt (31 mg, 1.2 eq.), EDAC.HCl (44 mg, 1.2 eq.) and 2-(2-amino-ethoxy)-ethanol (49 mg, 1.1 eq.) in DMF (2 mL) was added TEA (0.066 mL, 2.5 eq.). After stirring at rt for 7 days, the reaction was concentrated, diluted with DCM and then added solid sodium bicarbonate. After stirring at rt for 15 mins, the resulted suspension was loaded onto a silica gel column to give the titled compound as a yellow solid.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].[O:10]([C:17]1[C:18](O)=[C:19]([CH:24]=[CH:25][CH:26]=1)[C:20](OC)=[O:21])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>>[N:4]1([C:1]2[O:3][C:18]3[C:17]([O:10][C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[CH:26][CH:25]=[CH:24][C:19]=3[C:20](=[O:21])[CH:2]=2)[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1
Reactant: COC(=O)c1cccc(Oc2ccccc2)c1O
Reactant: CC(=O)N1CCOCC1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Product: O=c1cc(N2CCOCC2)oc2c(Oc3ccccc3)cccc12
Yield: 27.8 %

Procedure:
Condensation of the lithium enolate of N-acetyl morpholine (0.21 g, 1.6 mmol) with methyl 3-phenoxy-2-hydroxybenzoate (0.25 g, 1.0 mmol) followed by cyclodehydration with trifluoromethanesulfonic anhydride (0.60 ml, 3.6 mmol) as described above yielded TGX-134 as an off-white solid (0.090 g).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[Cl:19][C:20]1[C:25]([Cl:26])=[CH:24][N:23]=[C:22]2[N:27]([S:30]([C:33]3[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=3)(=[O:32])=[O:31])[CH:28]=[CH:29][C:21]=12.C([N-]C(C)C)(C)C.[Li+].[I:48]I>O1CCCC1>[Cl:19][C:20]1[C:25]([Cl:26])=[CH:24][N:23]=[C:22]2[N:27]([S:30]([C:33]3[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=3)(=[O:32])=[O:31])[C:28]([I:48])=[CH:29][C:21]=12
Reactant: II
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)c(Cl)cnc32)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: Cc1ccc(S(=O)(=O)n2c(I)cc3c(Cl)c(Cl)cnc32)cc1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
To a solution of diisopropylamine (4.85 mL, 34.1 mmol) in tetrahydrofuran (50 mL) at −10° C. under nitrogen was added dropwise 2.5M n-butyllithium in hexane (13.62 mL, 34.1 mmol) and the mixture was stirred at −10° C. for 30 minutes. A solution of Example 229A (8.3 g, 24.33 mmol) in tetrahydrofuran (220 mL) cooled to −78° C. was treated with the lithium diisopropylamide solution dropwise over 20 minutes and the mixture was stirred for 50 minutes at −78° C. A solution of iodine (8.64 g, 34.1 mmol) in tetrahydrofuran (30 mL) was added and the mixture was stirred for 20 minutes at −78° C. and allowed to warm to room temperature. The reaction was quenched with saturated aqueous sodium thiosulfate and extracted with ethyl acetate (150 mL). The organic layer was washed with water and brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography on silica gel (AnaLogix IntelliFlash 280) eluting with a gradient of 30-60% ethyl acetate in hexanes. The solid was triturated with 100 mL 15% ethyl acetate/hexane, filtered and dried under vacuum to afford the title compound. MS (ESI+) m/z 466.7 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:9]2[C:13]([C:14]([O:16]CC)=[O:15])=[CH:12][C:11]([CH:19]([CH3:21])[CH3:20])=[N:10]2)[CH:6]=[CH:7][CH:8]=1)#[N:2].O.[OH-].[Li+]>>[C:1]([C:3]1[CH:4]=[C:5]([N:9]2[C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]([CH:19]([CH3:21])[CH3:20])=[N:10]2)[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: CCOC(=O)c1cc(C(C)C)nn1-c1cccc(C#N)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CC(C)c1cc(C(=O)O)n(-c2cccc(C#N)c2)n1
Yield: 94 %

Procedure:
3-Cyanophenylboronic acid (0.4 g, 2.74 mmol), was reacted with Example B38 (0.5 g, 2.74 mmol) in the presence of copper (II) acetate (0.5 g, 2.74 mmol) at 80° C. for 3 hours in pyridine (3.5 ml) to provide ethyl 1-(3-cyanophenyl)-3-isopropyl-1H-pyrazole-5-carboxylate (0.18 g, 24% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.06 (m, 1H), 7.92 (m, 1H), 7.83 (m, 1H), 7.69 (m, 1H), 7.02 (s, 1H), 4.20 (q, J=6 Hz, 1H), 3.00 (m, 1H), 1.26 (d, J=6 Hz, 6H), 1.20 (t, J=6 Hz, 3H); MS (ESI) m/z: 284.2 (M+H+). Hydrolysis of the ester with lithium hydroxide monohydrate provided 1-(3-cyanophenyl)-3-isopropyl-1H-pyrazole-5-carboxylic acid in 94% yield. 1H NMR (400 MHz, DMSO-d6): δ 8.02 (m, 1H), 7.89 (m, 1H), 7.83 (m, 1H), 7.67 (m, 1H), 6.97 (s, 1H), 3.00 (m, 1H), 1.26 (q, J=6 Hz, 6H); MS (ESI) m/z: 256.0 (M+H+).
Reaction SMILES: [CH3:1][C:2]([NH:10][OH:11])=[C:3]1[CH:9]=[CH:8][C:6](=[O:7])[CH:5]=[CH:4]1.[CH3:12][C:13](C1C=CC(O)=CC=1)=[O:14].O[NH2:23]>S(Cl)(Cl)=O>[C:13]([NH:23][C:3]1[CH:4]=[CH:5][C:6]([OH:7])=[CH:8][CH:9]=1)(=[O:14])[CH3:12].[CH3:1][C:2]([NH:10][OH:11])=[C:3]1[CH:9]=[CH:8][C:6](=[O:7])[CH:5]=[CH:4]1
Reactant: NO
Reactant: CC(=O)c1ccc(O)cc1
Agent: CC(NO)=C1C=CC(=O)C=C1
Solvent: O=S(Cl)Cl
Product: CC(=O)Nc1ccc(O)cc1

Procedure:
N-acetyl-para-aminophenol is prepared by subjecting 4-hydroxyacetophenone oxime to a Beckmann rearrangement in the presence of a thionyl chloride catalyst and an alkyl alkanoate as the reaction solvent. An integrated process is disclosed wherein 4-hydroxyacetophenone is reacted with a hydroxyl amine salt and a base to obtain the ketoxime of the ketone, e.g., 4-hydroxyacetophenone oxime, extracting the ketoxime product from the reaction with alkanoate ester and subjecting the ketoxime dissolved in the ester to a Beckmann rearrangement in the presence of a thionyl chloride catalyst.
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:20]1[CH2:25][CH2:24][CH2:23][C@@H:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:21]1>CCCCO>[Br:1][C:2]1[C:3]([N:20]2[CH2:25][CH2:24][CH2:23][C@@H:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])[CH2:21]2)=[C:4]2[C:10]([NH:11][C:12]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)C1CCCC1
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)C4CCCC4)c23)C1
Temperature: 160 °C
Reaction time: 18 h
Yield: 22 %

Procedure:
A solution of N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopentanecarboxamide (205 mg, 0.629 mmol) in n-BuOH (5 mL) was treated with (R)-tert-butyl piperidin-3-ylcarbamate (629 mg, 3.14 mmol) and stirred at 160° C. for 18 hours in a sealed tube. The solvent was removed in vacuo, and the residue was dissolved in EtOAc (50 mL) and washed with water (2×10 mL). The organic layer was dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by C-18 reverse phase flash chromatography (Biotage SP4 unit, C-18 25M column, 5-80% CH3CN/water gradient; 25 CV) to yield a solid, which was crystallized from CH3CN to provide (R)-tert-butyl 1-(5-bromo-3-(cyclopentanecarboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (70 mg, 22% yield) as a solid. 1H NMR (400 MHz, (CD3)2SO) δ 11.56 (s, 1H), 9.36 (s, 1H), 8.14 (s, 1H), 7.64 (br s, 1H), 6.90 (br s, 1H), 3.56-3.47 (m, 1H), 3.20-3.11 (m, 2H), 3.04-2.97 (m, 1H), 2.81-2.74 (m, 1H), 1.91-1.80 (m, 4H), 1.78-1.70 (m, 3H), 1.67-1.59 (m, 3H), 1.55-1.50 (m, 2H), 1.42-1.34 (m, 1H); LCMS (APCI+) m/z 407.9 [(M-Boc)+H]+, Retention time=4.03 minutes (Method 2).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].I[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2([C:16]([F:19])([F:18])[F:17])[N:15]=[N:14]2)=[CH:9][CH:8]=1>CO>[N:1]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2([C:16]([F:19])([F:17])[F:18])[N:14]=[N:15]2)=[CH:11][CH:12]=1)=[N+:2]=[N-:3]
Reactant: FC(F)(F)C1(c2ccc(CI)cc2)N=N1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CO
Product: [N-]=[N+]=NCc1ccc(C2(C(F)(F)F)N=N2)cc1
Temperature: 45 °C
Reaction time: 6 h
Yield: 76.2 %

Procedure:
NaN3 (0.42 g, 6.2 mmol) was added to a MeOH (30 mL) solution of 3-[4-(iodomethyl)phenyl]-3-(trifluoromethyl)-3H-diazirine (1.01 g, 3.1 mmol). The solution was stirred at 45° C. (6 h). The methanol was evaporated and CH2Cl2 (30 mL) and water (30 mL) were added. The organic layer was extracted and the aqueous layer was washed with CH2Cl2 (1×30 mL). The organic layers were combined and concentrated in vacuum. Finally, the residue was purified by silica gel flash chromatography (0→30% EtOAc in hexanes) to obtain 570 mg (77%) of a pale yellow liquid: Rf=0.85 (1/9 EtOAc/hexanes); IR (nujol) 3298, 2927, 2859, 2100 (N3), 1694, 1615, 1459, 1374, 1236, 1162, 1055, 939, 805, 728 cm−1; 1H NMR (CDCl3): δ 4.37 (s, CH2), 7.21 (d, J=7.9 Hz, 2 C6H4), 7.35 (d, J=7.9 Hz, 2 C6H4); 13C NMR (CDCl3): δ 28.3 (q, J=40.2 Hz, C diazirine), 54.1 (CH2N3), 122.1 (q, J=273.0 Hz, CF3), 127.0 (C6H2), 128.5 (C6H2), 129.2 (C6H2), 137.2 (C6H2).