Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([Cl:10])[CH:3]=1.[N:11]([O-])=O.[Na+].O.O.Cl[Sn]Cl>C1COCC1.O.Cl>[ClH:10].[Cl:10][C:4]1[CH:3]=[C:2]([NH:1][NH2:11])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: O=N[O-]
Reactant: N#Cc1ccc(N)cc1Cl
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc(NN)cc1Cl
Temperature: -5 °C
Reaction time: 2 h

Procedure:
5 g of 4-amino-2-chlorobenzonitrile and 40 ml of concentrated HCl in 30 ml of THF are mixed at -5° C.; 2.26 g of NaNO2 in 30 ml of water are added and the mixture is left stirring for 2 hours, 30 g of SnCl2.2H2O in 30 ml of concentrated HCl are then added and stirring is maintained at -5° C. for 30 minutes.
Reaction SMILES: O[N:2]1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.C(N(CC)C(C)C)(C)C.[C:31]([O:35][C:36]([N:38]1[CH2:43][CH2:42][CH:41]([C:44]2[CH:49]=[CH:48][C:47]([NH:50][C:51]3[N:56]=[C:55]([CH2:57][CH2:58][C:59]4[C:64]([CH2:65][C:66]([O-])=[O:67])=[CH:63][CH:62]=[CH:61][N:60]=4)[C:54]([C:69]([F:72])([F:71])[F:70])=[CH:53][N:52]=3)=[CH:46][CH:45]=2)[CH2:40][CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32].[Li+].C(=O)([O-])[O-].[NH4+].[NH4+]>C1COCC1.CN(C=O)C>[NH2:2][C:66](=[O:67])[CH2:65][C:64]1[C:59]([CH2:58][CH2:57][C:55]2[C:54]([C:69]([F:71])([F:72])[F:70])=[CH:53][N:52]=[C:51]([NH:50][C:47]3[CH:46]=[CH:45][C:44]([CH:41]4[CH2:40][CH2:39][N:38]([C:36]([O:35][C:31]([CH3:33])([CH3:32])[CH3:34])=[O:37])[CH2:43][CH2:42]4)=[CH:49][CH:48]=3)[N:56]=2)=[N:60][CH:61]=[CH:62][CH:63]=1
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ncccc4CC(=O)[O-])n3)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ncccc4CC(N)=O)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1-Hydroxybenzotriazole (20.4 mg, 0.151 mmol), EDCI (29.0 mg, 0.151 mmol) and N,N-diisopropylethylamine (0.192 mL, 1.10 mmol) were added to a solution of lithium 2-(2-(2-(2-((4-(1-(tert-butoxycarbonyl)piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)pyridin-3-yl)acetate (I123) (81.3 mg, 0.137 mmol) in dry THF (6 mL) and dry DMF (1 mL) under an atmosphere of nitrogen. Ammonium carbonate (I06 mg, 1.10 mmol) was added in one portion to the stirred reaction mixture after 10 minutes. The reaction was left to stir at room temperature for 18 hours. The volatiles were removed in vacuo and the residue was diluted with EtOAc (50 mL) and washed with saturated NaHCO3 (50 mL). The aqueous layer was extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine (50 mL) and dried over Na2SO4. After filtration the solvent was removed in vacuo to afford a pale yellow oil. The crude material was purified by column chromatography on silica gel (0-100% EtOAc in petroleum benzine 40-60° C.) to afford the title compound (I124) (66.3 mg, 83%) as a white semi-solid; 1H NMR (400 MHz, CDCl3) δ 8.50 (d, J=0.4 Hz, 1H), 8.49 (dd, J=4.8, 1.7 Hz, 1H), 7.62 (s, 1H), 7.54 (dd, J=7.7, 1.7 Hz, 1H), 7.51 (d, J=8.7 Hz, 2H), 7.19-7.13 (m, 3H), 5.40-5.35 (m, 2H), 4.23 (s, 2H), 3.68 (s, 2H), 3.41-3.35 (m, 2H), 3.32-3.24 (m, 2H), 2.80 (t, J=12.6 Hz, 2H), 2.63 (tt, J=12.0, 3.4 Hz, 1H), 1.81 (d, J=12.5 Hz, 2H), 1.65-1.57 (m, peaks obscured by solvent), 1.48 (s, 9H). LCMS Method C: rt 5.25 min; m/z 607 [M+Na]+, 585 [M+H]+, 529 [M−tButyl+2H]+.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([NH:7][C:8]([C:10]23[CH2:19][CH:14]4[CH2:15][CH:16]([CH2:18][CH:12]([CH2:13]4)[CH2:11]2)[CH2:17]3)=[O:9])=[N:4][CH:3]=1.Br[CH2:21][CH2:22][O:23][CH3:24].[H-].[Na+]>O1CCCC1.CN(C)C=O.O>[Br:1][C:2]1[S:6]/[C:5](=[N:7]\[C:8]([C:10]23[CH2:11][CH:12]4[CH2:18][CH:16]([CH2:15][CH:14]([CH2:13]4)[CH2:19]2)[CH2:17]3)=[O:9])/[N:4]([CH2:21][CH2:22][O:23][CH3:24])[CH:3]=1
Reactant: O=C(Nc1ncc(Br)s1)C12CC3CC(CC(C3)C1)C2
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: COCCn1cc(Br)s/c1=N\C(=O)C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C

Procedure:
A solution of Example 131A (2.55 g, 7.43 mmol), 1-bromo-2-methoxyethane (0.77 mL, 8.15 mmol) and sodium hydride (60%) (386 mg, 9.66 mmol) in tetrahydrofuran/N,N-dimethylformamide (2:1) (60 mL) was heated at 75° C. for 12 hours. The mixture was cooled to ambient temperature, diluted with water, and extracted with dichloromethane. The organic extract was dried (Na2SO4), filtered and concentrated. Purification by chromatography (silica gel, 100% dichloromethane) afforded the title compound. MS (ESI) m/z 399 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][C:5]([F:8])([F:7])[CH2:4][C@@H:3]1[NH:9][C:10](=[O:22])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:17]1[N:21]=[CH:20][CH:19]=[N:18]1.F[C:24]1[C:29]([F:30])=[CH:28][C:27]([C:31]([F:34])([F:33])[F:32])=[CH:26][N:25]=1.CCN(C(C)C)C(C)C>CS(C)=O>[F:7][C:5]1([F:8])[CH2:4][C@H:3]([NH:9][C:10](=[O:22])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:17]2[N:18]=[CH:19][CH:20]=[N:21]2)[C@@H:2]([NH:1][C:24]2[C:29]([F:30])=[CH:28][C:27]([C:31]([F:34])([F:32])[F:33])=[CH:26][N:25]=2)[CH2:6]1
Reactant: N[C@H]1CC(F)(F)C[C@@H]1NC(=O)c1ccccc1-n1nccn1
Reactant: Fc1cc(C(F)(F)F)cnc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: O=C(N[C@H]1CC(F)(F)C[C@@H]1Nc1ncc(C(F)(F)F)cc1F)c1ccccc1-n1nccn1

Procedure:
A microwave vial was charged with N-[(1S,2S)-2-amino-4,4-difluorocyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide (Intermediate 46; 50 mg, 0.15 mmol), 2,3-difluoro-5-(trifluoromethyl)pyridine (CAS number 89402-42-6; 29 mg, 0.16 mmol) and DIPEA (26 μl, 0.15 mmol) in dry DMSO (485 μl). The reaction mixture was subjected to microwave irradiation at 120° C. for 30 minutes then partitioned between ethyl acetate and water. The organics were washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by column chromatography (silica, 0-60% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: [CH2:1]([C:5]1([CH3:30])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([OH:15])=[C:7]([C:16]2[NH:21][C:20]3[CH:22]=[CH:23][C:24]([OH:26])=[CH:25][C:19]=3[S:18](=[O:28])(=[O:27])[N:17]=2)[C:6]1=[O:29])[CH2:2][CH2:3][CH3:4].Br[CH2:32][C:33]([NH2:35])=[O:34].C(=O)([O-])[O-].[Cs+].[Cs+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O.C(OCC)(=O)C>[CH2:1]([C:5]1([CH3:30])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([OH:15])=[C:7]([C:16]2[NH:21][C:20]3[CH:22]=[CH:23][C:24]([O:26][CH2:32][C:33]([NH2:35])=[O:34])=[CH:25][C:19]=3[S:18](=[O:28])(=[O:27])[N:17]=2)[C:6]1=[O:29])[CH2:2][CH2:3][CH3:4]
Reactant: NC(=O)CBr
Reactant: CCCCC1(C)C(=O)C(C2=NS(=O)(=O)c3cc(O)ccc3N2)=C(O)c2ccccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCC1(C)C(=O)C(C2=NS(=O)(=O)c3cc(OCC(N)=O)ccc3N2)=C(O)c2ccccc21
Yield: 66.9 %

Procedure:
A solution of Example 27H (0.100 g, 0.235 mmol), 2-bromoacetamide (0.097 g, 0.703 mmol), cesium carbonate (0.382 g, 1.17 mmol), and tetrabutylammonium iodide (0.001 g, 0.024 mmol) in dimethylformamide (2.5 mL) was stirred at 25° C. for 72 hours. The mixture was diluted with ethyl acetate, washed with water and brine, dried with sodium sulfate, filtered, and concentrated in vacuo to give the free acid (0.076 g).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][NH:19][CH:20]([CH3:22])[CH3:21])=[CH:11][CH:10]=1)C1C=CC=CC=1>[Pd].C(O)C>[CH3:22][CH:20]([NH:19][CH2:18][CH2:17][CH2:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=1)[CH3:21]
Reactant: CC(C)NCCCOc1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)NCCCOc1ccc(O)cc1
Yield: 100.8 %

Procedure:
1-Benzyloxy-4-[3-(1-methylethyl)aminopropoxy]benzene (11.5 g) was added to an hydrogenation bottle containing 250 ml of ethanol and hydrogenated over 1 g of 10% palladium on carbon (room temperature; starting pressure of 50 psi). After the theoretical uptake of hydrogen, the mixture was filtered and the solvent distilled in vacuo giving 8.1 g of 4-[3-(1-methylethyl)aminopropoxy]phenol, mp 92°-100° (96.4% pure by gas chromatography). Mass spectrum was compatible.
Reaction SMILES: I[CH2:2][CH2:3][C@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5].[I-].[Na+].C(O)(C)C.O.O.[C:20]([OH:25])(=[O:24])[C:21]([OH:23])=[O:22].[CH3:26][NH2:27]>O1CCCC1>[C:20]([OH:25])(=[O:24])[C:21]([OH:23])=[O:22].[CH3:26][NH:27][CH2:2][CH2:3][C@@H:4]([OH:5])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:26][NH:27][CH2:2][CH2:3][C@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5]
Reactant: CN
Reactant: O[C@H](CCI)c1ccccc1
Agent: O=C(O)C(=O)O
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: C1CCOC1
Solvent: O
Product: CNCC[C@@H](O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (R)-3-iodo-1-phenylpropanol (5.0 g, 19 mmol) and catalytic amount of sodium iodide in tetrahydrofuran (20 mL) and 40% aqueous methylamine (40 mL) was stirred at room temperature for 5 hours. The reaction mixture was evaporated to 15 mL and the pH of the solution was adjusted to pH>12 via the addition of aqueous NaOH solution. The mixture was then twice extracted with toluene and the combined extracts were washed with brine. The toluene layer was evaporated to dryness and the residue dissolved in toluene (25 mL) and isopropanol (25 mL) and oxalic acid dihydrate (1.2 g, 9.5 mmol) was added and the mixture was stirred at room temperature for 2 hours. The resulting suspension was filtered and rinsed with toluene/isopropanol to give 3.0 g of (R)—N-methyl-3-hydroxy-3-phenylpropylamine hemioxalate salt as an off-white solid. The solid (2.9 g) was free based with sodium hydroxide solution and extracted with toluene. The extracts were washed with brine and then evaporated to dryness to give 2.2 g of (R)—N-methyl-3-hydroxy-3-phenylpropylamine as an off-white solid [α]D23=36° (c 1, CHCl3).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[CH:4]=[O:5].[BH4-].[Na+]>>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[CH2:4][OH:5]
Reactant: Cc1cccc(Cl)c1C=O
Agent: [BH4-]
Agent: [Na+]
Product: Cc1cccc(Cl)c1CO
Reaction time: 1.3 h

Procedure:
To a stirred solution of 2-chloro-6-methylbenzaldehyde (6.11 g, 39.5 mmol) in THF(2): methanol(3) (30 ml) was added in portion NaBH4 (2.24 g, 59.28 mmol) at 0° C. under argon. The reaction mixture was stirred at the same temperature for 1.3 hours and then quenched with cold sat. NH4Cl solution, extracted with EtOAc, dried over Na2SO4, filtered, concentrated, and purified by flash chromatography on a silica gel column (hex:ethyl acetate, 2:1) to give the title compound.
Reaction SMILES: Cl.[CH3:2][C:3]([CH3:33])([CH2:31][CH3:32])[CH2:4][C:5]1[N:6]=[C:7]([C:16]([OH:30])([CH3:29])[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:25]=[N:26][NH:27][CH:28]=3)=[CH:20][CH:19]=2)[N:8](S(N(C)C)(=O)=O)[CH:9]=1>CO>[CH3:2][C:3]([CH3:33])([CH2:31][CH3:32])[CH2:4][C:5]1[N:6]=[C:7]([C:16]([OH:30])([CH3:29])[CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[CH:28]=[N:27][NH:26][CH:25]=3)=[CH:22][CH:23]=2)[NH:8][CH:9]=1
Reactant: CCC(C)(C)Cc1cn(S(=O)(=O)N(C)C)c(C(C)(O)Cc2ccc(-c3cn[nH]c3)cc2)n1
Agent: Cl
Solvent: CO
Product: CCC(C)(C)Cc1c[nH]c(C(C)(O)Cc2ccc(-c3cn[nH]c3)cc2)n1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
Hydrogen chloride (4 M in 1,4-dioxane) (1 mL, 4 mmol) was added to a solution of 4-(2,2-dimethylbutyl)-2-{1-hydroxy-1-methyl-2-[4-(1H-pyrazol-4-yl)phenyl]ethyl}-N,N-dimethyl-1H-imidazole-1-sulfonamide (100 mg, 0.22 mmol) in methanol (1 mL). After stirring at 70° C. for 1 h, volatiles were removed in vacuo. The residue was partitioned between methanol/ethyl acetate and 10% aqueous sodium hydroxide. The aqueous phase was extracted with ethyl acetate. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo to afford the title compound. (M+H) found: 353.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[OH:11][C@@H:12]1[C@@H:19]2[N:15]([C:16](=[O:31])[N:17]([C:21]3[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[C:23]([Cl:29])[C:22]=3[CH3:30])[C@H:18]2[CH3:20])[CH2:14][CH2:13]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:20][C@H:18]1[N:17]([C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[C:23]([Cl:29])[C:22]=2[CH3:30])[C:16](=[O:31])[N:15]2[CH2:14][CH2:13][C:12](=[O:11])[C@H:19]12
Reactant: Cc1c(N2C(=O)N3CC[C@H](O)[C@H]3[C@@H]2C)ccc(C#N)c1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(N2C(=O)N3CCC(=O)[C@@H]3[C@H]2C)ccc(C#N)c1Cl
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of DMSO (20 μL) in CH2Cl2 (1 mL) at −78° C. was added oxalyl chloride (1.0 M in CH2Cl2, 131 μL). This mixture was stirred at −78° C. for 30 min. and then a solution of 61K in CH2Cl2 (20 mg in 1 mL). The reaction was stirred at −78° C. for 1 h and then i-Pr2NEt (100 μL) was added and the reaction was allowed to warm to rt over 1 h. The reaction was extracted with EtOAc and washed twice with 1N HCl and once with saturated NaHCO3. The organic layer was dried over MgSO4, filtered and concentrated. Purification by flash chromatography (silica gel, 40% EtOAc/CH2Cl2) provided the title compound (18 mg): MS (ES) m/z 304.42 [M+H]+
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[N+:14]([O-:16])=[O:15])[C:8](O)=[O:9].P(Cl)(Cl)(Cl)(Cl)[Cl:23]>C1C=CC=CC=1>[F:1][C:2]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[N+:14]([O-:16])=[O:15])[C:8]([Cl:23])=[O:9]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(Oc2ccc(F)cc2F)c1
Solvent: c1ccccc1
Product: O=C(Cl)c1ccc([N+](=O)[O-])c(Oc2ccc(F)cc2F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 103.5 %

Procedure:
A mixture of 3-(2,4-difluorophenoxy)-4-nitrobenzoic acid (1 g) and phosphorus pentachloride (0.74 g) in benzene (10 ml) was stirred for 30 minutes at room temperature. Benzene was evaporated under reduced pressure to give an oil of 3-(2,4-difluorophenoxy)-4-nitrobenzoyl chloride (1.1 g).
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][C:14]([C:16]([OH:18])=O)=[CH:15][C:10]=3[N:9]=[CH:8]2)=[CH:4][CH:3]=1.[CH:21]([C:24]1[CH:25]=[C:26]([C@@H:30]([NH2:32])[CH3:31])[CH:27]=[CH:28][CH:29]=1)([CH3:23])[CH3:22].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][C:14]([C:16]([NH:32][C@H:30]([C:26]4[CH:27]=[CH:28][CH:29]=[C:24]([CH:21]([CH3:23])[CH3:22])[CH:25]=4)[CH3:31])=[O:18])=[CH:15][C:10]=3[N:9]=[CH:8]2)=[CH:19][CH:20]=1
Reactant: CC(C)c1cccc([C@H](C)N)c1
Reactant: O=C(O)c1ccc2c(c1)ncn2Cc1ccc(Br)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)c1cccc([C@H](C)NC(=O)c2ccc3c(c2)ncn3Cc2ccc(Br)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The mixture of 1-(4-bromobenzyl)-1H-benzo[d]imidazole-5-carboxylic acid (521 mg, 1.57 mmol), (S)-1-(3-isopropylphenyl)ethanamine (314 mg, 1.88 mmol), HATU (1.19 g, 1.88 mmol) and DIPEA (607 mg, 4.71 mmol) in DMF (15 mL) was stirred at RT overnight. Then the mixture was poured into 20 mL of water, then extracted with EtOAc (10 mL×3). The combined organic layers was washed with water (10 mL) and brine (10 mL) and dried with Na2SO4. After filtration, the filtrate was concentrated under the reduced pressure. The residue was purified with Combiflash (DCM/EtOAc=4/1, silica gel) to give the title compound.
Reaction SMILES: [C:1]([CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH3:23])[C:8]2[CH:12]([CH2:13][C:14]([O:16]C(C)(C)C)=[O:15])[O:11][B:10]([OH:21])[C:9]=2[CH:22]=1)#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH3:23])[C:8]2[CH:12]([CH2:13][C:14]([OH:16])=[O:15])[O:11][B:10]([OH:21])[C:9]=2[CH:22]=1)#[N:2]
Reactant: Cc1cc(OCC#N)cc2c1C(CC(=O)OC(C)(C)C)OB2O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(OCC#N)cc2c1C(CC(=O)O)OB2O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.5 %

Procedure:
To a solution of tert-butyl 2-(6-(cyanomethoxy)-1-hydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (120 mg, 0.38 mmol) in 5 ml DCM was added TFA (5 mL) at 0° C. The reaction mixture was stirred for 30 min at room temperature and concentrated to dryness. The residue was purified by prep HPLC to give the title compound as a white solid (60 mg, yield: 60.8%). 1H NMR (400 MHz, DMSO-d) δ12.31 (s, 1H), 9.24 (s, 1H), 7.16 (d, J=2.4 Hz, 1H), 6.97 (d, J=2.4 Hz, 1H), 5.48-5.45 (m, 1H), 5.15 (s, 2H), 3.06-3.02 (m, 1H), 2.28 (s, 3H), 2.12-2.05 (m, 1H); MS (ESI) m/z=262 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:32]([F:35])([F:34])[F:33])=[C:6]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[C:24]4[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][C:19]=4[NH:18][N:17]=3)=[O:15])[CH2:10][CH2:9]2)[CH:7]=1.[ClH:36]>C(Cl)Cl.CCOCC>[ClH:36].[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:32]([F:35])([F:33])[F:34])=[C:6]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[C:24]4[CH2:23][CH2:22][NH:21][CH2:20][C:19]=4[NH:18][N:17]=3)=[O:15])[CH2:10][CH2:9]2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(C(=O)N3CCC(c4cc(F)ccc4C(F)(F)F)CC3)n[nH]c2C1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(c1n[nH]c2c1CCNC2)N1CCC(c2cc(F)ccc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 71 %

Procedure:
To a solution of tert-butyl 3-(4-(5-fluoro-2-(trifluoromethyl)phenyl) piperidine-1-carbonyl)-4,5-dihydro-1H-pyrazolo[3,4-c]pyridine-6(7H)-carboxylate (43, 107 mg, 0.21 mmol) in CH2Cl2 (2 mL) was added HCl (2N in Et2O, 2 mL). The mixture stirred for 18 h at ambient temperature. The reaction mixture was diluted with Et2O (20 mL) and the resulting solids were collected by filtration to provide (4-(5-fluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanone hydrochloride (44) as a white solid (66 mg, 71%): 1H NMR (500 MHz, DMSO-d6) δ 13.52-13.13 (m, 1H), 9.41 (br s, 2H), 7.77 (dd, J=9.0, 5.7 Hz, 1H), 7.62-7.50 (m, 1H), 7.32-7.21 (m, 1H), 5.00-4.83 (m, 1H), 4.75-4.58 (m, 1H), 4.37-4.19 (m, 2H), 3.41-3.24 (m, 2H, overlaps with H2O), 3.22-3.04 (m, 2H), 2.94-2.73 (m, 3H), 1.86-1.64 (m, 4H); ESI MS m/z 397 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].[N+](C=C(SC)SC)([O-])=O.[N+:21]([CH:24]=[C:25](SC)[NH:26][CH2:27]CSCC1NC=NC=1Br)([O-:23])=[O:22].CN>>[N+:21]([CH:24]=[C:25]([NH:26][CH3:27])[NH:11][CH2:10][CH2:9][S:8][CH2:7][C:6]1[NH:5][CH:4]=[N:3][C:2]=1[Br:1])([O-:23])=[O:22]
Reactant: NCCSCc1[nH]cnc1Br
Reactant: CSC(=C[N+](=O)[O-])NCCSCc1[nH]cnc1Br
Agent: CN
Agent: CSC(=C[N+](=O)[O-])SC
Product: CNC(=C[N+](=O)[O-])NCCSCc1[nH]cnc1Br

Procedure:
When 4-bromo-5-[(2-aminoethyl)thiomethyl]imidazole (from the dihydrobromide (4.8 g)) is reacted with 1-nitro-2,2-bis-methylthioethylene (2.0 g) according to the procedure of Example 8(i) and the resultant 1-nitro-2-methylthio-2-[2-((4-bromo-5-imidazolyl)methylthio)ethylamino]ethylene treated with methylamine by the procedure of Example 8(ii) there is produced 1-nitro-2-methylamino-2-[2-((4-bromo-5-imidazolyl)methylthio)ethylamino]ethylene.
Reaction SMILES: [N:1]1([S:5]([NH2:8])(=[O:7])=[O:6])[CH2:4][CH2:3][CH2:2]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:50]1[N:55]=[C:54]([S:56][CH2:57][C:58]2[CH:63]=[CH:62][CH:61]=[C:60]([F:64])[C:59]=2[F:65])[N:53]=[C:52]([O:66][C@@H:67]([CH3:71])[C@@H:68]([OH:70])[CH3:69])[CH:51]=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:65][C:59]1[C:60]([F:64])=[CH:61][CH:62]=[CH:63][C:58]=1[CH2:57][S:56][C:54]1[N:55]=[C:50]([NH:8][S:5]([N:1]2[CH2:4][CH2:3][CH2:2]2)(=[O:7])=[O:6])[CH:51]=[C:52]([O:66][C@@H:67]([CH3:71])[C@@H:68]([OH:70])[CH3:69])[N:53]=1
Reactant: NS(=O)(=O)N1CCC1
Reactant: C[C@H](O)[C@H](C)Oc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: C[C@H](O)[C@H](C)Oc1cc(NS(=O)(=O)N2CCC2)nc(SCc2cccc(F)c2F)n1

Procedure:
The title compound was prepared according to the procedure outlined in example 4 using a mixture of azetidine-1-sulfonamide (150 mg), tris(dibenzylideneacetone)dipalladium (0) (25 mg), 2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (XPHOS) (25 mg), cesium carbonate (244 mg) and (2S,3S)-3-({6-chloro-2-[(2,3-difluorobenzyl)thio]pyrimidin-4-yl}oxy)butan-2-ol (200 mg) in anhydrous dioxane (10 ml). Purification was by reverse phase HPLC eluting with acetonitrile/aq. 0.1% ammonium acetate mixtures to give title compound as a white solid. Yield: 60 mg
Reaction SMILES: [CH3:1]I.[ClH:3].[Br:4][C:5]1[CH:6]=[C:7]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]1[CH:12]([NH:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:11][CH2:10][CH2:9][C:8]2=1.[H-].[Na+].Cl>C1COCC1>[ClH:3].[Br:4][C:5]1[CH:6]=[C:7]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH3:1])[C:13]1[CH:12]([NH:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:11][CH2:10][CH2:9][C:8]2=1
Reactant: Brc1ccc2[nH]c3c(c2c1)CCCC3NCCc1ccccc1
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1c2c(c3cc(Br)ccc31)CCCC2NCCc1ccccc1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
6-Bromo-9-methyl-N-(2-phenylethyl)-2,3,4,9-tetrahydro-1H-carbazol-1-amine hydrochloride salt was prepared by addition of methyl iodide (0.016 mL, 0.25 mmol) to a solution of 6-bromo-N-(2-phenylethyl)-2,3,4,9-tetrahydro-1H-carbazol-1-amine hydrochloride salt (0.05 g, 0.12 mmol) and sodium hydride (0.04 mL, 0.25 mmol) in THF (2.0 mL) that was under inert atmosphere and cooled to 0° C. The mixture was allowed to warm to room temperature and stirred for 12 hrs. The reaction was quenched with saturated (“sat.”) ammonium chloride (“NH4Cl”) (2.0 mL), ethyl acetate was added (10 mL), the organic layer was separated and washed with sat. NaCl (2.0 mL), dried over sodium sulfate (“Na2SO4”), filtered and evaporated to leave an oily residue. Purification by flash chromatography with 10-50% gradient ethyl acetate/hexanes eluent afforded a clear oil that was converted to the HCl salt to give a white solid (0.005 g, 9%). 1H-NMR (CDCl3): δ 7.57 (s, 1H), 7.31-7.21 (m, 7H), 7.09 (d, 1H), 3.86 (m, 1H), 3.53 (s, 3H), 3.19-3.13 (m, 1H), 2.94-2.87 (m, 1H), 2.84-2.80 (m, 2H), 2.74-2.67 (m, 1H), 2.55-2.47 (m, 1H), 2.17-2.11 (m, 1H), 1.83-1.70 (m, 3H); MS m/z 381, 383 (M−1).
Reaction SMILES: [C:1]([Si:5]([CH3:28])([CH3:27])[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([C:18]2[S:22][C:21]([CH2:23][OH:24])=[C:20]([CH3:25])[CH:19]=2)([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:9][C:8]=1[CH3:26])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:36]1([CH3:46])[CH:41]=[CH:40][C:39]([S:42](Cl)(=[O:44])=[O:43])=[CH:38][CH:37]=1>CCOCC>[C:1]([Si:5]([CH3:28])([CH3:27])[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([C:18]2[S:22][C:21]([CH2:23][O:24][S:42]([C:39]3[CH:40]=[CH:41][C:36]([CH3:46])=[CH:37][CH:38]=3)(=[O:44])=[O:43])=[C:20]([CH3:25])[CH:19]=2)([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:9][C:8]=1[CH3:26])([CH3:2])([CH3:4])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCC(CC)(c1ccc(O[Si](C)(C)C(C)(C)C)c(C)c1)c1cc(C)c(CO)s1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCC(CC)(c1ccc(O[Si](C)(C)C(C)(C)C)c(C)c1)c1cc(C)c(COS(=O)(=O)c2ccc(C)cc2)s1
Reaction time: 8 h
Yield: 54 %

Procedure:
To a solution of (5-{1-[4-(tert-butyl-dimethyl-silanyloxy)-3-methyl-phenyl]-1-ethyl-propyl}-3-methyl-thiophen-2-yl)-methanol (1.0 g, 2.39 mmol) in Et2O (5 ml) is added triethyl amine (666 μl, 4.78 mmol). The mixture is added to a solution of p-toluenesulfonyl chloride (501 mg, 2.62 mmol) in Et2O (5 ml) and stirred overnight. The reaction is filtered, concentrated and chromatographed (12 g SiO2, 5% EtOAc/Hex) to yield the title compound (740 mg, 55%).