Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[CH2:15]([OH:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[H-].[Na+]>C1COCC1>[CH2:15]([O:22][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=[N+]([O-])c1ccc(F)c(C(F)(F)F)c1
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(OCc2ccccc2)c(C(F)(F)F)c1
Yield: 78.7 %

Procedure:
To a solution of 2-fluoro-5-nitrobenzotrifluoride (500 mg, 2.48 mmol) and benzyl alcohol (267 mg, 2.48 mmol) in THF was added sodium hydride (95.1 mg, 2.48 mmol) at 0° C. The reaction was followed by TLC and quenched with saturated ammonium chloride solution after 0.5 h. The mixture was extracted with dichloromethane three times. The combined organic layer was dried over sodium sulfate and concentrated. The residue was triturated with 2.5 mL of hexanes and ethyl acetate (7:1) and a yellow precipitate was collected by filtration to give 1-benzyloxy-4-nitro-2-trifluoromethylbenzene (580 mg, 79%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[S:16][CH2:15][C:14]2([CH2:20][CH2:19][CH2:18][CH2:17]2)[NH:13]1.Br[CH2:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][O:24]1>>[CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[S:16][CH2:15][C:14]2([CH2:17][CH2:18][CH2:19][CH2:20]2)[N:13]1[CH2:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][O:24]1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C1NC2(CCCC2)CS1
Reactant: BrCC1CCCCO1
Product: Cc1cc([N+](=O)[O-])ccc1N=C1SCC2(CCCC2)N1CC1CCCCO1

Procedure:
1-Hydroxymethylcyclopentanamine was prepared according to Method B1c. The 2-hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. 1-Chloromethylcyclopentanamine HCl salt was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method C1e to give 2-(2-methyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with 2-(bromomethyl)tetrahydro-2H-pyran according to Method D2e to give 2-(2-methyl-4-nitrophenylimino)-1-(tetrahydro-2H-pyran-2-ylmethyl)-3-thia-1-azaspiro[4.4]nonane.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:14]3[CH:15]=[N:16][CH:17]=[C:18]([F:19])[C:13]=3[N:12]([C:20]([CH3:31])([CH3:30])[CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH:11]=2)=[O:9])[CH:5]=[N:6][CH:7]=1.[CH:32]1([C:35]2[CH:39]=[CH:38][N:37]([CH2:40][C:41](O)=[O:42])[N:36]=2)[CH2:34][CH2:33]1.CCN(C(C)C)C(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>C1COCC1>[C:26]([Si:23]([CH3:24])([CH3:25])[O:22][CH2:21][C:20]([N:12]1[C:13]2[C:18]([F:19])=[CH:17][N:16]=[CH:15][C:14]=2[C:10]([C:8]([C:4]2[CH:3]=[C:2]([NH:1][C:41](=[O:42])[CH2:40][N:37]3[CH:38]=[CH:39][C:35]([CH:32]4[CH2:33][CH2:34]4)=[N:36]3)[CH:7]=[N:6][CH:5]=2)=[O:9])=[CH:11]1)([CH3:31])[CH3:30])([CH3:29])([CH3:28])[CH3:27]
Reactant: O=C(O)Cn1ccc(C2CC2)n1
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cncc(N)c2)c2cncc(F)c21
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cncc(NC(=O)Cn3ccc(C4CC4)n3)c2)c2cncc(F)c21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (5-amino-pyridin-3-yl)-{1-[2-(tert-butyl-dimethyl-silanyloxy)-1,1-dimethyl-ethyl]-7-fluoro-1H-pyrrolo[3,2-c]pyridin-3-yl}-methanone (Preparation 29, 35 mg, 79 μmol), (3-cyclopropyl-pyrazol-1-yl)-acetic acid (17.74 mg, 106 μmol) and DIPEA (48.97 μL, 277 μmol) in THF (3 mL), T3P (166 μL, 277 μmol) was added and the mixture stirred at 25° C. for 18 hours. The reaction was evaporated under reduced pressure, the residue partitioned between water and ethyl acetate, the organic extracts washed with saturated sodium bicarbonate solution, dried over sodium sulphate, evaporated in vacuo and triturated with pentane-ether to afford the title compound as an off white solid (91%, 42 mg) that was taken directly on to the next step.
Reaction SMILES: [C:1]1(=[O:15])[N:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11](O)=[O:12])[C:4](=[O:14])[CH:3]=[CH:2]1.S(Cl)([Cl:18])=O>>[C:1]1(=[O:15])[N:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([Cl:18])=[O:12])[C:4](=[O:14])[CH:3]=[CH:2]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CCCCCN1C(=O)C=CC1=O
Product: O=C(Cl)CCCCCN1C(=O)C=CC1=O

Procedure:
The 6-maleimidocaproic acid is reacted with excess thionyl chloride at 50° C. for three hours, and then the excess thionyl chloride is distilled off to leave 6-maleimidocaproic chloride.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][OH:21])=[CH:15][C:14]=2[F:22])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=O.[NH2:23][O:24][CH2:25][CH2:26][OH:27].C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-]>CO>[F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][OH:21])=[CH:15][C:14]=2[F:22])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([NH:23][O:24][CH2:25][CH2:26][OH:27])=[O:7]
Reactant: O=C(O)c1ccc(F)c(F)c1Nc1ccc(CCO)cc1F
Reactant: NOCCO
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CO
Product: O=C(NOCCO)c1ccc(F)c(F)c1Nc1ccc(CCO)cc1F

Procedure:
3,4-Difluoro-2-[2-fluoro-4-(2-hydroxyethyl)anilino]benzoic acid was dissolved in MeOH and prepared from reaction with 2(aminooxy)ethanol and DMT-MM by the general procedure of Example 6, Step B, affording a crude yellow oil after workup which was purified by filtration through a plug of silica gel (100% EtOAc as eluant). 3,4-Difluoro-2-[2-fluoro-4-(2-hydroxyethyl)anilino]-N-(2-hydroxyethoxy)benzamide was isolated as a viscous, transparent oil (57%). 1H NMR [400 MHz, (CD3)2SO] δ 11.85 (v br s, 1 H), 8.77 (br s, 1 H), 7.44-7.37 (m, 1 H), 7.15-7.05 (m, 1 H), 7.06 (dd, J=12.5, 1.7 Hz, 1 H), 6.90 (dd, J=8.2, 1.7 Hz, 1 H), 6.81 (ddd, J=8.8, 8.8, 4.5 Hz, 1 H), 4.75 (br s, 1 H), 4.63 (t, J=5.2 Hz, 1 H), 3.86 (t, J=5.0 Hz, 2 H), 3.61-3.52 (m, 4 H), 2.66 (t, J=6.9 Hz, 2 H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13]C)=[O:12])=[CH:8][CH:9]=2)[C:4]([C:15]2[N:27](S(C3C=CC(C)=CC=3)(=O)=O)[C:18]3=[N:19][CH:20]=[C:21]4[CH:25]=[N:24][N:23]([CH3:26])[C:22]4=[C:17]3[CH:16]=2)=[CH:3]1.[OH-].[Na+].[Li+].[OH-]>O1CCOCC1.O>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=[O:12])=[CH:8][CH:9]=2)[C:4]([C:15]2[NH:27][C:18]3=[N:19][CH:20]=[C:21]4[CH:25]=[N:24][N:23]([CH3:26])[C:22]4=[C:17]3[CH:16]=2)=[CH:3]1
Reactant: COC(=O)c1ccc2c(c1)c(-c1cc3c4c(cnc3n1S(=O)(=O)c1ccc(C)cc1)cnn4C)cn2C
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cn1cc(-c2cc3c(ncc4cnn(C)c43)[nH]2)c2cc(C(=O)O)ccc21
Temperature: 85 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
To a flask was added methyl 1-methyl-3-(1-methyl-6-tosyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridin-7-yl)-1H-indole-5-carboxylate (0.42 g, 0.82 mmol, prepared using D from Preparation #1 with methyl 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-5-carboxylate [Preparation #19]) and NaOH (0.30 g, 7.5 mmol) in 1,4-dioxane (10 mL) and water (2 mL). The mixture was heated to about 85° C. After about 1 h, LiOH (0.196 g, 8.18 mmol) was added and heating was continued at about 100° C. for about 5 h. The mixture was cooled and concentrated under reduced pressure to remove most of the organics. The mixture was diluted with water (30 mL) then adjusted to about pH 4 with AcOH. The mixture was filtered and the solids washed with water (5 mL). The solids were dried to a constant weight under vacuum at about 60° C. to give 1-methyl-3-(1-methyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridin-7-yl)-1H-indole-5-carboxylic acid the title compound (0.17 g, 60%): LC/MS (Table 2, Method a) Rt=1.73 min; MS m/z 346 (M+H)+. Syk IC50=A.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][N:13]([C:20]2[O:24][C:23]3[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=3[CH:21]=2)[C:14](=[O:19])[CH:15]=[CH:16][CH2:17]Br)=[CH:6][CH:5]=1.O.[OH-].[OH:32][CH2:33][CH2:34][N:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CC(=O)OCC>[CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][N:13]([C:20]2[O:24][C:23]3[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=3[CH:21]=2)[C:14](=[O:19])[CH:15]=[CH:16][CH2:17][O:32][CH2:33][CH2:34][N:35]2[CH2:39][CH2:38][CH2:37][CH2:36]2)=[CH:6][CH:5]=1
Reactant: OCCN1CCCC1
Reactant: COC(=O)c1ccc(OCCN(C(=O)C=CCBr)c2cc3ccccc3o2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(OCCN(C(=O)C=CCOCCN2CCCC2)c2cc3ccccc3o2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 0.3 %

Procedure:
To a solution of 4-[2-(3-benzofuran-2-yl-4-bromobut-2-enoylamino)ethoxy]benzoic acid methyl ester (300 mg, 0.654 mmol) in dry DMF (4 ml), cessium hydroxide monohydrate (121 mg, 0.72 mmol), tetrabutylammonium iodide (49 mg, 0.13 mmol) and 1-(2-hydroxy-ethyl)pyrrolidine (85 ul, 0.72 mmol) were added. The reaction mixture was stirred overnight at rt and then diluted with EA (20 ml) and washed with water and brine. After drying over sodium sulfate, the solvent was evaporated under vacuum and the crude was purified on preparative TLC, DCM/MeOH (9/1) to give 4-{2-[3-benzofuran-2-yl-4-(2-pyrrolidin-1-yl-ethoxy)but-2-enoylamino]ethoxy}benzoic acid methyl ester (0.94 mg) as an oil.
Reaction SMILES: COC1C=CC=CC=1C1NC(=O)C2C(=CC=CC=2)N=1.[NH2:20][C:21]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[CH:26][C:22]=1[C:23]([NH2:25])=[O:24].[CH3:36][O:37][C:38]1[CH:39]=[C:40]([CH:43]=[CH:44][CH:45]=1)[CH:41]=O>>[CH3:36][O:37][C:38]1[CH:39]=[C:40]([C:41]2[NH:25][C:23](=[O:24])[C:22]3[C:21](=[CH:29][CH:28]=[C:27]([N:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)[CH:26]=3)[N:20]=2)[CH:43]=[CH:44][CH:45]=1
Reactant: NC(=O)c1cc(N2CCCCC2)ccc1N
Reactant: COc1cccc(C=O)c1
Agent: COc1ccccc1-c1nc2ccccc2c(=O)[nH]1
Product: COc1cccc(-c2nc3ccc(N4CCCCC4)cc3c(=O)[nH]2)c1
Yield: 51.9 %

Procedure:
According to the preparation of 42, 27 (1.0 g, 4.6 mmol) and 3-methoxybenzaldehyde (34) (0.6 g, 4.6 mmol) were used to afford 57 (0.8 g, 55.0%) as pale yellow prism crystals.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:7]([CH3:8])=[N:6][N:5]([CH2:9][C@@H:10]2[C@H:13]([NH:14][C:15](=[O:31])/[C:16](=[N:23]\[O:24][C:25]3([C:28]([OH:30])=[O:29])[CH2:27][CH2:26]3)/[C:17]3[N:18]=[C:19]([NH2:22])[S:20][CH:21]=3)[C:12](=[O:32])[N:11]2[S:33]([OH:36])(=[O:35])=[O:34])[N:4]=1.[C:37]([O:41][C:42]([NH:44][CH2:45][CH2:46][CH2:47][N:48]([C:56](=[N:62][C:63]([O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:64])N1C=CC=N1)[C:49](=[O:55])[O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:43])([CH3:40])([CH3:39])[CH3:38].CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:22][C:19]1[S:20][CH:21]=[C:17](/[C:16](=[N:23]/[O:24][C:25]2([C:28]([OH:30])=[O:29])[CH2:27][CH2:26]2)/[C:15]([NH:14][C@@H:13]2[C:12](=[O:32])[N:11]([S:33]([OH:36])(=[O:34])=[O:35])[C@@H:10]2[CH2:9][N:5]2[N:4]=[C:3]([CH2:2][NH:1]/[C:56](=[N:62]/[C:63]([O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:64])/[N:48]([C:49]([O:50][C:51]([CH3:52])([CH3:53])[CH3:54])=[O:55])[CH2:47][CH2:46][CH2:45][NH:44][C:42](=[O:43])[O:41][C:37]([CH3:40])([CH3:39])[CH3:38])[C:7]([CH3:8])=[N:6]2)=[O:31])[N:18]=1
Reactant: CC(C)(C)OC(=O)N=C(N(CCCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)n1cccn1
Reactant: Cc1nn(C[C@@H]2[C@H](NC(=O)/C(=N\OC3(C(=O)O)CC3)c3csc(N)n3)C(=O)N2S(=O)(=O)O)nc1CN
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nn(C[C@@H]2[C@H](NC(=O)/C(=N\OC3(C(=O)O)CC3)c3csc(N)n3)C(=O)N2S(=O)(=O)O)nc1CN/C(=N/C(=O)OC(C)(C)C)N(CCCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a soln of 1-(((Z)-(2-(((2R,3S)-2-((4-(aminomethyl)-5-methyl-2H-1,2,3-triazol-2-yl)methyl)-4-oxo-1-sulfoazetidin-3-yl)amino)-1-(2-aminothiazol-4-yl)-2-oxoethylidene)amino)oxy)cyclopropanecarboxylic acid (33.9 mg, 0.062 mmol) and tert-butyl (3-((tert-butoxycarbonyl)amino)propyl)(((tert-butoxycarbonyl)imino)(1H-pyrazol-1-yl)methyl)carbamate (54.2 mg, 0.116 mmol) in DMF (624 μl) at 0° C. was added DIPEA (32.7 μl, 0.187 mmol). After stirring at rt for 16 h, the solution was concentrated in vacuo and used as such without further purification. LCMS: Rt=0.75 min, m/z=943.7 (M+1) Method 2m_acidic.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][C:14]([CH3:16])=C)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C[O:20]CC1>O.CCOC(C)=O.O=[Os](=O)(=O)=O>[CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][C:14](=[O:20])[CH3:16])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C(C)CC1CCN(Cc2ccccc2)C1
Reactant: C1CCOC1
Agent: O=[Os](=O)(=O)=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)CC1CCN(Cc2ccccc2)C1
Reaction time: 16 h

Procedure:
To a rapidly stirred solution of 1-4 (7.0 g, 33 mmol) in THF (200 mL) and H2O (150 mL) was added NaIO4 (21 g, 100 mmol) followed by addition of OsO4 (10 mL; 2.5% solution). After 16 hrs, an additional amount of OsO4 (10 mL) was added, and the reaction was stirred for 6 hrs. The reaction was diluted with EtOAc, washed with sat. NaHCO3 and brine, dried (MgSO4), and concentrated to give 1-5 as a brown oil.
Reaction SMILES: [OH:1][C@@:2]1([C:33]([F:36])([F:35])[F:34])[C:14]2[CH:13]=[C:12]([O:15][CH2:16][CH2:17][C:18]([OH:21])([CH3:20])[CH3:19])[CH:11]=[C:10]([C:22]3[CH:23]=[N:24][N:25]([C:27]([CH3:32])([CH3:31])[C:28]([OH:30])=O)[CH:26]=3)[C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.O[N:38]1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.N.Cl>CN(C)C=O.O>[OH:1][C@@:2]1([C:33]([F:35])([F:34])[F:36])[C:14]2[CH:13]=[C:12]([O:15][CH2:16][CH2:17][C:18]([OH:21])([CH3:20])[CH3:19])[CH:11]=[C:10]([C:22]3[CH:23]=[N:24][N:25]([C:27]([CH3:32])([CH3:31])[C:28]([NH2:38])=[O:30])[CH:26]=3)[C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2
Reactant: CC(C)(O)CCOc1cc(-c2cnn(C(C)(C)C(=O)O)c2)c2c(c1)[C@@](O)(C(F)(F)F)c1ccccc1-2
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(O)CCOc1cc(-c2cnn(C(C)(C)C(N)=O)c2)c2c(c1)[C@@](O)(C(F)(F)F)c1ccccc1-2
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.1 %

Procedure:
Under a nitrogen atmosphere, 2-{4-[(9R)-9-hydroxy-2-(3-hydroxy-3-methylbutyloxy)-9-(trifluoromethyl)-9H-fluoren-4-yl]-1H-pyrazol-1-yl}-2-methylpropionic acid (66.7 g) was dissolved in N,N-dimethylformamide (480 ml), 1-hydroxybenzotriazole (HOBt) 1 hydrate (27.6 g), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (WSC) hydrochloride (34.6 g) and 28% aqueous ammonia (24.5 ml) were added, and the mixture was stirred at room temperature overnight. The reaction mixture was ice-cooled, water (630 ml) and 2N hydrochloric acid (330 ml) were added dropwise, and the mixture was extracted with ethyl acetate (800 ml). The obtained aqueous layer was extracted again with ethyl acetate (500 ml). The obtained organic layers were combined, and washed successively with water (500 ml, twice), saturated aqueous sodium hydrogen carbonate (500 ml), and saturated brine (500 ml). The obtained organic layer was dried over anhydrous sodium sulfate, the insoluble material was filtered off, and the solvent in the filtrate was evaporated to give the title compound (60.0 g).
Reaction SMILES: [C:1](Br)#[N:2].[C:4]([O:8][C:9]([N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:10])([CH3:7])([CH3:6])[CH3:5].CCN(C(C)C)C(C)C.O>ClCCl>[C:4]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:1]#[N:2])[CH2:13][CH2:12]1)=[O:10])([CH3:7])([CH3:5])[CH3:6]
Reactant: N#CBr
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(C#N)CC1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 99.9 %

Procedure:
3.76 g bromcyane was added to 6 g piperazine-1-carboxylic acid tert-butyl ester and 6.3 mL DIPEA in 30 mL dichlormethane at 0° C. The reaction was stirred 1.5 h at 0° C. Water and dichlormethane was added and the layers were separated. The organic layer was washed with brine and water and evaporated to give 6.8 g of the desired product.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[C:4]1=[O:17].[S:18]1[C:22]([S:23](Cl)(=[O:25])=[O:24])=[CH:21][C:20]2[CH:27]=[CH:28][CH:29]=[CH:30][C:19]1=2.C(N(CC)CC)C>C(Cl)Cl.CCOC(C)=O>[C:12]([C:11]1[CH:10]=[C:9]([CH:16]=[CH:15][CH:14]=1)[CH2:8][N:5]1[CH2:6][CH2:7][C@H:3]([NH:2][S:23]([C:22]2[S:18][C:19]3[CH:30]=[CH:29][CH:28]=[CH:27][C:20]=3[CH:21]=2)(=[O:24])=[O:25])[C:4]1=[O:17])#[N:13]
Reactant: O=S(=O)(Cl)c1cc2ccccc2s1
Reactant: N#Cc1cccc(CN2CC[C@H](N)C2=O)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: N#Cc1cccc(CN2CC[C@H](NS(=O)(=O)c3cc4ccccc4s3)C2=O)c1
Reaction time: 16 h
Yield: 79 %

Procedure:
To a solution of 3-(3-(S)-amino-2-oxo-pyrrolidin-1-ylmethyl)-benzonitrile hydrochloride (0.36 g, 1.43 mmol) in 15 mL of CH2Cl2 is added benzo[b]thiophene-2-sulfonyl chloride (0.32 g, 1.38 mmol). To the resulting solution is added triethylamine (0.29 g, 2.88 mmol). After 16 h, the solution is diluted with EtOAc. The solution is washed with 1N HCl, saturated NaHCO3, and saturated NaCl. The organic layer is dried over MgSO4, filtered and concentrated. The title compound (0.45 g, 1.09 mmol) is obtained as white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)[C:5]([F:17])=[CH:4][N:3]=1.Cl.[Cl:19][C:20]1[C:28]2[N:27]=[CH:26][N:25](C3CCCCO3)[C:24]=2[CH:23]=[CH:22][C:21]=1[CH2:35][NH:36][CH3:37].CCN(C(C)C)C(C)C>CCCCO>[Cl:19][C:20]1[C:28]2[N:27]=[CH:26][NH:25][C:24]=2[CH:23]=[CH:22][C:21]=1[CH2:35][N:36]([CH3:37])[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)[C:5]([F:17])=[CH:4][N:3]=1
Reactant: CNCc1ccc2c(ncn2C2CCCCO2)c1Cl
Reactant: Fc1cnc(Cl)nc1Nc1cc(C2CC2)[nH]n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CN(Cc1ccc2[nH]cnc2c1Cl)c1ncc(F)c(Nc2cc(C3CC3)[nH]n2)n1
Temperature: 120 °C

Procedure:
A vial was charged with 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-5-fluoropyrimidin-4-amine (55, 95 mg, 0.37 mmol, CASRN 854434-98-5), the bis-HCl salt of 220 (185 mg, 0.52 mmol), DIPEA (0.33 mL) and n-BuOH (0.8 mL), sealed and heated at 120° C. for 96 h. The reaction mixture was concentrated in vacuo. The crude mixture was purified by preparative HPLC to afford 93.2 mg (60%) of I-86: MS (ESI) m/z=413.1 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9]O)=[CH:4][CH:3]=1.[ClH:11]>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].ClC1C=CC=CC=1>[Cl:11][CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: Cl
Reactant: OCCc1ccc(F)cc1
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Solvent: Clc1ccccc1
Product: Fc1ccc(CCCl)cc1

Procedure:
A mixture of 7 g 2-(4-fluoro-phenyl)-ethanol, 25 mL of chlorobenzene, 42 mL of 37% HCl, and 0.9 g of Aliquat® 336 (tricaprylylmethyl ammonium chloride) was heated to reflux for 3 days, cooled and extracted into 3×100 mL of hexane. The combined extracts were dried over magnesium sulfate and concentrated under reduced pressure. The resulting oil was mainly 1-(2-chloro-ethyl)-4-fluoro-benzene:
Reaction SMILES: Cl.[C:2]([C:6]1[CH:11]=[C:10]([S:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:9]=[C:8]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:7]=1[OH:23])([CH3:5])([CH3:4])[CH3:3].C(N(CC)CC)C.[CH2:31]([O:33][C:34]([C:36]1[NH:37][C:38]([CH3:46])=[C:39]([S:42](Cl)(=[O:44])=[O:43])[C:40]=1[CH3:41])=[O:35])[CH3:32]>ClCCl>[CH2:31]([O:33][C:34]([C:36]1[NH:37][C:38]([CH3:46])=[C:39]([S:42]([N:16]2[CH2:17][CH2:18][CH:13]([S:12][C:10]3[CH:9]=[C:8]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:7]([OH:23])=[C:6]([C:2]([CH3:5])([CH3:4])[CH3:3])[CH:11]=3)[CH2:14][CH2:15]2)(=[O:43])=[O:44])[C:40]=1[CH3:41])=[O:35])[CH3:32]
Reactant: CCOC(=O)c1[nH]c(C)c(S(=O)(=O)Cl)c1C
Reactant: CC(C)(C)c1cc(SC2CCNCC2)cc(C(C)(C)C)c1O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1[nH]c(C)c(S(=O)(=O)N2CCC(Sc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)CC2)c1C
Reaction time: 0.05 h
Yield: 80.4 %

Procedure:
To 2,6-di-tert-butyl-4-(piperidin-4-ylsulfanyl)-phenol hydrochloride (Ex. 3c, 500 mg, 1.4 mmol) in 5 mL of dichloromethane was added triethylamine (495 mg, 4.9 mmol). The mixture was stirred for 3 min followed by the addition of 4-chlorosulfonyl-3,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester (446 mg, 1.68 mmol). The stirring was continued for 3 h at room temperature. The reaction mixture was diluted with Ethyl acetate/hexanes (15 mL, 1:1 v/v), and washed with water (2×20 mL), 0.5 M HCl (2×20 mL) and water (40 mL). It was dried over Na2SO4 and concentrated under reduced pressure to give a brown oil. Chromatography (5-40% Ethyl acetate/hexanes) gave 4-[4-(3,5-di-tert-butyl-4-hydroxy-phenylsulfanyl)-piperidine-1-sulfonyl]-3,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester as a light-pink foamy solid (620 mg, 80%). ESI/CI-MS m/z 551 ([M+H]+), 549 ([M−H]−).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[OH:11][CH:12]1[CH2:16][CH2:15][NH:14][CH2:13]1.C(N(CC)CC)C>C1COCC1>[N+:8]([C:5]1[CH:4]=[N:3][C:2]([N:14]2[CH2:15][CH2:16][CH:12]([OH:11])[CH2:13]2)=[N:7][CH:6]=1)([O-:10])=[O:9]
Reactant: OC1CCNC1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cnc(N2CCC(O)C2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.8 %

Procedure:
To a solution of 2-chloro-5-nitro-pyrimidine (638 mg, 4 mmol) in THF (15 mL) cooled to 0° C. was added 3-hydroxypyrrolidine (392 mg, 4.5 mmol) and triethylamine (1.2 mL). The mixture was stirred at room temperature overnight. Solids were filtered out and the solution was concentrated. The residue was dissolved in ethyl acetate and extracted with water. Organic layer was washed with dilute aqueous citric acid solution. After the evaporation of solvents, the residue was treated with ether and the yellow solid was filtered to give N-(5-nitro-pyrimidin-2-yl)-pyrrolidin-3-ol (570 mg). LCMS calcd for C8H10N4O3 m/e 210.19, obsd 211.0 (ES, M+H). Hydrogenation of the nitro compound, as above, provided N-(5-aminopyrimidin-2-yl)-pyrrolidin-3-ol.
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:46])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20][O:21][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][C:24]=4Br)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:34])[C:12]=2[C@H:35]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(#N)C>[C:42]([O:41][C@@H:35]([C:12]1[C:13]([CH3:34])=[N:14][C:15]2=[CH:19][C:18]3=[N:17][N:16]2[C:11]=1[N:8]1[CH2:7][CH2:6][C:5]([CH3:46])([O:4][CH2:1][CH:2]=[CH:3][C:24]2[CH:25]=[C:26]([C:29]([F:32])([F:31])[F:30])[CH:27]=[CH:28][C:23]=2[CH2:22][O:21][CH2:20]3)[CH2:10][CH2:9]1)[C:36]([O:38][CH2:39][CH3:40])=[O:37])([CH3:45])([CH3:43])[CH3:44]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(COCc4ccc(C(F)(F)F)cc4Br)nn23)CC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc3nn2c1N1CCC(C)(CC1)OCC=Cc1cc(C(F)(F)F)ccc1COC3
Temperature: 120 °C
Reaction time: 23 h
Yield: 63 %

Procedure:
To a pressure tube flushed with N2 were added (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(((2-bromo-4-(trifluoromethyl)benzyl)oxy)methyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.200 g, 0.281 mmol), acetonitrile (8 ml) and triethylamine (0.392 ml, 2.81 mmol). Added to this solution were triphenylphosphine (0.022 g, 0.084 mmol) and tris(dibenzylideneacetone)dipalladium (0) (0.026 g, 0.028 mmol). The tube was sealed and stirred at 120° C. for 23 h. The mixture was cooled, filtered and concentrated to give a yellow residue that was purified by flash chromatography (Biotage; 0%-100% EtOAc/hexane; 20 CV) to give the title compound (0.1115 g, 0.177 mmol, 62.9% yield) as a yellow foam. LCMS (M+H) calcd for C34H44F3N4O4: 631.31. found: 631.3.