Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[CH2:11][C:9](=O)[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2]1.[O:12]1CCBN1.CSC.B>C1COCC1>[CH2:1]1[CH:11]([OH:12])[CH2:9][C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2]1
Reactant: O=C1CCCc2ccccc21
Reactant: B1CCON1
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: OC1CCc2ccccc2C1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Preparation of the Compound of Formula (II) wherein R1 is CH3 ##STR12## Cis, exo-3-amino-2-hydroxybornane (1.0 g, 5.9 mmol), toluene (18 mL), and trimethylboroxine (0.56 mL) were combined at ambient temperature and stirred for 16 hr. Water, toluene and excess boroxine were distilled off until about 8 mL volume remained. The reaction was chased with toluene (3×11 mL), and the remainder of toluene removed under vacuum to afford the oxazaborolidine as a pale yellow oil (1.10 g, 98%). To a solution of α-tetralone (2.92 g, 19.7 mmol), THF (80 mL), and the oxazaborolidine derived from cis, exo-3-amino-2-hydroxybornane (228 mg, 1.2 mmol) under a nitrogen atmosphere was added borane methylsulfide complex (2M in THF, 7.0 mL, 14 mmol) over 75 min. After the addition was complete, the contents stirred for an additional 15 min, cooled to 0° C., and quenched with methanol (27 mL). After stirring the quenched reaction for 18 hrs the solvents were removed under vacuum, the residual oil was dissolved in methylene chloride (50 mL), washed with pH 4 phosphate buffer (50 mL), water (50 mL), treated with magnesium sulfate, and the solvent was removed under vacuum to give the (R) tetralol as a colorless oil 3.16 g (90% ee).
Reaction SMILES: [NH:1]1[C:11](=[O:12])[C:10]2[NH:9][C:7](=[O:8])[NH:6][C:5]=2[NH:4][C:2]1=[O:3].[OH-].[Na+:14]>>[C:10]12[NH:9][C:7](=[O:8])[N-:6][C:5]=1[NH:4][C:2]([NH:1][C:11]2=[O:12])=[O:3].[Na+:14]
Reactant: O=c1[nH]c(=O)c2[nH]c(=O)[nH]c2[nH]1
Agent: [Na+]
Agent: [OH-]
Product: O=c1[n-]c2[nH]c(=O)[nH]c(=O)c2[nH]1
Temperature: 70 °C
Reaction time: 24 h

Procedure:
Monosodium urate (MSU) crystals were prepared by dissolving 1.68 g of uric acid in 500 mL of 0.01 M NaOH and heating to 70° C.55,56 NaOH was added as required to maintain the pH between 7.1 and 7.2 and the solution was filtered and incubated at room temperature with slow stirring for 24 hours.
Reaction SMILES: [C:1]1([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][CH2:20][OH:21])[CH2:13][CH2:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl[C:23]1[N:32]=[C:31]2[C:26]([CH:27]=[CH:28][C:29](=[O:34])[N:30]2[CH3:33])=[CH:25][CH:24]=1>C1COCC1>[CH3:33][N:30]1[C:31]2[C:26](=[CH:25][CH:24]=[C:23]([O:21][CH2:20][CH2:19][CH2:18][CH2:17][N:14]3[CH2:13][CH2:12][N:11]([C:1]4[C:10]5[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=5)[CH:4]=[CH:3][CH:2]=4)[CH2:16][CH2:15]3)[N:32]=2)[CH:27]=[CH:28][C:29]1=[O:34]
Reactant: OCCCCN1CCN(c2cccc3ccccc23)CC1
Reactant: Cn1c(=O)ccc2ccc(Cl)nc21
Solvent: C1CCOC1
Product: Cn1c(=O)ccc2ccc(OCCCCN3CCN(c4cccc5ccccc45)CC3)nc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 77.7 %

Procedure:
To a solution of 4-(4-naphthalen-1-yl-piperazin-1-yl)-butan-1-ol (422 mg, 1.48 mmol) in THF (5 mL) cooled to 0° C. was added 7-chloro-1-methyl-1H-[1,8]naphthyridin-2-one (303 mg, 1.56 mmol) as a solution in THF (9 mL) via cannula. The reaction was stirred for about 2 h at 0° C. The reaction was quenched with saturated NH4Cl and the mixture was extracted with EtOAc. The organic layer was washed with saturated NaHCO3 and brine, dried over Na2SO4 and concentrated. Purification by LC (4% MeOH/CH2Cl2) gave the title compound as a white foam (507 mg, 1.15 mmol, 77%). A portion of the title compound (243 mg, 0.549 mmol) was dissolved in Et2O and 1 N HCl in Et2O (0.55 mL) was added. The resulting white precipitate was collected by filtration, washed with Et2O and dried to give a white solid (248 mg). MS: APCI: M+1: 443.3 (Exact Mass: 442.24).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:53]([F:56])([F:55])[F:54])=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][CH2:11][CH:12]3[CH2:15][CH:14]([N:16]([CH2:20][C@@H:21]4[C@H:25]5[O:26]C(C)(C)[O:28][C@H:24]5[C@H:23]([N:31]5[C:35]6[N:36]=[CH:37][N:38]=[C:39]([NH:40]CC7C=CC(OC)=CC=7OC)[C:34]=6[CH:33]=[CH:32]5)[CH2:22]4)[CH:17]([CH3:19])[CH3:18])[CH2:13]3)[NH:7][C:6]=2[CH:52]=1>FC(F)(F)C(O)=O.O>[NH2:40][C:39]1[C:34]2[CH:33]=[CH:32][N:31]([C@@H:23]3[CH2:22][C@H:21]([CH2:20][N:16]([CH:14]4[CH2:13][CH:12]([CH2:11][CH2:10][C:8]5[NH:7][C:6]6[CH:52]=[C:2]([Cl:1])[C:3]([C:53]([F:55])([F:54])[F:56])=[CH:4][C:5]=6[N:9]=5)[CH2:15]4)[CH:17]([CH3:19])[CH3:18])[C@@H:25]([OH:26])[C@H:24]3[OH:28])[C:35]=2[N:36]=[CH:37][N:38]=1
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN(C(C)C)C3CC(CCc4nc5cc(C(F)(F)F)c(Cl)cc5[nH]4)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)N(C[C@H]1C[C@@H](n2ccc3c(N)ncnc32)[C@H](O)[C@@H]1O)C1CC(CCc2nc3cc(C(F)(F)F)c(Cl)cc3[nH]2)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
7-((3aS,4R,6R,6aR)-6-(((3-(2-(6-chloro-5-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(isopropyl)amino)methyl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-N-(2,4-dimethoxybenzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (525 mg, 0.683 mmol) was dissolved in a mixture of Trifluoroacetic Acid (9 ml) and Water (1 ml) which had been pre-cooled at 0° C. in an ice bath. The solution was stirred at 0° C. for 30 minutes, then warmed to RT. After 4 h at RT, the mixture was concentrated. The residue was taken up in 20 ml MeOH and concentrated. This procedure was repeated twice and the residue placed on high vacuum. The material was taken up in 15 ml MeOH (gave a slurry) and was treated with 500 mg K2 CO3 and 15 drops of water. The mixture was allowed to stir for 1 hr, during which time the solution was found to be basic. The mixture was filtered through a fine frit, the solids were washed with 10 ml MeOH and the filtrate was concentrated to yield an off white solid. The material was left on high vacuum overnight. The crude material was purified by flash chromatography (SiO2, eluting with 12% 7N NH3 in CH3OH/CH2Cl2) to give a colorless glass/stiff foam. 1H NMR (400 MHz, MeOD) δH ppm 8.06 (s, 1 H), 7.89 (d, J=2.07 Hz, 1 H), 7.69 (d, J=2.28 Hz, 1 H), 7.21 (dd, J=3.42, 1.76 Hz, 1 H), 6.59 (d, J=3.52 Hz, 1 H), 4.33 (t, J=6.84 Hz, 1 H), 3.89 (q, J=5.25 Hz, 1 H), 3.03 (m, 0.5 H), 2.89 (m, 2 H), 2.70 (m, 0.5 H), 2.49 (m, 1 H), 2.40 (m, 2 H), 2.27 (br. s., 2 H), 2.16 (d, J=7.26 Hz, 4 H), 2.06 (m, 2 H), 1.91 (m, 2 H), 1.62 (m, 1 H), 1.52 (m, 1 H).
Reaction SMILES: FC(F)(F)C([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[C:21]3[C:20]([N:22]([CH3:24])[CH3:23])=[N:19][CH:18]=[N:17][C:16]=3[N:15](CO)[CH:14]=2)[CH:8]=1)=O.C(=O)([O-])[O-].[K+].[K+]>CO.[Cl-].[Na+]>[CH3:23][N:22]([CH3:24])[C:20]1[C:21]2[C:13]([C:9]3[CH:8]=[C:7]([CH2:6][OH:5])[CH:12]=[CH:11][CH:10]=3)=[CH:14][NH:15][C:16]=2[N:17]=[CH:18][N:19]=1
Reactant: CN(C)c1ncnc2c1c(-c1cccc(COC(=O)C(F)(F)F)c1)cn2CO
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CO
Product: CN(C)c1ncnc2[nH]cc(-c3cccc(CO)c3)c12
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3-[4-(dimethylamino)-7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]benzyl trifluoroacetate (C27) (from the previous step, 400 mg, ≦0.996 mmol) and potassium carbonate (500 mg, 3.6 mmol) in methanol (10 mL) was stirred at 80° C. for 30 minutes. The reaction mixture was diluted with saturated aqueous sodium chloride solution (50 mL) and extracted with dichloromethane (3×60 mL); the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Purification via preparative HPLC (Column: Phenomenex Gemini C18, 8 μm; Mobile phase A: ammonia in water, pH 10; Mobile phase B: acetonitrile; Gradient: 21% to 33% B) afforded the product as a white solid. Yield: 77.7 mg, 0.290 mmol, 29% over two steps. LCMS m/z 268.9 [M+H+]. 1H NMR (400 MHz, CDCl3) δ 10.83 (br s, 1H), 8.39 (s, 1H), 7.50 (br s, 1H), 7.38-7.42 (m, 2H), 7.29-7.34 (m, 1H), 7.11 (s, 1H), 4.78 (s, 2H), 2.84 (s, 6H).
Reaction SMILES: [F:1][CH:2]([F:31])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([O:20][C@@H:21]3[CH2:25][CH2:24][C@@H:23]([NH2:26])[CH2:22]3)[CH:9]=2)[C:6]2[CH:27]=[CH:28][CH:29]=[CH:30][C:5]=2[N:4]=1.[C:32](O)(=[O:35])[CH2:33][OH:34].ON1C2C=CC=CC=2N=N1.N=C=N.[N-]=C=O.C(=O)([O-])[O-]>CN(C)C=O>[F:31][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:11]=[C:10]([O:20][C@@H:21]3[CH2:25][CH2:24][C@@H:23]([NH:26][C:33](=[O:34])[CH2:32][OH:35])[CH2:22]3)[CH:9]=2)[C:6]2[CH:27]=[CH:28][CH:29]=[CH:30][C:5]=2[N:4]=1
Reactant: O=C(O)CO
Reactant: N[C@@H]1CC[C@@H](Oc2cc(-n3c(C(F)F)nc4ccccc43)nc(N3CCOCC3)n2)C1
Agent: N=C=N
Agent: O=C([O-])[O-]
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(CO)N[C@@H]1CC[C@@H](Oc2cc(-n3c(C(F)F)nc4ccccc43)nc(N3CCOCC3)n2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
To a solution of rel-(1R,3R)-3-({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}oxy)cyclopentanamine (10.8 mg), glycolic acid (1.9 mg), and 1-hydroxybenzotriazole (3.4 mg) in N,N-dimethylformamide (1.0 mL) was added a PS-Carbodiimide (Biotage Inc.) (100 mg), followed by stirring at room temperature overnight. To the reaction solution were added a PS-Isocyanate (Biotage Inc.) (50 mg) and a MP-Carbonate (Biotage Inc.) (50 mg), followed by stirring for four hours, and the insoluble matter was removed by filtration. The filtrate was concentrated under reduced pressure to obtain rel-N-[(1R,3R)-3-({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}oxy)cyclopentyl]-2-hydroxyacetamide (7.2 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=1.[O:10]1[C:14]2([CH2:19][CH2:18][C:17](=[O:20])[CH2:16][CH2:15]2)[O:13][CH2:12][CH2:11]1>>[CH3:9][O:8][C:4]1[CH:3]=[C:2]([C:17]2([OH:20])[CH2:18][CH2:19][C:14]3([O:13][CH2:12][CH2:11][O:10]3)[CH2:15][CH2:16]2)[CH:7]=[CH:6][CH:5]=1
Reactant: COc1cccc(Br)c1
Reactant: O=C1CCC2(CC1)OCCO2
Product: COc1cccc(C2(O)CCC3(CC2)OCCO3)c1

Procedure:
The title compound was prepared as a white solid from 1-bromo-3-methoxy-benzene (Aldrich) and 1,4-dioxa-spiro[4.5]decan-8-one using the procedure described in Step A of Example 1.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]([N:8]([C:10]1[C:19]([F:20])=[C:18]([F:21])[CH:17]=[CH:16][C:11]=1[C:12]([O:14]C)=O)[CH3:9])=[O:7])[CH3:2].FC1C(NC)=C(C=CC=1F)C(OC)=O.C(=O)([O-])[O-].[K+].[K+].ClC(=O)CC(OCC)=O>C1COCC1.O>[F:21][C:18]1[C:19]([F:20])=[C:10]2[C:11]([C:12]([OH:14])=[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:22])[C:6](=[O:7])[N:8]2[CH3:9])=[CH:16][CH:17]=1
Reactant: CCOC(=O)CC(=O)N(C)c1c(C(=O)OC)ccc(F)c1F
Agent: CCOC(=O)CC(=O)Cl
Agent: CNc1c(C(=O)OC)ccc(F)c1F
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1c(O)c2ccc(F)c(F)c2n(C)c1=O
Temperature: 24 °C
Reaction time: 3 h

Procedure:
Methyl 2-(3-ethoxy-N-methyl-3-oxopropanamido)-3,4-difluorobenzoate. At 0° C., a suspension of methyl 3,4-difluoro-2-(methylamino)benzoate (1.10 g, 5.47 mmol) and potassium carbonate (0.98 g, 7.1 mmol) in THF (10 mL) was treated dropwise with ethyl 3-chloro-3-oxopropanoate (0.90 mL, 7.11 mmol). The mixture was warmed to 24° C., stirred for 3 hours, diluted with water, and extracted with EtOAc. The combined organic layers were dried over MgSO4, and evaporated. Purification by flash chromatography (EtOAc/hexanes) gave the title compound. MS (ESI) m/z: Calculated; 315.3: Observed; 316.1. 1H NMR (300 MHz, CDCl3) δ ppm 7.81-7.91 (1H, m), 7.28-7.37 (1H, m), 4.12 (2H, q, J=7.1 Hz), 3.92 (3H, s), 3.23 (3H, s), 3.10 (2H, s), 1.23 (3H, t, J=7.2 Hz).
Reaction SMILES: [F:1][C:2]([F:28])([O:6][C:7]1[CH:8]=[C:9]([NH:13][C:14]2[N:19]=[C:18]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]([C:26]#[N:27])[CH:21]=3)[CH:17]=[CH:16][N:15]=2)[CH:10]=[CH:11][CH:12]=1)[CH:3]([F:5])[F:4].[H-].C([Al+]CC(C)C)C(C)C.C1COCC1>CO>[F:28][C:2]([F:1])([O:6][C:7]1[CH:8]=[C:9]([NH:13][C:14]2[N:19]=[C:18]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]([CH2:26][NH2:27])[CH:21]=3)[CH:17]=[CH:16][N:15]=2)[CH:10]=[CH:11][CH:12]=1)[CH:3]([F:5])[F:4]
Reactant: N#Cc1cc(-c2ccnc(Nc3cccc(OC(F)(F)C(F)F)c3)n2)ccn1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Solvent: CO
Product: NCc1cc(-c2ccnc(Nc3cccc(OC(F)(F)C(F)F)c3)n2)ccn1
Temperature: 25 °C

Procedure:
100 mg (0.26 mmol) of N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-(2-cyano-4-pyridyl)-2-pyrimidineamine and 1.28 ml (1.0M in THF, 1.28 mmol) of diisobutylaluminium hydride/THF solution are stirred for 1 h at -20°. After the addition of 2 ml of methanol, the reaction mixture is heated to RT and the reaction product is isolated by filtration. After concentration under reduced pressure using a rotovapor and chromatography [methylene chloride:methanol:ammonia (conc.)=95:5:]N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-(2-aminomethyl-4-pyridyl)-2-pyrimidineamine is obtained; m.p. 64°-67°, FAB-MS: 394 (M+ +H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14](Cl)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[Br:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1>>[Br:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH:27][C:14]([C:12]2[S:13][C:9]([S:8][C:7]3[C:2]([Cl:1])=[CH:3][N:4]=[CH:5][C:6]=3[Cl:20])=[C:10]([N+:17]([O-:19])=[O:18])[CH:11]=2)=[O:15])=[CH:24][CH:23]=1
Reactant: NCc1ccc(Br)cc1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: O=C(NCc1ccc(Br)cc1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carbonyl chloride (150 mg, 0.41 mmol) and 4-bromo-benzylamine (91 mg, 0.49 mmol). The title compound was obtained as a yellow solid (19 mg, 35% yield). 1H NMR (400 MHz, d6-DMSO) δ: 9.41 (1H, m), 8.99 (2H, s), 8.46 (1H, s), 7.53 (2H, dd), 7.24 (2H, dd), 4.43 (2H, m). MS m/z: 515.93, 517.96, 519.92 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:35])=[C:14]([C:30](OCC)=[O:31])[C:15](=[O:29])[N:16]3[CH2:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][C:23]3=[O:28])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:36][CH2:37][C@@H:38]([OH:40])[CH3:39]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:35])=[C:14]([C:30]([NH:36][CH2:37][C@@H:38]([OH:40])[CH3:39])=[O:31])[C:15](=[O:29])[N:16]3[CH2:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][C:23]3=[O:28])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN2CCCCC2=O)c1=O
Reactant: C[C@H](O)CN
Product: C[C@H](O)CNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN2CCCCC2=O)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[3-(2-oxo-1-piperidinyl)propyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and (2S)-1-amino-2-propanol using methods similar to Example 563 to provide an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.11 (d, J=5.90 Hz, 3 H), 1.64-1.80 (m, 6 H), 2.19 (t, J=5.69 Hz, 2 H), 3.16-3.27 (m, 4 H), 3.34-3.49 (m, 2 H), 3.78-3.84 (m, 1 H), 4.16-4.25 (m, 4 H), 4.96 (d, J=4.84 Hz, 1 H), 7.11-7.19 (m, 2 H), 7.38-7.45 (m, 2 H), 8.00 (s, 1 H), 8.56 (s, 1 H), 10.43 (t, J=5.48 Hz, 1 H), 17.23 (s, 1 H); ES+ MS: 511 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[C:13]1[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:16]2=[N:17][CH:18]=[C:19]([CH2:21][NH2:22])[N:20]=[C:15]2[CH:14]=1.[O:32]1[CH2:36][CH2:35][CH2:34][C:33]1=[O:37].N1C=NC=N1.C1CCN2C(=NCCC2)CC1>C(Cl)Cl>[OH:37][CH2:33][CH2:34][CH2:35][C:36]([NH:22][CH2:21][C:19]1[N:20]=[C:15]2[CH:14]=[C:13]([C:6]3[C:5]4[C:9](=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=4)[N:8]([CH3:12])[CH:7]=3)[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:29])[CH3:31])[C:16]2=[N:17][CH:18]=1)=[O:32]
Reactant: COc1ccc2c(c1)c(-c1cc3nc(CN)cnc3n1COCC[Si](C)(C)C)cn2C
Reactant: O=C1CCCO1
Agent: c1nc[nH]n1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc2c(c1)c(-c1cc3nc(CNC(=O)CCCO)cnc3n1COCC[Si](C)(C)C)cn2C
Temperature: 60 °C
Reaction time: 8 h
Yield: 41.8 %

Procedure:
A flask was charged with (6-(5-methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanamine (0.300 g, 0.686 mmol, Preparation #I.1), dihydrofuran-2(3H)-one (0.063 mL, 0.823 mmol), 1,2,4-triazole (0.009 g, 0.13 mmol), DBU (0.021 mL, 0.13 mmol) and DCM (10 mL). The mixture was heated to about 60° C. and stirred overnight. The mixture was concentrated under reduced pressure and the residue was diluted with EtOAc (10 mL) and washed with water (10 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuo. The material was purified by silica gel chromatography with an elution gradient of 0 to 100% EtOAc/heptane to give 4-hydroxy-N-((6-(5-methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)methyl)butanamide (0.150 g, 42%): LC/MS (Table 2, Method b) Rt=2.40 min; MS m/z 524 (M+H)+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@H:5]([CH2:7][CH:8]([CH3:10])[CH3:9])[NH2:6].C(N(CC)C(C)C)(C)C.C([O:23][C:24](=O)[CH:25]=[C:26]([O:29][C:30]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=1[F:37])[CH2:27]Br)C>C(#N)C>[CH3:2][O:3][C:4](=[O:11])[C@@H:5]([N:6]1[CH2:27][C:26]([O:29][C:30]2[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=2[F:37])=[CH:25][C:24]1=[O:23])[CH2:7][CH:8]([CH3:10])[CH3:9]
Reactant: CCOC(=O)C=C(CBr)Oc1cc(F)ccc1F
Reactant: COC(=O)[C@@H](N)CC(C)C
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](CC(C)C)N1CC(Oc2cc(F)ccc2F)=CC1=O
Temperature: 60 °C
Reaction time: 1 h
Yield: 17.4 %

Procedure:
A mixture of (L)-leucine methyl ester hydrochloride (1.28 g, 7.08 mmol) in acetonitrile (17.7 mL) was treated with N,N-diisopropylethylamine (1.15 mL, 6.95 mmol). After addition was complete, the mixture was stirred at 60° C. for 1 h. At this time, the reaction was cooled to 25° C., treated with N,N-diisopropylethylamine (1.15 mL, 6.95 mmol) and acetonitrile (17.7 mL) and then heated to 80° C. Upon reaching 80° C., the reaction was treated with a solution of 4-bromo-3-(2,5-difluoro-phenoxy)-but-2-enoic acid ethyl ester (1.56 g, 6.44 mmol) in acetonitrile (16.1 mL). After the addition was complete, the reaction mixture was heated to 100° C. where it stirred overnight. At this time, the reaction mixture was cooled to 25° C. and was concentrated in vacuo. The residue was diluted with dichloromethane (75 mL) and was washed with a 2N aqueous hydrochloric acid solution (1×100 mL), a saturated aqueous sodium bicarbonate solution (1×100 mL), a saturated aqueous sodium chloride solution (1×100 mL), dried over sodium sulfate, filtered and concentrated in vacuo. Purification by Analogix flash chromatography (40 g, 15-50% ethyl acetate/hexanes) afforded (S)-2-[4-(2,5-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid methyl ester (0.38 g, 17%) as a yellow oil: HR-ES-MS m/z calculated for C17H19NO4F2 [M+H]+ 340.1355, observed 340.1355; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.87 (d, J=6.6 Hz, 3H), 0.92 (d, J=6.6 Hz, 3H), 1.35-1.53 (m, 1H), 1.53-1.69 (m, 1H), 1.72-1.89 (m, 1H), 3.66 (s, 3H), 4.13-4.33 (m, 2H), 4.73 (dd, J=11.5, 4.5 Hz, 1H), 5.07 (s, 1H), 7.13-7.35 (m, 1H), 7.42-7.64 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1([NH:6][C:7]([CH:9]2[CH2:14][CH2:13][N:12]([CH:15]3[CH2:18][C:17]4([CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19]4)[CH2:16]3)[CH2:11][CH2:10]2)=[O:8])[CH2:5][CH2:4][CH2:3]1.[C:30]([OH:36])([C:32]([F:35])([F:34])[F:33])=[O:31]>C(Cl)Cl>[F:33][C:32]([F:35])([F:34])[C:30]([OH:36])=[O:31].[CH2:18]1[C:17]2([CH2:22][CH2:21][NH:20][CH2:19]2)[CH2:16][CH:15]1[N:12]1[CH2:11][CH2:10][CH:9]([C:7]([NH:6][C:2]2([CH3:1])[CH2:5][CH2:4][CH2:3]2)=[O:8])[CH2:14][CH2:13]1
Reactant: CC1(NC(=O)C2CCN(C3CC4(CCN(C(=O)OC(C)(C)C)C4)C3)CC2)CCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(NC(=O)C2CCN(C3CC4(CCNC4)C3)CC2)CCC1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
LCMS (Method A): m/z 406 (M+H)+ (ES+), at 1.81 min, UV inactive tert-Butyl 2-{4-[(1-methylcyclobutyl)carbamoyl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate (0.627 g, 1.55 mmol) was dissolved in DCM (8 mL) and TFA (2 mL) was added. The reaction mixture was stirred at rt overnight under nitrogen, then the solvents were removed in vacuo, to give 1-(6-azaspiro[3.4]oct-2-yl)-N-(1-methylcyclobutyl)piperidine-4-carboxamide trifluoroacetate as a dark yellow oil which was used directly without further purification. The residue was dissolved in DCM (10 mL) and NEt3 (0.49 g, 0.65 mL, 4.64 mmol) and ethyl chloroformate (0.25 mg, 0.18 mL, 0.57 mmol) were added and the reaction mixture was stirred at rt overnight under nitrogen. The solvents were removed in vacuo, and the residue was partitioned between DCM and sat. NaHCO3 sol., organic layer washed with sat. NaCl sol. and dried over MgSO4. The residue was purified by column chromatography (normal phase, [Biotage SNAP cartridge KP-sil 10 g, 40-63 μm, 60 A, 12 mL per min, gradient 0% to 10% MeOH in DCM]) to give ethyl 2-{4-[(1-methylcyclobutyl)carbamoyl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate (0.04 g, 13%) as a yellow gum as a mixture of diastereomers.
Reaction SMILES: C([O:4][C:5]([CH3:7])=[CH2:6])(=O)C.N(OC(C)(C)C)=O.[Cl:15][C:16]1[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[C:17]=1N>CC(C)=O.C(OCC)(=O)C>[Cl:15][C:16]1[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[C:17]=1[CH2:4][C:5](=[O:6])[CH3:7]
Reactant: C=C(C)OC(C)=O
Reactant: Nc1c(Cl)cc(Cl)cc1Cl
Agent: CC(C)(C)ON=O
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CC(=O)Cc1c(Cl)cc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 103.2 %

Procedure:
In a 1.5 l sulfonation flask equipped with mechanical stirring, cooling funnel, dropping funnel and thermometer under nitrogen at ambient temperature filled with acetone (240 ml), were added isopropenyl acetate (66 ml, 0.60 mol), tert-butyl nitrite (40 ml, 0.30 mol) and cupric sulfate pentahydrate (2.5 g, 0.001 mol). The resulting light green-blue suspension is stirred for 15 min at ambient temperature. A solution of 2,4,6-trichloroaniline (40 g, 0.20 mol), dissolved in acetone (320 ml) was added dropwise over a period of 2 hours. During the addition, bubbling observed, temperature rose to 30° C. and the mixture turned green. 1 Hour after the addition, an amber solution was obtained. The mixture was stirred for 6 hours. Completion of the reaction was confirmed by GC-MS. The crude mixture was concentrated under reduce pressure to remove most of the acetone and the residue was dissolved in ethyl acetate (300 ml) and wash with 1M hydrochloric acid (2×300 ml), water (2×300 ml) potassium carbonate solution (300 ml) followed by water (300 ml). Combined basic aqueous were re-extracted with of ethyl acetate (150 ml). Combined organics were dried over sodium sulfate, and the organics were concentrated under reduced pressure to give crude 1-(2,4,6-trichloro-phenyl)-propan-2-one (53 g) as a dark brown oil. The crude was dissolved again in ethyl acetate (200 ml) and washed with 1M sodium hydroxide (300 ml) 1M hydrochloric acid (100 ml) and water (200 ml). The organic layers were dried and evaporated to give crude 1-(2,4,6-trichloro-phenyl)-propan-2-one 49 g dark brown oil which crystallized.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=2)=[CH:7][CH:6]=1)=[O:3].[NH:22]1[CH2:27][CH2:26][CH:25]([N:28]2[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[N:30]=[CH:29]2)[CH2:24][CH2:23]1.C(NC(C)C)(C)C>>[F:19][C:18]([F:21])([F:20])[C:15]1[CH:16]=[CH:17][C:12]([O:11][C:8]2[CH:9]=[CH:10][C:5]([O:4][C:2]([N:22]3[CH2:23][CH2:24][CH:25]([N:28]4[C:32]5[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=5[N:30]=[CH:29]4)[CH2:26][CH2:27]3)=[O:3])=[CH:6][CH:7]=2)=[N:13][CH:14]=1
Reactant: O=C(Cl)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reactant: c1ccc2c(c1)ncn2C1CCNCC1
Solvent: CC(C)NC(C)C
Product: O=C(Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)N1CCC(n2cnc3ccccc32)CC1

Procedure:
The crude product was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 1-piperidine-4-yl-1H-benzimidazole, 5 equivalent of diisopropylamine was added, preparative HPLC (method C) (23%, colourless crystals). HPLC-MS m/z=483.3 (M+1), Rt: 3.14 min.