Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH2:5]/[C:6](/[C:16]1[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=1)=[C:7](/[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)\[CH2:8][OH:9])(=[O:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=[O:28].CC(=CC)C.P(=O)(O)(O)O.[O-]Cl=O.[Na+]>ClCCl.C1COCC1.CC(O)(C)C.O>[C:1]([O:4][CH2:5]/[C:6](/[C:16]1[CH:17]=[CH:18][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:20][CH:21]=1)=[C:7](/[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)\[C:8]([OH:28])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Reactant: CC(=O)OC/C(=C(\CO)c1ccccc1)c1ccc(S(C)(=O)=O)cc1
Agent: CC=C(C)C
Agent: O=P(O)(O)O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(=O)OC/C(=C(\C(=O)O)c1ccccc1)c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
To a solution of 38.3 g of (2Z)-4-hydroxy-2-[4-(methylsulfonyl)phenyl]-3-phenylbut-2-enyl acetate in 500 mL of dichloromethane, 47 g of Dess-Martin reagent was added and the resulted mixture was stirred at rt for 2 hr. Then 2 mL of water was added and the resulted mixture was stirred at rt for 1 hr. Then the mixture was filtered and evaporated. The crude thus obtained was dissolved in a solvent mixture of 200 mL of THF with 200 mL of t-BuOH. To the resulting mixture, 30 mL of 2-methyl-2-butene was added and followed by the addition of 200 mL of 1.2 M of phosphoric acid and 200 mL of 1 M of NaClO2. The resulting mixture was stirred at rt for 30 min. The organic phase was separated and the aqueous phase was extracted with EtOAc. The organic phase was combined, dried over Na2SO4, filtered, and then evaporated. The crude was purified by recrystallization from ether to afford 37 g of the titled compound as white solid. 1H NMR (acetone-d6, 500 M Hz): δ 7.76 (d, 2H), 7.43 (d, 2H), 7.18–7.12 (m, 3H), 7.12–7.08 (m, 2H), 5.24 (s, 2H), 3.05 (s, 3H), 1.88 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:18])[NH:16][CH:17]=2)=[O:11])=[CH:4][CH:3]=1.IC.[C:28](=O)([O-])[O-].[K+].[K+]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:18])[N:16]([CH3:28])[CH:17]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccccc1[C@@H](CC(=O)c1ccc(=O)[nH]c1)c1ccc(Br)cc1
Agent: [K+]
Solvent: CI
Product: Cc1ccccc1[C@@H](CC(=O)c1ccc(=O)n(C)c1)c1ccc(Br)cc1

Procedure:
In analogy to example 161, step 1, 5-[(S)-3-(4-bromo-phenyl)-3-o-tolyl-propionyl]-1H-pyridin-2-one was reacted with iodomethane in the presence of potassium carbonate to give the title compound as a white solid, MS (ESI+): m/z=410.1 [M+H]+.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[CH:12]=[CH:11][N:10]2[N:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:15]=[C:9]2[CH:8]=1.[OH-].[NH4+].CN(C)[CH:27]=[O:28]>>[Cl:6][C:7]1[CH:12]=[CH:11][N:10]2[N:13]=[C:14]([C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)[C:15]([CH:27]=[O:28])=[C:9]2[CH:8]=1
Reactant: Fc1ccc(-c2cc3cc(Cl)ccn3n2)cc1
Reactant: CN(C)C=O
Agent: [NH4+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1c(-c2ccc(F)cc2)nn2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Phosphorous oxychloride (0.6 mL, 6.4 mmol) was added to N,N-dimethylformamide (10 mL) and the resulting mixture stirred at room temperature for 10 minutes. 5-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine (1.0 g, 4.1 mmol) was added and the reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into ice-water and neutralized to pH 7 with aquous ammonium hydroxide. The resulting slurry was extracted with dichloromethane (3×40 mL). The combined organics were washed with brine, dried (magnesium sulfate), filtered and concentrated to give, after recrystallization from acetonitrile, 5-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine-3-carbaldehyde (0.95 g, 85%) as a white solid. 1H-NMR (CDCl3): δ10.07 (s, 1H), 8.49 (d, 1H), 8.44 (d, 1H), 7.78 (q, 2H), 7.22 (t, 2H), 7.07 (dd, 1H); MS m/z 275 (M+1).
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[CH:10]=[C:11]([NH2:14])[CH:12]=[CH:13][C:8]=2[CH2:7][N:6]([CH2:15][CH3:16])[CH2:5][CH2:4]1)[CH3:2].Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:26]=2[C:27]([NH:29][CH3:30])=[O:28])[C:21]([Cl:36])=[CH:20][N:19]=1>>[Cl:36][C:21]1[C:22]([NH:24][C:25]2[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:26]=2[C:27]([NH:29][CH3:30])=[O:28])=[N:23][C:18]([NH:14][C:11]2[CH:12]=[CH:13][C:8]3[CH2:7][N:6]([CH2:15][CH3:16])[CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[C:9]=3[CH:10]=2)=[N:19][CH:20]=1
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: CCN1CCN(CC)c2cc(N)ccc2C1
Product: CCN1CCN(CC)c2cc(Nc3ncc(Cl)c(Nc4c(F)cccc4C(=O)NC)n3)ccc2C1

Procedure:
The title compound was prepared from 1,4-Diethyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-ylamine and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide in an analogous manner to 712. Product was isolated as a tan solid (0.026 g, 26%); Mp 111-117° C.; LCMS (m/e) 498 (M); 1H-NMR (DMSO, 400 MHz) δ 9.35 (s, 1H), 9.11 (s, 1H), 8.53 (d, 1H), 8.16 (s, 1H), 7.45-7.49 (t, 2H, J=7.07 Hz), 7.38-7.40 (q, 1H, J=6.57 Hz), 7.10-7.12 (d, 1H, J=8.33 Hz), 6.95 (s, 1H), 6.79-6.81 (d, 1H, J=8.08 Hz), 3.54 (s, 1H), 2.97-2.98 (q, 2H, J=6.83 Hz), 2.87 (s, 2H), 2.73-2.74 (s, 6H), 2.39 (m, 2H), 1.07-1.11 (t, 3H, J=6.82 Hz), 1.00-1.03 (t, 3H, J=6.82 Hz).
Reaction SMILES: [CH2:1]([NH:4][C:5]1[N:13]=[C:12]([NH2:14])[N:11]=[C:10]2[C:6]=1[N:7]=[CH:8][NH:9]2)[CH:2]=[CH2:3].[F:15][C@@H:16]1[C@@H:20]([CH2:21][OH:22])[O:19][C@@H:18](N2C=CC(=O)NC2=O)[CH2:17]1.[N-]=[N+]=[N-].[K+].[C@@H]1(N2C=C(C)C(=O)NC2=O)O[C@H](CO)[C@@H](O)C1>P([O-])([O-])([O-])=O.[K+].[K+].[K+].CO>[CH2:1]([NH:4][C:5]1[N:13]=[C:12]([NH2:14])[N:11]=[C:10]2[C:6]=1[N:7]=[CH:8][N:9]2[C@@H:18]1[O:19][C@H:20]([CH2:21][OH:22])[C@@H:16]([F:15])[CH2:17]1)[CH:2]=[CH2:3]
Reactant: O=c1ccn([C@H]2C[C@H](F)[C@@H](CO)O2)c(=O)[nH]1
Reactant: C=CCNc1nc(N)nc2[nH]cnc12
Agent: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C=CCNc1nc(N)nc2c1ncn2[C@H]1C[C@H](F)[C@@H](CO)O1
Temperature: 45 °C
Reaction time: 168 h
Yield: 46.3 %

Procedure:
6-(Allylamino)-2-amino-9H-purine (0.51 g, 2.6 mmoles) and 2',3'-dideoxy-3'-fluorouridine (0.50 g, 2.2 mmoles) were suspended in 50 ml 10 mM potassium phosphate buffer, pH 7.0, containing 0.40% potassium azide. Purine nucleoside phosphorylase (1120 I.U.) and thymidine phosphorylase (10,000 I.U.) (Krenitsky, et al., Biochemistry, 20, 3615, 1981 and U.S. Pat. No. 4,381,344) immobilized on DEAE cellulose was added and the suspension was stirred at 45° C. After 7 days, 100 ml MeOH was added to the reaction mixture. The resulting mixture was applied to a column containing AG1-X2 (OH-- form, 2.5×10 cm) and eluted with MeOH. Fractions containing were pooled, concentrated, and flash chromatographed on silica gel (2.5×20 cm) with dichloromethane:acetone:methanol (96:2:2). Solvent was removed and lyophilization yielded 0.314 g of 6-(allylamino)-2-amino-9-(2,3-dideoxy-3-fluoro-β-D-erythro-pentofuranosyl)-9H-purine (46%): mp 128°-129° C.; TLC Rf 0.70 (silica gel, MeCN:15N NH4OH:H2O/85:5:10); [α]D20 -15.2 (c=0.5, DMF); UV λmax (ε×10-3) at pH 7, 281 (14.7); at pH 13, 281 (14.0); 1H NMR (300 MHz, DMSO-d6) δ7.91 (s, 1H, H8), 7.44-7.48 (b, 1H, NH), 6.20 (dd, 1H, H1', J=9.3 Hz, J=5.6 Hz), 5.82-5.95 (M, 3H), 5.51 (t, 1H, OH5', J=5.8 Hz), 5.38 (dd, 1H, H3', J=53.7 Hz, J=4.3 Hz), 5.03-5.14 (m, 2H), 4.25 (dt, 1H, H4', J=27.4 Hz, J=4.5 Hz), 4.0-5.05 (b, 2H, NCH2), 3.57 (t, 2H, H5', and H5", J=5.0 Hz), and 2.75-3.00 and 2.45-2.62 (m, 2H, H2' and H2" ; MS (ci) 309 (M+1), 289 (M-F), 191 (MH2 --C5H8FO2).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[CH:15]=[C:16]([NH:19][C:20](=[O:26])[CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH:17]=[CH:18][C:13]=3[O:12][C:11]2([CH3:28])[CH3:27])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[H-].[Na+].[CH3:31]I.O>CN(C=O)C>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[C:14]3[CH:15]=[C:16]([N:19]([CH3:31])[C:20](=[O:26])[CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH:17]=[CH:18][C:13]=3[O:12][C:11]2([CH3:28])[CH3:27])=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(C2c3cc(NC(=O)CC(C)(C)C)ccc3OC2(C)C)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1ccc(C2c3cc(N(C)C(=O)CC(C)(C)C)ccc3OC2(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 0 %

Procedure:
To a solution of N-(3-(4-isopropylphenyl)-2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide (110 mg, 290 mmol) obtained in Example 320 in DMF (3 mL) was added sodium hydride (a 60% dispersion in liquid paraffin, 12.8 mg, 319 mmol) at 0° C. and the mixture was stirred at room temperature for 30 minutes. Methyl iodide (8.0 g, 319 mmol) was added to the reaction solution and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction solution and the product was extracted with diisopropyl ether. The combined extracts were washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain 47 mg (yield: 41%) of the title compound. Melting point: 78-79° C. (ethyl acetate-hexane).
Reaction SMILES: Br[CH2:2][C:3]([CH3:16])=[CH:4][CH2:5][O:6][C:7]1[CH:15]=[CH:14][C:10]2[O:11][CH2:12][O:13][C:9]=2[CH:8]=1.[CH2:17]([OH:21])[CH:18]([CH3:20])[CH3:19]>>[CH2:17]([O:21][CH2:2][C:3]([CH3:16])=[CH:4][CH2:5][O:6][C:7]1[CH:15]=[CH:14][C:10]2[O:11][CH2:12][O:13][C:9]=2[CH:8]=1)[CH:18]([CH3:20])[CH3:19]
Reactant: CC(C)CO
Reactant: CC(=CCOc1ccc2c(c1)OCO2)CBr
Product: CC(=CCOc1ccc2c(c1)OCO2)COCC(C)C

Procedure:
1.6 g (0.0165 mol) of sodium-isobutylate in 75 cc of isobutanol are added dropwise at 70° during the course of 15 minutes to 4.3 g (0.015 mol) of 5-(4-bromo-3-methyl-2-butenyloxy)-1,3-benzodioxol which is dissolved in 130 cc of isobutanol After 3 hours at this temperature the reaction mixture is filtered, the solvent is distilled off at reduced pressure and the residue is dissolved in ether. The ether solution is washed with saturated salt solution, is dried with sodium sulphate and evaporated. The residue is chromatographed on silica gel with chloroform. 5-(4-isobutoxy-3-methyl-2-butenyloxy)-1,3-benzodioxol is obtained as colourless oil. nD20 = 1.5158.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].I[CH2:8][CH3:9].[Cl:10][C:11]1[CH:32]=[CH:31][C:14]([CH2:15][NH:16][C:17]([C:19]2[C:20]([OH:30])=[C:21]3[CH:27]=[C:26]([CH2:28][OH:29])[S:25][C:22]3=[N:23][CH:24]=2)=[O:18])=[CH:13][CH:12]=1>CN(C=O)C.O>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:15][NH:16][C:17]([C:19]2[C:20](=[O:30])[C:21]3[CH:27]=[C:26]([CH2:28][OH:29])[S:25][C:22]=3[N:23]([CH2:8][CH3:9])[CH:24]=2)=[O:18])=[CH:31][CH:32]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2sc(CO)cc2c1O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CO)sc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Potassium carbonate (0.87 g) and iodoethane (0.5 mL) are added to a solution of N-(4-chlorobenzyl)-4-hydroxy-2-(hydroxymethyl)thieno[2,3-b]pyridine-5-carboxamide (2.0 g, prepared as described in U.S. Pat. No. 6,239,142) in anhydrous DMF (60 mL). The reaction mixture is stirred at room temperature for 18 h. The mixture is diluted with water (150 mL) and filtered. The resulting white powder is washed with water (15 mL) followed by diethyl ether (15 mL) and dried in a vacuum oven to afford 1.64 g of the title compound as a white solid. Physical characteristics. M.p. 169-172° C.; 1H NMR (300 MHz, DMSO-d6) δ 10.65, 8.74, 7.37, 7.29, 5.81, 4.70, 4.54, 4.32, 1.44. HRMS (FAB) m/z 377.0720 (M+H)+. Anal. Found. C, 56.87; H, 4.77; N, 7.38; Cl, 9.35; S, 8.44.
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][C:5]2[N:6](C(OCC(C)C)=O)[C:7]([NH:9][CH2:10][CH2:11][F:12])=[N:8][C:4]=2[CH:3]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30]2[C:31]([N:37]3[CH2:43][C:42]4[CH:44]=[C:45](B(O)O)[CH:46]=[CH:47][C:41]=4[O:40][CH2:39][CH2:38]3)=[N:32][CH:33]=[N:34][C:35]=2[CH3:36])=[CH:25][CH:24]=1.O1CCOCC1.CCN(C(C)C)C(C)C>C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[F:12][CH2:11][CH2:10][NH:9][C:7]1[NH:6][C:5]2[CH:20]=[CH:21][C:2]([C:45]3[CH:46]=[CH:47][C:41]4[O:40][CH2:39][CH2:38][N:37]([C:31]5[C:30]([CH2:29][C:26]6[CH:25]=[CH:24][C:23]([F:22])=[CH:28][CH:27]=6)=[C:35]([CH3:36])[N:34]=[CH:33][N:32]=5)[CH2:43][C:42]=4[CH:44]=3)=[CH:3][C:4]=2[N:8]=1
Reactant: CC(C)COC(=O)n1c(NCCF)nc2cc(Br)ccc21
Reactant: Cc1ncnc(N2CCOc3ccc(B(O)O)cc3C2)c1Cc1ccc(F)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ncnc(N2CCOc3ccc(-c4ccc5[nH]c(NCCF)nc5c4)cc3C2)c1Cc1ccc(F)cc1
Temperature: 95 °C
Reaction time: 0.5 h
Yield: 24.8 %

Procedure:
Isobutyl 5-bromo-2-(2-fluoroethylamino)-1H-benzo[d]imidazole-1-carboxylate (76 mg, 0.21 mmol) and (4-{5-[(4-fluorophenyl)methyl]-6-methylpyrimidin-4-yl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)boronic acid (example 8 step 2) (100 mg, 0.25 mmol), and [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (8.5 mg, 0.01 mmol) were taken into dioxane (1 mL) and water (200 uL) followed by addition of DIPEA (180 uL, 1.03 mmol) and the mixture was heated to 95° C. over 12 h. On cooling to room temperature the crude mixture was diluted with ethyl acetate and dried over anhydrous sodium sulfate then filtered through a bed of silica gel. The filtrate was concentrated and the residue taken into methanol (5 mL) and basified by addition of 5 drops of 50% aqueous sodium hydroxide. The methanol solution was stirred for 0.5 h at room temperature then concentrated. The residue was partitioned with isopropyl acetate and 1M aqueous sodium hydroxide. The organic phase was washed twice with additional 1M aqueous sodium hydroxide then dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography using 20:1 ethyl acetate:ethanol then 10% methanol in dichloromethane as eluent. Fractions containing pure material were concentrated and the residue triturated with ethyl ether. The suspension collected by filtration to give N-(2-fluoroethyl)-5-(4-{5-[(4-fluorophenyl)methyl]-6-methylpyrimidin-4-yl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-1H-benzimidazol-2-amine (27.4 mg, 25% yield). 1H NMR (400 MHZ, DMSO-d6): 10.84 (br s, 1H), 8.50 (s, 1H), 7.34 (d, 1H), 7.26 (br s, 1H), 7.18 (d, 1H), 7.12 (d, 4H), 6.98-6.91 (m, 3H), 6.85 (s, 1H), 4.68 (m, 1H), 4.55 (m, 1H), 4.46 (s, 2H), 4.25 (br s, 2H), 4.01 (s, 2H), 3.77 (br s, 2H), 2.16 (s, 3H). MS (EI) for C30H28F2N6O: 528 (MH+).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:11][C:12]1[CH:13]=[C:14]([NH2:19])[CH:15]=[CH:16][C:17]=1[F:18]>CN(C=O)C.C(OCC)(=O)C.FC(F)(F)S([O-])(=O)=O.[Ag+]>[Cl:11][C:12]1[CH:13]=[C:14]([NH:19][C:2]2[C:3]3[CH:10]=[CH:9][NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:15]=[CH:16][C:17]=1[F:18]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: Clc1ncnc2[nH]ccc12
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Fc1ccc(Nc2ncnc3[nH]ccc23)cc1Cl
Temperature: 95 °C
Reaction time: 15 h
Yield: 92.9 %

Procedure:
To a solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (767.9 mg, 5 mmol) and 3-chloro-4-fluoro-phenylamine (873.4 mg, 6 mmol) in 25 mL of dry DMF under nitrogen was added silver trifluoromethanesulfonate (1.54 g, 6 mmol). The mixture was stirred at 95° C. for 15 hours. The cooled reaction was diluted with ethyl acetate (70 mL) and filtered through celite, washed thoroughly with ethyl acetate. The filtrate was washed with brine (5×). The brine was extracted with ethyl acetate which was then washed with brine. The combined ethyl acetate was dried (magnesium sulfate), concentrated and purified to give 1.22 g (93%) of (3-chloro-4-fluoro-phenyl)-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine as an off-white solid. m.p. 274-275° C. 1H NMR (360 MHz, DMSO-d6) δ 11.78 (br s, 1H, NH), 9.41 (s, 1H), 8.31 (s, 1H), 8.28 (m, 1H), 7.79 (m, 1H), 7.37 (t, 1H), 7.25 (m, 1H), 6.76 (m, 1H). MS 263.4 [M++1].
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([NH:6][C:7](=[O:12])[C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[Li]C(C)(C)C.[B:20](OC)([O:23]C)[O:21]C.Cl>C1COCC1>[CH3:9][C:8]([CH3:11])([CH3:10])[C:7]([NH:6][C:5]1[CH:13]=[CH:14][C:2]([B:20]([OH:23])[OH:21])=[CH:3][CH:4]=1)=[O:12]
Reactant: CC(C)(C)C(=O)Nc1ccc(Br)cc1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)Nc1ccc(B(O)O)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 4-bromo-N-pivaloylaniline (1.56 g, 6 mmol) in dry THF (50 ml) at −78° C. was added t-BuLi (1.5 M in pentane, 13.3 ml, 20 mmol) and the yellow mixture was stirred for 1 h at −78° C. under N2. The reaction was quenched with B(OCH3)3 (1.7 ml, 15 mmol) and stirred for another 1 h at −78° C. The reaction mixture was then warmed to room temperature and hydrolysed with 0.5 M hydrochloric acid (50 ml) and extracted with EtOAc (3×80 ml), dried (Na2SO4) and concentrated to ca. 40 ml. n-Hexane (120 ml) was added slowly and the colorless crystalline product was filtered off and dried, yielding 1.26 g (95%).
Reaction SMILES: [OH-].[Na+].[CH2:3]([C@H:5]1[O:7][CH2:6]1)Cl.[CH2:8]([OH:14])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH2:8]([O:14][CH2:3][C@H:5]1[O:7][CH2:6]1)[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: ClC[C@@H]1CO1
Reactant: CCCCCCO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Product: CCCCCCOC[C@@H]1CO1
Reaction time: 3 h

Procedure:
To a mixture of 50% sodium hydroxide (40 g), (S)-epichlorohydrin (24 g) and tetrabutyl ammonium hydrogen sulfate (400 mg) is added dropwise n-hexanol (6 ml) while cooling at 20°-25° C. After stirring the reaction mixture at the same temperature for additional 3 hours, water is added to the mixture and the product is extracted with ether. The extract is purified by distillation under reduced pressure to give (S)-n-hexylglycidyl ether (3.35 g).
Reaction SMILES: [CH3:1][C:2]([CH3:9])=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:10]([NH2:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CCO>[CH2:10]([NH:17][C:2]([CH3:9])([CH3:1])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NCc1ccccc1
Reactant: CCOC(=O)C=C(C)C
Solvent: CCO
Product: CCOC(=O)CC(C)(C)NCc1ccccc1
Yield: 21.1 %

Procedure:
A solution of ethyl 3,3-dimethylacrylate (19.3 g, 0.151 mol) in EtOH (150 mL) was added benzylamine (16.2 g, 0.151 mol) and refluxed for 24 h. The reaction mixture was concentrated in vacuo. The distillation of the residue gave ethyl 3-benzylamino-3-methylbutyrate as a colorless oil (7.48 g, 21%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[CH:5][C:4]=1[N:12]1[CH:16]=[C:15]([CH3:17])[N:14]=[CH:13]1>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([NH2:9])[CH:6]=[CH:5][C:4]=1[N:12]1[CH:16]=[C:15]([CH3:17])[N:14]=[CH:13]1
Reactant: COc1cc([N+](=O)[O-])ccc1-n1cnc(C)c1
Agent: [Pd]
Solvent: CCO
Product: COc1cc(N)ccc1-n1cnc(C)c1
Reaction time: 0.25 h
Yield: 78.3 %

Procedure:
1-(2-Methoxy-4-nitro-phenyl)-4-methyl-1H-imidazole (2520 mg, 10.8 mmol) dissolved in ethanol (110 mL) was stirred under an atmosphere of hydrogen at room temperature for 3½ hours in the presence of 10% palladium on charcoal (252 mg). The catalyst was filtered off and washed with ethanol. The solvent of the filtrate was evaporated under reduced pressure. The crude product was purified on silica gel using dichloromethane/methanol (19:1 v/v) as eluent. The fraction containing the product was suspended in diethyl ether, stirred for 15 minutes, filtered and dried to yield the title compound (1719 mg, 78%) as a yellow solid. MS ISP (m/e): 204.3 (100) [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.48 (s, 1H), 6.91 (d, 1H), 6.88 (s, 1H), 6.35 (s, 1H), 6.17 (d, 1H), 3.68 (s, 3H), 2.11 (s, 3H).
Reaction SMILES: [N:1]#[C:2]Br.[NH:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([C@@H:16]([NH:18][C:19](=[O:21])[CH3:20])[CH3:17])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1.CCN(C(C)C)C(C)C>C1COCC1.ClCCl>[C:2]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([C@@H:16]([NH:18][C:19](=[O:21])[CH3:20])[CH3:17])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)#[N:1]
Reactant: N#CBr
Reactant: CC(=O)N[C@@H](C)c1ccc(C2CCNCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(=O)N[C@@H](C)c1ccc(C2CCN(C#N)CC2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1.37 g (13.0 mmol) Cyanogen bromide are added to a mixture of 2.0 g (8.12 mmol) (S)—N-[1-(4-piperidin-4-yl-phenyl)-ethyl]-acetamide (V.1) and 4.86 mL (28.4 mmol) DIPEA in 15 mL THF and 15 mL dichloromethane. The mixture is stirred for 4 h at rt. After that time, the solvents are removed in vacuo. The residue is taken up in ethylacetate, the mixture is washed with water and the organic layer is concentrated. After addition of diethyl ether the precipitate is collected by filtration, followed by washing with diethylether to yield the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=O)[CH:5]=[N:6][CH:7]=1.C(O)(=O)[CH2:11][C:12]([OH:14])=[O:13].N1CCCCC1>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:11][C:12]([OH:14])=[O:13])[CH:5]=[N:6][CH:7]=1
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1cncc(Br)c1
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)C=Cc1cncc(Br)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 154.5 %

Procedure:
5-Bromo-pyridin-3-carbaldehyde (15.0 g, 80.6 mmol), malonic acid (18.9 g, 181.4 mmol), and piperidine (6.6 mL, 66.9 mmol) were added to pyridine (48.9 mL). The reaction mixture was stirred at 100° C. for 1 hour, concentrated under reduced pressure, and then distilled water was added thereto. The mixture was filtered and then the resulting solid was dried under reduced pressure to give 28.4 g of the titled compound as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[CH:20]=[C:19]([OH:21])[C:13]3[CH2:14][C:15]([CH3:18])([CH3:17])[O:16][C:12]=3[CH:11]=2)=[O:9])=[N:3]1.Cl[CH2:23][C:24]1[N:29]=[C:28]([C:30]2[CH:35]=[N:34][CH:33]=[CH:32][N:31]=2)[N:27]=[C:26]([OH:36])[CH:25]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[CH:20]=[C:19]([O:21][CH2:23][C:24]3[CH:25]=[C:26]([OH:36])[N:27]=[C:28]([C:30]4[CH:35]=[N:34][CH:33]=[CH:32][N:31]=4)[N:29]=3)[C:13]3[CH2:14][C:15]([CH3:18])([CH3:17])[O:16][C:12]=3[CH:11]=2)=[O:9])=[N:3]1
Reactant: Oc1cc(CCl)nc(-c2cnccn2)n1
Reactant: Cn1ccc(NC(=O)c2cc(O)c3c(c2)OC(C)(C)C3)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cn1ccc(NC(=O)c2cc(OCc3cc(O)nc(-c4cnccn4)n3)c3c(c2)OC(C)(C)C3)n1
Temperature: 60 °C
Yield: 9.8 %

Procedure:
To a solution of 4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide (31a) (80 mg, 0.280 mmol) and 6-(chloromethyl)-2-(pyrazin-2-yl)pyrimidin-4-ol (124 mg, 0.557 mmol) in 3 mL of DMF was added Cs2CO3 (181 mg, 0.557 mmol). The mixture was heated at 60° C. overnight, then filtered, washed with EtOAc, concentrated, and purified by reverse phase HPLC to give a white solid (13 mg, 10% yield). 1H NMR (400 MHz, CDCl3) δ 9.67 (d, J=1.52 Hz, 1 H) 8.83 (d, J=2.53 Hz, 1 H) 8.65-8.67 (m, 1 H) 8.50 (s, 1 H) 7.27-7.31 (m, 1 H) 7.06 (d, J=1.01 Hz, 1 H) 6.88 (s, 1 H) 6.76-6.82 (m, 1 H) 6.72 (s, 1 H) 5.13 (s, 2 H) 3.81 (s, 3 H) 3.11 (s, 2 H) 1.49-1.55 (m, 6 H); LCMS for C24H23N7O4 m/z 474.00 (M+H+).