Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[N:8]2[C@H:4]([O:5][C:6]([CH:9]=[CH2:10])=[CH:7]2)[CH2:3]1.[C:11]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([SH:21])=[CH:17][CH:16]=1)(=[O:13])[CH3:12]>>[C:11]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([S:21][CH2:10]/[CH:9]=[C:6]2/[CH2:7][N:8]3[C@H:4]([O:5]/2)[CH2:3][C:2]3=[O:1])=[CH:17][CH:16]=1)(=[O:13])[CH3:12]
Reactant: C=CC1=CN2C(=O)C[C@H]2O1
Reactant: CC(=O)Nc1ccc(S)cc1
Product: CC(=O)Nc1ccc(SC/C=C2/CN3C(=O)C[C@H]3O2)cc1

Procedure:
(5R)-7-Oxo-3-vinyl-4-oxa-1-azabicyclo[3.2.0]hept-2-ene (2.6 mmole) and p-acetamidophenyl mercaptan (0.5 g) were converted into the title compound using the process described in Example 1. The title compound was obtained as a colourless gum (102 mg), [α]D25 =+39.3° (c 1.0, CHCl3), (Found: M+ ; 304.0896; C15H16N2O3S requires 304.0882). νmax (CHCl3): 3380, 3280, 1790, 1720, 1690 (sh), 1665, 1590, 1496 cm-1. δ(CDCl3): 2.08 (3H, s), 2.60-3.50 (5H, complex), 4.18 (1H, d, J 14 Hz), 4.35 (1H, t, J 7 Hz), 5.30 (1H, d, J 2 Hz), 7.10-7.40 (4H, complex), 7.80 (1H, br.s). m/e: 304 (M+, 12%), 138 (100), 96 (62).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[F:32][C:33]([F:44])([F:43])[C:34]1[CH:42]=[CH:41][C:37]([C:38]([OH:40])=O)=[CH:36][CH:35]=1.[CH3:45][N:46]1[C:50]([C:51]2[CH:52]=[C:53]([NH2:66])[CH:54]=[CH:55][C:56]=2[O:57][CH2:58][CH2:59][N:60]2[CH2:65][CH2:64][O:63][CH2:62][CH2:61]2)=[CH:49][CH:48]=[N:47]1>C1COCC1>[CH3:45][N:46]1[C:50]([C:51]2[CH:52]=[C:53]([NH:66][C:38](=[O:40])[C:37]3[CH:36]=[CH:35][C:34]([C:33]([F:32])([F:44])[F:43])=[CH:42][CH:41]=3)[CH:54]=[CH:55][C:56]=2[O:57][CH2:58][CH2:59][N:60]2[CH2:65][CH2:64][O:63][CH2:62][CH2:61]2)=[CH:49][CH:48]=[N:47]1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Reactant: Cn1nccc1-c1cc(N)ccc1OCCN1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cn1nccc1-c1cc(NC(=O)c2ccc(C(F)(F)F)cc2)ccc1OCCN1CCOCC1
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 28.5 %

Procedure:
A solution of HATU (98.0 mg, 0.260 mmol), triethylamine (55.7 μl, 0.400 mmol) and 4-trifluoromethyl-benzoic acid (49.0 mg, 0.260 mmol) in THF (1.0 mL) was stirred at room temperature. After 15 min, 3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenylamine (60.0 mg, 0.200 mmol) was added, and the mixture was stirred at 100° C. for 10 minutes in microwave. The mixture was purified by HPLC to give title compound as a white solid (TFA salt, 27 mg, 28%). 1H NMR (DMSO-d6, 400 MHz) δ 2.96-3.10 (m, 2H), 3.16-3.19 (m, 2H), 3.52-3.60 (m, 4H), 3.70 (s, 3H), 3.84-3.87 (m, 2H), 4.39 (t, J=5.05 Hz, 2H), 6.31 (d, J=1.77 Hz, 1H), 7.28 (d, J=9.09 Hz, 1H), 7.51 (d, J=1.77 Hz, 1H), 7.75 (d, J=2.78 Hz, 1H), 7.94 (d, J=8.34 Hz, 2H), 8.16 (d, J=8.84 Hz, 2H), 8.89 (s, 1H), 10.5 (s, 1H). Exact mass calculated for C24H25F3N4O3 474.2. found 475.4 (M+).
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][N:5]([C:16](=[O:24])[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)[C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH2:15])(=[O:14])=[O:13])=[CH:8][CH:7]=1.[C:25](Cl)(=[O:27])[CH3:26].CCN(CC)CC>C(Cl)Cl>[CH3:1][S:2][CH2:3][CH2:4][N:5]([C:16](=[O:24])[C:17]1[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=1)[C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][C:25](=[O:27])[CH3:26])(=[O:13])=[O:14])=[CH:8][CH:7]=1
Reactant: CC(=O)Cl
Reactant: CSCCN(C(=O)c1ccc(F)cc1)c1ccc(S(N)(=O)=O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CSCCN(C(=O)c1ccc(F)cc1)c1ccc(S(=O)(=O)NC(C)=O)cc1
Yield: 80.3 %

Procedure:
A solution of 4-[(2-methylthio-ethyl)-(4-fluoro-benzoyl)-amino]-benzenesulfonamide (0.32 g, 0.88 mmol), acetyl chloride (0.069 mL, 76 mg, 0.97 mmol), and Et3N (0.13 mL, 97 mg, 0.96 mmol) in CH2Cl2 (9 mL) was heated at reflux for 2 h. After cooling, the mixture was evaporated in vacuo, and the residue was purified by MPLC (CH2Cl2 to 60:40 CH2Cl2/EtOAc) to afford 0.29 g (81%) of 4-[(2-methylthio-ethyl)-(4-fluoro-benzoyl)-amino]-N-acetyl-benzenesulfonamide as a colorless glass; 1H NMR δ 2.03 (s, 3H), 2.15 (s, 3H), 2.77 (m, 2H), 4.15 (m, 2H), 6.90 (dd, 2H, J=7.5, 7.5), 7.24 (d, 2H, J=9.0), 7.32 (dd, 2H, J=3.0, 9.0), 7.92 (d, 2H, J=9.0), 9.1 (br s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:4][C:5]([CH3:20])=[C:6]([CH3:19])[C:7]=1[NH:8][CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15].Cl.[Cl:29][CH2:30][C:31](=N)OCC>C(Cl)(Cl)Cl>[Cl:29][CH2:30][C:31]1[N:8]([CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:7]2[C:6]([CH3:19])=[C:5]([CH3:20])[N:4]=[C:3]([O:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:2]=2[N:1]=1
Reactant: CCOC(=N)CCl
Reactant: Cc1nc(Oc2ccccc2)c(N)c(NCCNC(=O)OC(C)(C)C)c1C
Agent: Cl
Solvent: ClC(Cl)Cl
Product: Cc1nc(Oc2ccccc2)c2nc(CCl)n(CCNC(=O)OC(C)(C)C)c2c1C
Temperature: 60 °C
Reaction time: 5 h
Yield: 64.1 %

Procedure:
tert-Butyl 2-[(3-amino-5,6-dimethyl-2-phenoxypyridin-4-yl)amino]ethylcarbamate (17.9 g, 48.1 mmol), prepared as described in U.S. Pat. No. 6,545,016 Example 23, Parts A through C, was dissolved in chloroform (250 mL). Ethyl 2-chloroacetimidate hydrochloride (15.2 g, 96 mmol) was added to the solution and the reaction mixture was stirred at 60° C. for 5 hours. Additional ethyl 2-chloroacetimidate hydrochloride (1.9 g) was added to the reaction mixture and stirred for 0.5 hours. The reaction mixture was cooled and filtered. The filtrate was diluted with chloroform (250 mL), washed with brine (2×300 mL), and the layers were separated. The combined organics were dried over magnesium sulfate, filtered with CELITE filter aid, and concentrated under reduced pressure. The material was recrystallized and filtered from acetonitrile to yield 13.28 g of tert-butyl 2-[2-(chloromethyl)-6,7-dimethyl-4-phenoxy-1H-imidazo[4,5-c]pyridin-1-yl]ethylcarbamate as a white solid.
Reaction SMILES: [N+:1]([C:4]1[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].OO.NC(N)=[O:20].FC(F)(F)C(OC(=O)C(F)(F)F)=O>ClCCl>[N+:1]([C:4]1[C:5]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[N+:6]([O-:20])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: NC(N)=O
Reactant: O=[N+]([O-])c1cccnc1-c1ccccc1
Agent: OO
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: O=[N+]([O-])c1ccc[n+]([O-])c1-c1ccccc1
Temperature: 10 °C
Reaction time: 0.75 h
Yield: 75.3 %

Procedure:
In a 250 mL three-necked round-bottomed flask equipped with a thermometer, droppingbfunnel and a condensor, 11.62 g of 3-nitro-2-phenyl-pyridine is dissolved in 58.0 ml of dichloromethane. Then, 13.65 g of H2O2 urea adduct is added. Under cooling with an ice/water bath, 16.40 ml trifluoroacetic acid anhydride is added dropwise over 25 minutes (temperature below 12° C.). After stirring at 10° C. for 45 minutes, the cooling bath is removed and the mixture is stirred at an ambient temperature for 18 hours. Afterwards, 150 ml of water is added (pH about 1) and extraction is carried out with dichloromethane (3×100 ml). After washing the organic phase with 10% aqueous sodium sulfite solution, it is dried over Na2SO4. After purification by chromatography on a pad of silica gel (eluent: first dichloromethane, then ethyl acetate), 9.45 g of the title compound is obtained as a yellow-green solid (MP: 116-117° C.).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:12])([CH3:11])[CH2:9][OH:10])=[CH:4][CH:3]=1.CC1(C)COB(B2OCC(C)(C)CO2)OC1.C([O-])(=O)C.[K+].Br[C:35]1[CH:36]=[C:37]2[C:41](=[CH:42][C:43]=1[Cl:44])[NH:40][N:39]=[C:38]2[C:45]([OH:47])=[O:46].C(=O)([O-])[O-].[K+].[K+].Cl>O1CCOCC1.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.CCO>[Cl:44][C:43]1[CH:42]=[C:41]2[C:37]([C:38]([C:45]([OH:47])=[O:46])=[N:39][NH:40]2)=[CH:36][C:35]=1[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:12])([CH3:11])[CH2:9][OH:10])=[CH:4][CH:3]=1
Reactant: O=C(O)c1n[nH]c2cc(Cl)c(Br)cc12
Reactant: CC(C)(CO)c1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CCO
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(CO)c1ccc(-c2cc3c(C(=O)O)n[nH]c3cc2Cl)cc1
Temperature: 130 °C
Yield: 20.2 %

Procedure:
A suspension of 2-(4-bromophenyl)-2-methylpropan-1-ol (168 mg, 0.73 mmol), 5,5,5′,5′-tetramethyl-2,2′-bi-1,3,2-dioxaborinane (275 mg, 0.81 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (30 mg, 0.037 mmol) and potassium acetate (216 mg, 2.20 mmol) in 1,4-dioxane (2 mL) was sealed in a pressure tube and heated to 130° C. for 1 hour. To the mixture was added 5-bromo-6-chloro-1H-indazole-3-carboxylic acid (100 mg, 0.36 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (14.7 mg, 0.018 mmol), 2N aqueous potassium carbonate solution (0.5 mL, 1.0 mmol) and EtOH (2 mL). The reaction mixture was sealed and heated to 130° C. for 1 hour. Water (3 mL) was added to the reaction mixture, followed by 1N HCl solution to adjust the pH to 2. The layers were separated and the aqueous layer was extracted with EtOAc (3×5 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by reverse phase HPLC (Column: Waters XBridge C18 19×100 mm, 5 μm; Mobile phase A: 0.03% NH4OH in water (v/v); Mobile phase B: 0.03% NH4OH in MeCN (v/v); 90.0% H2O/10.0% MeCN linear to 70.0% H2O/30.0% MeCN in 8.5 min, 70.0% H2O/30.0% MeCN linear to 0% H2O/100% MeCN in 0.5 min HOLD at 0% H2O/100% MeCN from 9.0 to 10.0 min. Flow: 25 mL/min) to afford the title compound (25.1 mg, 20% yield). MS (ES+) 345.1 (M+H)+. Retention time=1.59 minutes (Column: Waters XBridge dC18 4.6×50 mm, 5 μm; Mobile phase A: 0.03% NH4OH in water (v/v); Mobile phase B: 0.03% NH4OH in MeCN (v/v); Gradient: 95:5 A:B linear to 5:95 A:B in 4.0 min, hold at 5:95 A:B to 5.0 min. Flow: 2 mL/min).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:21])[CH2:10][C:11]2[NH:15][C:14]3[CH2:16][CH2:17][CH2:18][CH:19]([CH3:20])[C:13]=3[N:12]=2)=[CH:5][CH:4]=1.C[O-].[Na+].[C:25](OC)(=[O:28])[C:26]#[CH:27]>>[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:10]2[CH:27]=[CH:26][C:25](=[O:28])[N:15]3[C:14]4[CH2:16][CH2:17][CH2:18][CH:19]([CH3:20])[C:13]=4[NH:12][C:11]=23)=[O:21])=[CH:5][CH:4]=1
Reactant: C#CC(=O)OC
Reactant: CC1CCCc2[nH]c(CC(=O)c3ccc(F)cc3)nc21
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Product: CC1CCCc2c1[nH]c1c(C(=O)c3ccc(F)cc3)ccc(=O)n21

Procedure:
The compound is prepared as described in example 20 with 200 mg (0.65 mmol) of 1-(4-fluorophenyl)-2-(4-methyl-4,5,6,7-tetrahydro-1H-benzimidazol-2-yl)ethanone hydrochloride (example XVI), 50 mg (0.93 mmol) of sodium methylate and 54.4 mg (0.65 mmol) methyl propiolate.
Reaction SMILES: I[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[C:11]2[N:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]3[C:19]([O:24][CH3:25])=[N:20][CH:21]=[CH:22][CH:23]=3)[N:12]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:33][C:34]([OH:38])([C:36]#[CH:37])[CH3:35]>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH3:25][O:24][C:19]1[C:18]([NH:17][C:13]2[N:14]=[CH:15][N:16]=[C:11]([N:8]3[C:9]4[C:5](=[CH:4][CH:3]=[C:2]([C:37]#[C:36][C:34]([CH3:35])([OH:38])[CH3:33])[CH:10]=4)[CH:6]=[N:7]3)[N:12]=2)=[CH:23][CH:22]=[CH:21][N:20]=1
Reactant: COc1ncccc1Nc1ncnc(-n2ncc3ccc(I)cc32)n1
Reactant: C#CC(C)(C)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ncccc1Nc1ncnc(-n2ncc3ccc(C#CC(C)(C)O)cc32)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a pressure tube was added 4-(6-iodo-1H-indazol-1-yl)-N-(2-methoxypyridin-3-yl)-1,3,5-triazin-2-amine (100 mg, 0.22 mmol), followed by triethylamine (0.7 mL) and THF (0.7 mL). Copper(I) iodide (4.28 mg, 0.022 mmol), PdCl2(PPh3)2 (15.76 mg, 0.022 mmol) and 2-methylbut-3-yn-2-ol (0.04 ml, 0.45 mmol) were then added and the reaction vessel was sealed and stirred at RT for 1 hr.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]2[N:17]=[C:16]([NH2:18])[C:15]([N+:19]([O-:21])=[O:20])=[CH:14][CH:13]=2)[N:5]2[CH:22]=[C:23]([CH3:25])[N:24]=[C:4]2[CH:3]=1.[CH3:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[C:31]([CH3:33])[CH:32]=1>>[CH3:26][C:27]1[CH:28]=[C:29]([C:2]2[N:7]=[C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]3[N:17]=[C:16]([NH2:18])[C:15]([N+:19]([O-:21])=[O:20])=[CH:14][CH:13]=3)[N:5]3[CH:22]=[C:23]([CH3:25])[N:24]=[C:4]3[CH:3]=2)[CH:30]=[C:31]([CH3:33])[CH:32]=1
Reactant: Cc1cc(C)cc(B(O)O)c1
Reactant: Cc1cn2c(NCCNc3ccc([N+](=O)[O-])c(N)n3)nc(Cl)cc2n1
Product: Cc1cc(C)cc(-c2cc3nc(C)cn3c(NCCNc3ccc([N+](=O)[O-])c(N)n3)n2)c1

Procedure:
In analogy to the procedure described for Example 7, 4 mg (3% of theory) of the product are obtained starting from 120 mg (0.32 mmol) of N6-{2-[(7-chloro-2-methylimidazo[1,2-c]pyrimidin-5-yl)amino]ethyl}-3-nitropyridine-2,6-diamine (Example 31A) by coupling with 57 mg (0.38 mmol) of (3,5-dimethylphenyl)boronic acid and subsequent purification by preparative HPLC.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:3])[CH3:2].[Br:16]Br.O>C(Cl)(Cl)Cl>[Br:16][CH2:2][C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:3]
Reactant: CC(=O)c1ccccc1-c1ccccc1
Reactant: BrBr
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C(CBr)c1ccccc1-c1ccccc1
Reaction time: 0.25 h
Yield: 114.4 %

Procedure:
To a solution of 1.86 g of 2-acetyl-biphenyl in 10 ml of anhydrous chloroform, a solution of 1.29 g of bromine in 1.5 ml of anhydrous chloroform was added at 15°-20° C. When the addition was complete, the solution was stirred for 15 minutes, then poured into water. The chloroformic solution was washed with sodium bicarbonate and water, dried over calcium chloride and evaporated to dryness. 2.54 g of 2-bromoacetyl-biphenyl were obtained; the product could be used for reaction with imidazole without further purification.
Reaction SMILES: Cl[CH:2]([Cl:10])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[CH:11](=[O:14])[CH2:12][CH3:13].CCOCC.O>O1CCCC1>[Cl:10][C:2]1([C:3]([O:5][C:6]([CH3:7])([CH3:8])[CH3:9])=[O:4])[CH:11]([CH2:12][CH3:13])[O:14]1
Reactant: CCC=O
Reactant: CC(C)(C)OC(=O)C(Cl)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CCC1OC1(Cl)C(=O)OC(C)(C)C
Temperature: -20 °C
Reaction time: 0.33 h

Procedure:
4 ml of tert.-butyl dichloroacetate and 2 ml of propanal diluted with 2 ml of tetrahydrofuran were mixed together and cooled to -20° C. 28 ml of 0.9M/l of potassium tert.-butylate in tetrahydrofuran were introduced over 12 minutes and at -20° C. followed by allowing the temperature to rise to 20° C. over 1 hour 20 minutes. 25 ml of ether and 25 ml of water were added, followed by stirring, decanting, and re-extracting with ether. The organic phase was washed with water saturated with sodium chloride, then dried and concentrated to dryness to obtain 4.7 g of 1,1-dimethylethyl 2-chloro-3-ethyloxirane carboxylate.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.[C:12](Cl)(=[O:14])[CH3:13].[Sn](Cl)(Cl)(Cl)Cl.B(F)(F)F.[Cl-].[Cl-].[Cl-].[Al+3].[N+](C1C=CC=CC=1)([O-])=O>[Cl-].[Cl-].[Zn+2].C(Cl)Cl.C(#N)C.C(=S)=S.[N+](C)([O-])=O>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12](=[O:14])[CH3:13])[CH:8]=2)[CH:3]=1
Reactant: CC(=O)Cl
Reactant: Brc1ccc2ccccc2c1
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: FB(F)F
Agent: [Al+3]
Solvent: O=[N+]([O-])c1ccccc1
Solvent: ClCCl
Solvent: CC#N
Product: CC(=O)c1ccc2cc(Br)ccc2c1
Reaction time: 4 h

Procedure:
The compound of formula (II), 2-bromonaphthalene, is reacted with about 1 to 4 molar equivalents, preferably about 1.5 molar equivalents, of an acetyl halide, preferably acetyl chloride, in the presence of about 0.1 to 15 molar equivalents, preferably about 5 to 7 molar equivalents, of a Friedel-Crafts catalyst such as ferric chloride, zinc dichloride, tin tetrachloride, boron trifluoride or preferably aluminum trichloride, in a suitable solvent such as nitromethane, carbon disulphide, acetonitrile, methylene chloride or preferably nitrobenzene. The reaction is conducted at a temperature of about 25°-100° C., preferably about 50° C., for about 1-24 hours, preferably about 4 hours, giving the compound of formula (III), 2-bromo-6-acetylnaphthalene. When the reaction is substantially complete, the product of formula (III) is isolated by conventional means, for example crystallization.
Reaction SMILES: [CH3:1][N:2]([CH:12]1[CH:17]([CH3:18])[CH2:16][CH2:15][NH:14][CH2:13]1)[C:3]1[C:4]2[CH:11]=[CH:10][NH:9][C:5]=2[N:6]=[CH:7][N:8]=1.[C:19]([CH2:21][C:22](OCC)=[O:23])#[N:20].C(N(CC)CC)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O.C1(C)C=CC=CC=1>[CH3:18][C@@H:17]1[CH2:16][CH2:15][N:14]([C:22](=[O:23])[CH2:21][C:19]#[N:20])[CH2:13][C@@H:12]1[N:2]([CH3:1])[C:3]1[C:4]2[CH:11]=[CH:10][NH:9][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: CCOC(=O)CC#N
Reactant: CC1CCNCC1N(C)c1ncnc2[nH]ccc12
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: C[C@@H]1CCN(C(=O)CC#N)C[C@@H]1N(C)c1ncnc2[nH]ccc12
Temperature: 100 °C
Reaction time: 24 h
Yield: 105.5 %

Procedure:
To a clean, dry, nitrogen-purged 1.0 L reactor were charged methyl-(4-methyl-piperidin-3-yl)-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine (32.0 g, 0.130 mol), toluene (160 ml), ethyl cyanoacetate (88.53 g, 0.783 mol) and triethyl amine (26.4 g, 0.261 mol). The reaction was heated to 100° C. and held for 24 hours. The reaction was washed with water (160 ml). The organic layer concentrated to a volume of 10 ml and water (20 ml) was added. The residual toluene was removed by distillation and the mixture was cooled to room temperature. Acetone (224 ml) was added followed by citric acid (27.57 g, 0.144 mol) in water (76 ml). The resulting slurry was stirred for 7 hours. The solids were isolate by filtration, washed with acetone (96 ml), and dried under vacuum to afford 42.85 g (65.3%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1/[C:11](/[NH:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:12]/[C:13]([O:15]C)=O.C[Si]([N:28]=[C:29]=[S:30])(C)C.CCCCCCC.CCOC(C)=O>CC1CCCO1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[N:17]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:29](=[S:30])[NH:28][C:13](=[O:15])[CH:12]=1
Reactant: C[Si](C)(C)N=C=S
Reactant: CCOC(=O)CN/C(=C\C(=O)OC)c1ccc(OC)cc1OC
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Solvent: CC1CCCO1
Product: CCOC(=O)Cn1c(-c2ccc(OC)cc2OC)cc(=O)[nH]c1=S
Temperature: 110 °C
Reaction time: 1 h

Procedure:
To a solution of (Z)-methyl 3-(2,4-dimethoxyphenyl)-3-((2-ethoxy-2-oxoethyl)amino)acrylate (4.68 g, 15.1 mmol) in 2-methyltetrahydrofuran (38 mL) was added (trimethylsilyl)isothiocyanate (12.9 mL, 90.8 mmol). The resulting solution was purged with nitrogen gas for 3 times, and the mixture was heated at 110° C. for 18 hours. The mixture was cooled down to room temperature and the solvent was removed under reduced pressure to give a red solid. This residue was suspended in a mixture of 3:1 heptane/EtOAc (200 mL), and it was stirred at room temperature for 1 hour. The solid was filtered, and triturated with CH2Cl2 (100 mL), concentrated under reduced pressure and dried under vacuum the title compound (4.42 g, 87%) as a pink solid. This material was used without further purification in the next step.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([OH:8])[C:5]#[C:6][CH3:7].Cl[C:10]1[CH:15]=[C:14]([CH2:16][C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=2[F:24])[N:13]=[CH:12][N:11]=1.[Cl-].[NH4+]>O1CCCC1>[F:24][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]([F:23])[C:17]=1[CH2:16][C:14]1[CH:15]=[C:10]([O:8][CH:4]([CH3:3])[C:5]#[C:6][CH3:7])[N:11]=[CH:12][N:13]=1
Reactant: Fc1cccc(F)c1Cc1cc(Cl)ncn1
Reactant: CC#CC(C)O
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC#CC(C)Oc1cc(Cc2c(F)cccc2F)ncn1
Temperature: 25 °C
Yield: 133.6 %

Procedure:
In 1 ml of tetrahydrofuran was suspended 0.04 g of sodium hydride (60% in oil), to which 0.2 ml of a tetrahydrofuran solution containing 0.06 g of 3-pentyn-2-ol was slowly added dropwise under stirring at room temperature. The mixture was stirred at room temperature for 20 minutes, and 0.4 ml of a tetrahydrofuran solution containing 0.15 g of 4-chloro-6-(2,6-difluorobenzyl)pyrimidine was slowly added dropwise at room temperature, followed by stirring for 3 hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution and extracted three times with ethyl acetate. The organic layers were combined, washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.24 g of 4-(2,6-difluorobenzyl)-6-(1-methyl-2-butynyloxy)pyrimidine (the present compound (147)).
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]([CH2:11][CH3:12])([CH3:10])[CH2:8][CH3:9])[CH:3]=1.[CH3:13][O:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:16]=1[C:17](Cl)=[O:18]>C1(C)C=CC=CC=1>[CH2:8]([C:7]([C:4]1[CH:3]=[C:2]([NH:1][C:17](=[O:18])[C:16]2[C:20]([O:24][CH3:25])=[CH:21][CH:22]=[CH:23][C:15]=2[O:14][CH3:13])[O:6][N:5]=1)([CH3:10])[CH2:11][CH3:12])[CH3:9]
Reactant: CCC(C)(CC)c1cc(N)on1
Reactant: COc1cccc(OC)c1C(=O)Cl
Solvent: Cc1ccccc1
Product: CCC(C)(CC)c1cc(NC(=O)c2c(OC)cccc2OC)on1
Temperature: 25 °C
Yield: 91.6 %

Procedure:
To a stirred solution of 3.36 Kg of 5-amino-3-(1-ethyl-1-methylpropyl)isoxazole in 65 liters of toluene was added portion-wise over thirty minutes 4.015 Kg of 2,6-dimethoxybenzoyl chloride. The reaction mixture was heated to reflux and stirred for forty-eiht hours. It was then cooled to room temperature and concentrated to a volume of about 25 liters by evaporation of the solvent under reduced pressure. The product precipitated and was collected by filtration, washed with fresh toluene, and air dried to provide 6.084 Kg of N-[3-(1-ethyl-1-methylpropyl]-5-isoxazolyl]-2,6-dimethoxybenzamide. M.P. 172°-174° C. Yield 91%.
Reaction SMILES: Cl[C:2]1[C:7]2[C:8](=[O:22])[N:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=3[O:20][CH3:21])[CH2:10][C:6]=2[C:5]([F:23])=[C:4]([NH:24][C@@H:25]2[CH2:30][CH2:29][O:28][CH2:27][C@@H:26]2[NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[N:3]=1.CC1(C)C(C)(C)OB([C:47]2[S:48][C:49]([CH3:52])=[CH:50][CH:51]=2)O1>O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:21][O:20][C:13]1[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:12]=1[CH2:11][N:9]1[CH2:10][C:6]2[C:5]([F:23])=[C:4]([NH:24][C@@H:25]3[CH2:30][CH2:29][O:28][CH2:27][C@@H:26]3[NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[N:3]=[C:2]([C:47]3[S:48][C:49]([CH3:52])=[CH:50][CH:51]=3)[C:7]=2[C:8]1=[O:22]
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)s1
Reactant: COc1ccc(CN2Cc3c(F)c(N[C@@H]4CCOC[C@@H]4NC(=O)OC(C)(C)C)nc(Cl)c3C2=O)c(OC)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ccc(CN2Cc3c(F)c(N[C@@H]4CCOC[C@@H]4NC(=O)OC(C)(C)C)nc(-c4ccc(C)s4)c3C2=O)c(OC)c1
Yield: 54.4 %

Procedure:
A solution of tert-butyl (3R,4R)-4-(4-chloro-2-(2,4-dimethoxybenzyl)-7-fluoro-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)tetrahydro-2H-pyran-3-ylcarbamate (51 mg, 0.093 mmol), 4,4,5,5-tetramethyl-2-(5-methylthiophen-2-yl)-1,3,2-dioxaborolane (104 mg, 0.463 mmol), and bis(triphenylphosphine)palladium chloride (65.0 mg, 0.093 mmol) in dioxane (1 mL) and saturated Na2CO3 aq (1 mL) was heated to 140° C. for 40 min. After filtering out the solids, the solvent was removed from the filtrate. The resulting residue was dissolved in MeOH and DCM (10 mL) and was purified via preparative HPLC eluting with water (0.05% TFA) and ACN (80%, 0.035% TFA). The collected fractions were combined and solvent was stripped to dryness via rotary evaporation to give the title compound (31 mg, 55%). [M+H] calc'd for C31H37FN4O6S, 613; found, 613.