Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:10])[CH3:9])=[N:6][CH:7]=1.[N+:11]([C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1)([O-:13])=[O:12].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N+:11]([C:14]1[CH:19]=[CH:18][C:17]([C:2]2[CH:3]=[CH:4][C:5]([C:8](=[O:10])[CH3:9])=[N:6][CH:7]=2)=[CH:16][CH:15]=1)([O-:13])=[O:12]
Reactant: CC(=O)c1ccc(Br)cn1
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(=O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cn1
Temperature: 80 °C

Procedure:
To a stirred solution of 1-(5-bromopyridin-2-yl)ethanone (100 mg, 0.5 mmol) in toluene (4 mL) and ethanol (2 mL) was added (4-nitrophenyl)boronic acid (160 mg, 1 mmol), 2M Na2CO3 (1.4 mL), and Pd(PPh3)4 (6 mg, 0.005 mmol), the reaction was purged with argon, and then heated at 80° C. for about 6 h. The reaction mixture was concentrated, diluted with water (50 mL), and extracted with ethyl acetate (2×100 mL). The combined organic extracts were washed with brine solution (10 mL), organic layer was dried over Na2SO4 and concentrated under vacuum to obtain crude product. The crude product was purified by flash chromatography (silica gel, 60-120μ) using 10% ethyl acetate in hexane eluent to afford 1-(5-(4-nitrophenyl)pyridin-2-yl)ethanone as off white solid (105 mg, 86% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.14 (s, 1H), 8.40-8.34 (m, 3H), 8.08 (dd, 3H), 2.67 (s, 3H), LC-MS m/z calcd for [M+H]+ 243.07. found 243.2.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][C:7]1[C:8]([NH:14][C:15]2[CH:19]=[C:18]([CH:20]3[CH2:22][CH2:21]3)[NH:17][N:16]=2)=[N:9][C:10](Br)=[N:11][CH:12]=1)(=[O:3])[CH3:2].[C:23]([NH:27][S:28]([C:31]1[S:32][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:34][CH:35]=1)(=[O:30])=[O:29])([CH3:26])([CH3:25])[CH3:24].C([O-])([O-])=O.[K+].[K+].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>[C:1]([O:4][CH2:5][CH2:6][C:7]1[C:8]([NH:14][C:15]2[CH:19]=[C:18]([CH:20]3[CH2:22][CH2:21]3)[NH:17][N:16]=2)=[N:9][C:10]([C:33]2[S:32][C:31]([S:28](=[O:30])(=[O:29])[NH:27][C:23]([CH3:24])([CH3:25])[CH3:26])=[CH:35][CH:34]=2)=[N:11][CH:12]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCCc1cnc(Br)nc1Nc1cc(C2CC2)[nH]n1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)s1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)OCCc1cnc(-c2ccc(S(=O)(=O)NC(C)(C)C)s2)nc1Nc1cc(C2CC2)[nH]n1
Temperature: 90 °C
Yield: 59.5 %

Procedure:
A mixture of 2-(2-bromo-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidin-5-yl)ethyl acetate (366 mg, 1.0 mmol, 1.0 eq), N-tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-sulfonamide (517 mg, 1.5 mmol, 1.5 eq), PdCl2(dppf) (81.6 mg, 0.1 mmol, 0.1 eq), K2CO3 (417 mg, 3.0 mmol, 3.0 eq), dioxane (15 mL) and water (2 mL) was heated for 1 h at 90° C. under nitrogen atmosphere. The solvent was removed and the residue was purified by silica gel chromatography (PE/EtOAc=1:1) to yield 2-(2-(5-(N-tert-butylsulfamoyl)thiophen-2-yl)-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidin-5-yl)ethyl acetate (300 mg, 60%). LC-MS (m/z)=505.1 [M+H]+; 1H NMR (400 MHz, DMSO-d6): δ 0.73-0.74 (m, 2H), 0.96-0.97 (m, 2H), 1.16 (s, 9H), 1.90-1.94 (m, 1H), 1.97 (s, 3H), 2.96 (t, J=5.6 Hz, 2H), 4.17 (d, J=5.6 Hz, 2H), 6.47 (s, 1H), 7.58 (d, J=4.0 Hz, 1H), 7.72 (d, J=4.0 Hz, 1H), 7.87 (s, 1H), 8.13 (s, 1H), 9.37 (s, 1H), 12.19 (s, 1H)
Reaction SMILES: [O:1]=[CH:2][CH:3]=[C:4]1[O:10][CH:9]2[N:6]([C:7](=[O:11])[CH2:8]2)[CH2:5]1.O=CC=C1OC2N(C(=O)C2)C1C(OCC1C=CC=CC=1)=O>O1CCCC1>[O:1]=[CH:2]/[CH:3]=[C:4]1\[CH2:5][N:6]2[CH:9]([O:10]\1)[CH2:8][C:7]2=[O:11]
Reactant: O=CC=C1CN2C(=O)CC2O1
Agent: O=CC=C1OC2CC(=O)N2C1C(=O)OCc1ccccc1
Solvent: C1CCOC1
Product: O=C/C=C1\CN2C(=O)CC2O1
Reaction time: 4 h
Yield: 49 %

Procedure:
Preparation of 3-oxoethylidene-7-oxo-4-oxa-1-azabicyclo [3.2.0] heptane (V) from synthetic (I):- A solution of (D) (21.6 mg, 11 mol) prepared by hydrogenation of benzyl 3-oxoethylidene-7-oxo-4-oxa-1-azabicyclo[3.2.0]heptane-2-carboxylate (II) (90 mg, 0.31 mmol) in tetrahydrofuran (90 ml) was allowed to stand at room temperature for four hours when h.p.l.c. (conditions B) showed no further increase in the signal due to (E-V). The reaction mixture was evaporated to dryness and redissolved in ethyl acetate (50 ml). The ethyl acetate solution was washed with saturated NaHCO3, 0.1M HCl and saturated NaCl, dried with magnesium sulphate, and evaporated to an oil (50 mg). Semi-preparative h.p.l.c. of this residue (conditions C) gave E-3-oxoethylidene-7-oxo-4-oxa- 1 -azabicyclo[3.2.0]heptane (8.3 mg, 49%) CD Δε237.4 6.1 CH3CN); λmax.(CH3CN) 249 nm (εl3,399 dm3 mol−1 cm−1); Vmax. 1 794, 1 669, 1 638, and 1 591 cm−1;, δH(250 MHz, CDCl3) 3.19 (1H, d, J 16.7 Hz, 6β-H), 3.59 (1H, ddd, J 0.9, 2.8 and 16.6 Hz, 6α-H), 3.99 (1H, d, J 17.5 Hz, 2α-H), 5.06 (1H, dd, J 1.5 and 17.4 Hz 2β-H), 5.72 (1H, d, J 2.8 Hz, 5-H), 5.87 (1H, ddd, J 1.7, 1.7 and 3.5 Hz, 8-H) and 9.57 (1H, d, J 5.0 Hz, 9-H); addition of R-2,2,2-trifiuoro-1-(9-anthryl)ethanol (1000%) caused separation of the signals due to the 2β proton chemical shift caused both sets of 2β protons to loose their smaller coupling. The two sets of 2β proton signals were in the ratio 2:1 m/z 153 (M+, 23%), 125 (M+-CO, 12%), 111 (M+CH2CO, 24%) and 55 (M+-98, 100%). Further elution gave Z-3-oxoethylidene-7-oxo-4-oxa-1-azabicyclo[3.2.0]heptane containing 5% of the E isomer (2.3 mg, 14%), Vmax. 1 792 and 1 660 c−1 (br); dH (250 MHz, CDCl3) 3.25 (1H, d, J 16.8, 6b-H), 3.52 (1H, ddd, J 0.8, 2.8 and 16.9 Hz, 6α-H), 3.85 (1H, d, J 16.8 Hz, 2α-H), 4.68 (1H, dd, J 0.8 and 17.0 Hz, 2β-H), 5.23 (1H, dt, J 1.0 and 7.9 Hz, 8-H), and 9.96 (1H, d, J 7.8 Hz); m/z 153 (M+24%) 125 (M+CO, 11%) 111, (M+CH2CO, 29%), and 55 (M+-98, 100%).
Reaction SMILES: [OH:1][C:2]1[CH:24]=[N:23][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[N:8]([CH2:11][CH2:12][CH2:13][O:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)[C:9](=[O:10])[C:4]=2[CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].CN(C)CC(O)=O.Br[C:39]1[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=1>O1CCOCC1.CC(=O)OCC.O.[Cu]I>[CH3:22][N:6]1[C:5]2[N:23]=[CH:24][C:2]([O:1][C:39]3[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=3)=[CH:3][C:4]=2[C:9](=[O:10])[N:8]([CH2:11][CH2:12][CH2:13][O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)[C:7]1=[O:21]
Reactant: Brc1cccnc1
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2cc(O)cnc21
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2cc(Oc3cccnc3)cnc21
Temperature: 135 °C
Yield: 73.2 %

Procedure:
To a mixture of 6-hydroxy-1-methyl-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (See Compound 36, step 2, 500 mg, 1.49 mmol), CuI (85.2 mg, 0.45 mmol), Cs2CO3 (971.6 mg, 2.98 mmol) and 2-(dimethylamino)acetic acid (76.87 mg, 0.75 mmol) in dioxane (20 mL) was added 3-bromopyridine (588.9 mg, 3.73 mmol). The reaction was heated at 135° C. for 5 h followed by heating at 100° C. for 18 h, cooled to RT then diluted with EA (25 mL) and water (10 mL). The organic layer was washed with water (20 mL) and brine (20 mL), dried over Na2SO4 and concentrated to a residue which was purified by chromatography eluted with PE/EA (10:1 to 1:1) to give 1-methyl-6-(pyridin-3-yloxy)-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (450 mg, 73.2% yield) as a yellow oil. LCMS: [MH+-THP] 329 and TR=1.065 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]2[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:7][CH:6]=[CH:5][N:4]=1.[CH2:18]([N:25]1[CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.OP(O)(O)=O>C(O)(=O)C>[CH2:18]([N:25]1[CH2:26][CH:27]=[C:28]([C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:8]2[C:3]([O:2][CH3:1])=[N:4][CH:5]=[CH:6][CH:7]=2)[CH2:29][CH2:30]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: COc1ncccc1-c1cc2ccccc2[nH]1
Agent: O=P(O)(O)O
Solvent: CC(=O)O
Product: COc1ncccc1-c1[nH]c2ccccc2c1C1=CCN(Cc2ccccc2)CC1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(2-methoxy-pyridin-3-yl)-1H-indole (0.43 g, 1.94 mmol) in acetic acid (12 ml) was added 1-benzyl-piperidin-4-one (1.10 g, 5.82 mmol) and H3PO4 (4 ml). The reaction was stirred at 100° C. for 3 h. The reaction was cooled to room temperature and poured into ice/NH4OH and filtered. The solid was washed with water and dissolved in dichloromethane. The crude product was purified by flash column chromatography (SiO2, 66% EtOAc in hexanes). The desired product was obtained as a tan solid (0.64 g, 83%). LCMS: 396.75 [M+H].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][NH2:18])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[F:19][C:20]([F:27])([F:26])[C:21](OCC)=[O:22]>CO.O1CCCC1>[F:19][C:20]([F:27])([F:26])[C:21]([NH:18][CH2:17][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([S:9][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[CH:11][CH:12]=1)=[O:22]
Reactant: CCOC(=O)C(F)(F)F
Reactant: COc1ccc(Sc2ccc(CCN)cc2)cc1
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(Sc2ccc(CCNC(=O)C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 2-[4-[(4-methoxyphenyl)thio]phenyl]-ethanamine (6.3 g) in methanol (45 ml) and tetrahydrofuran (10 ml) was added ethyl trifluoroacetate (2.89 ml), and the mixture was stirred at room temperature for 1 hour. The mixture was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=2/1) to give 2,2,2-trifluoro-N-[2-[4-[(4-methoxyphenyl)thio]phenyl]ethyl]acetamide (3.95 g).
Reaction SMILES: Br[C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][CH2:8][C:7]2([CH2:15][CH2:14][N:13]([C:16]3[CH:25]=[N:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]=3)[CH2:12][CH2:11]2)[C:6]1=[O:26].[CH3:31][N:32]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[N:33]1.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.COCCOC.O.CCO>[CH3:31][N:32]1[CH:36]=[C:35]([C:2]2[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=2[CH2:4][N:5]2[CH2:10][CH2:9][CH2:8][C:7]3([CH2:15][CH2:14][N:13]([C:16]4[CH:25]=[N:24][C:23]5[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=5)[N:17]=4)[CH2:12][CH2:11]3)[C:6]2=[O:26])[CH:34]=[N:33]1
Reactant: O=C1N(Cc2ccccc2Br)CCCC12CCN(c1cnc3ccccc3n1)CC2
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Solvent: O
Product: Cn1cc(-c2ccccc2CN2CCCC3(CCN(c4cnc5ccccc5n4)CC3)C2=O)cn1
Temperature: 120 °C
Yield: 194.8 %

Procedure:
The mixture of 2-(2-bromobenzyl)-9-(quinoxalin-2-yl)-2,9-diazaspiro[5.5]undecan-1-one (58 mg, 0.11 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole [761446-44-0] (34 mg, 0.16 mmol), (Ph3P)2PdCl2 and sodium carbonate (39 mg, 0.37 mmol) in the solvent mixture DME/H2O/EtOH (2 ml, 7:3:2) was placed in a microwave tube. The tube was sealed and the suspension was heated at 120° C. over 1 h under microwave conditions. The reaction mixture was concentrated under reduced pressure. Methanol was added and the mixture filtered through PL-thiol MP SPE cartridge (previously washed with MeOH) and evaporated to give 100 mg of a yellow oil which was purified by preparative HPLC (column Waters Sunfire C18, 5 um, 4.6×50 mm, flow 5 ml/min, solvent A: Water+0.1% TFA; Solvent B: Acetonitrile+0.1% TFA/gradient 5-100% B in 2.5 min). The product containing fractions were adjusted to pH 7 with aqueous sodium bicarbonate an extracted with ethyl acetate to yield the title compound (35 mg, 66%). [1H NMR (600 MHz, DMSO-d6) ppm 8.84 (s, 1H), 7.92 (s, 1H), 7.81 (d, J=8.1 Hz, 1H), 7.54-7.64 (m, 3H), 7.32-7.42 (m, 2H), 7.22-7.31 (m, 2H), 7.02-7.11 (m, 1H), 4.59 (s, 2H), 4.22-4.34 (m, 2H), 3.44 (t, J=11.1 Hz, 2H), 3.13 (t, J=5.9 Hz, 2H), 2.02-2.13 (m, 2H), 1.86-1.95 (m, 2H), 1.75-1.85 (m, 2H), 1.61 (d, J=13.5 Hz, 2H); LCMS RtC=3.11 min, [M+H]+=467.2].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH:4]=[CH:5][C:6]1[CH:11]=[C:10](I)[CH:9]=[C:8]([F:13])[CH:7]=1.[C:15]([O:19][C:20]([N:22]1[CH2:25][CH2:24][C@H:23]1[CH2:26][O:27][C:28]1[CH:29]=[N:30][CH:31]=[C:32]([Sn](C)(C)C)[CH:33]=1)=[O:21])([CH3:18])([CH3:17])[CH3:16].C(OC(N1CC[C@H]1COC1C=C(C2C=C(CCCO)C=CC=2)C=NC=1)=O)(C)(C)C>>[CH3:1][O:2][C:3](=[O:14])[CH:4]=[CH:5][C:6]1[CH:7]=[C:8]([F:13])[CH:9]=[C:10]([C:32]2[CH:31]=[N:30][CH:29]=[C:28]([O:27][CH2:26][C@@H:23]3[CH2:24][CH2:25][N:22]3[C:20]([O:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:21])[CH:33]=2)[CH:11]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc([Sn](C)(C)C)c1
Reactant: COC(=O)C=Cc1cc(F)cc(I)c1
Agent: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(-c2cccc(CCCO)c2)c1
Product: COC(=O)C=Cc1cc(F)cc(-c2cncc(OC[C@@H]3CCN3C(=O)OC(C)(C)C)c2)c1

Procedure:
This compound is prepared by Stille coupling of 3-fluoro-5-iodocinnamic acid methyl ester and 3-[[1-(tert-butoxycarbonyl)-2(S)-azetidinyl]methoxy]-5-(trimethylstannyl)pyridine, using the same procedure as described above for the preparation of 3-[3-[5-[[1-(tert-butoxycarbonyl)-2(S)-azetidinyl]methoxy]-3-pyridyl]phenyl]-1-propanol.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:16]([C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[CH:26](Cl)[Cl:27])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[O:32]([C:39]1[CH:40]=[C:41]([C:45](Cl)([Cl:47])[Cl:46])[CH:42]=[CH:43][CH:44]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[O:1]([C:8]1[CH:9]=[C:10]([CH3:11])[CH:13]=[CH:14][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[O:16]([C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[CH2:26][Cl:27])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1.[O:32]([C:39]1[CH:40]=[C:41]([CH:42]=[CH:43][CH:44]=1)[CH:45]([Cl:46])[Cl:47])[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: ClC(Cl)(Cl)c1cccc(Oc2ccccc2)c1
Agent: ClC(Cl)c1cccc(Oc2ccccc2)c1
Agent: ClCc1cccc(Oc2ccccc2)c1
Product: Cc1cccc(Oc2ccccc2)c1
Yield: 41 %

Procedure:
Exactly the same procedure as in Example 19 is followed except that 1 g of N-diethyleneoxy-2-benzothiazolyl sulfenamide is used in place of 1 g of N-pentamethylenedithiocarbamic acid piperidinium salt. The result shows 2.1% of m-phenoxybenzyl chloride, 95.6% of m-phenoxybenzal chloride, 1.8% of m-phenoxyphenyl trichloromethane and 0.5% of nuclear-chlorinated products. The similar reaction without the above sulfenamide gives 41.0% of m-phenoxytoluene, 45.7% of m-phenoxybenzyl chloride, 12.1% of m-phenoxybenzal chloride and 1.2% of nuclear-chlorinated compounds.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH2:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[CH:5][N:4]=1.[C:25]([C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[C:29]([F:34])[CH:28]=1)#[N:26]>C(O)(C)C>[ClH:2].[C:25]([C:27]1[CH:33]=[CH:32][C:30]([NH:31][C:3]2[C:12]3[C:7](=[CH:8][C:9]([O:15][CH2:16][CH2:17][CH2:18][N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[C:10]([O:13][CH3:14])[CH:11]=3)[N:6]=[CH:5][N:4]=2)=[C:29]([F:34])[CH:28]=1)#[N:26]
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Reactant: N#Cc1ccc(N)c(F)c1
Agent: Cl
Solvent: CC(C)O
Product: COc1cc2c(Nc3ccc(C#N)cc3F)ncnc2cc1OCCCN1CCOCC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
5M Isopropanolic hydrogen chloride (1.5 ml) was added to a solution of 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (202 mg, 0.6 mmol), (prepared as described for the starting material in Example 18), and 4-cyano-2-fluoroaniline (100 mg, 0.72 mmol), (U.S. Pat. No. 4,120,693), in isopropanol (5 ml) heated at 50° C. The mixture was then heated at 80° C. for 2 hours, allowed to cool to ambient temperature and left standing overnight. The resulting precipitate was collected by filtration and the solid was then partitioned between methylene chloride and water and 1M aqueous sodium hydroxide solution (0.8 ml) was added. The organic layer was separated, washed with brine, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by flash chromatography eluting with methylene chloride/methanol (94/6). The purified solid was dissolved in methylene chloride and 2.2M ethereal hydrogen chloride was added. The precipitated product was collected by filtration, washed with ether and dried under vacuum to give 4-(4-cyano-2-fluoroanilino)-6-methoxy 7-(3-morpholinopropoxy)quinazoline hydrochloride (125 mg, 39%).
Reaction SMILES: FC(F)(F)[C:3]([CH:5]1[CH:10]2[C:11]([CH3:13])([CH3:12])[C:7]([CH3:14])([CH2:8][CH2:9]2)[C:6]1=[O:15])=O.C([O-])([O-])=O.[K+].[K+].C1OCCOCCOCCOCCOCCOC1.C=O>C1C=CC=CC=1>[CH3:12][C:11]1([CH3:13])[C:7]2([CH3:14])[C:6]([C:5](=[CH2:3])[CH:10]1[CH2:9][CH2:8]2)=[O:15]
Reactant: CC12CCC(C(C(=O)C(F)(F)F)C1=O)C2(C)C
Agent: C1COCCOCCOCCOCCOCCO1
Agent: C=O
Agent: O=C([O-])[O-]
Solvent: c1ccccc1
Product: C=C1C(=O)C2(C)CCC1C2(C)C
Temperature: 80 °C
Yield: 102.5 %

Procedure:
To a solution of 3-(trifluoroacetyl)camphor (45 mg, 0.19 mmol) in benzene (10 mL) were added K2CO3 (82 mg, 0.59 mmol), 18-crown-6 (13 mg, 0.05 mmol), and paraformaldehyde (200 mg, 6.59 mmol). The suspension was heated to 80° C. for 2 h and then heated to reflux (oil bath=90° C.) for 4 h. The mixture was allowed to cool to room temperature, saturated aqueousNH4Cl (10 mL) was added, and the resulting mixture was extracted with EtOAc (3×10 mL). The organics were dried over Na2SO4 and concentrated under reduced pressure. SiO2 flash chromatography (5% Et2O in hexanes) afforded the α-methylene camphor as a pale yellow oil (32 mg) in 95% yield.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[CH:6]=[C:5]1[C:13]([O:15]CC)=O.[Br:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21](Br)[C:20]=1[CH3:26].C(=O)([O-])[O-].[Cs+].[Cs+].CNCCNC>CNCCNC.[Cu].O1CCOCC1>[Br:18][C:19]1[C:20]([CH3:26])=[C:21]([N:1]2[CH2:2][CH2:3][N:4]3[C:12]4[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=4[CH:6]=[C:5]3[C:13]2=[O:15])[CH:22]=[CH:23][CH:24]=1
Reactant: Cc1c(Br)cccc1Br
Reactant: CCOC(=O)c1cc2c(n1CCN)CCCC2
Agent: [Cu]
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1c(Br)cccc1N1CCn2c(cc3c2CCCC3)C1=O
Temperature: 105 °C
Yield: 57 %

Procedure:
A 50-mL three-neck round-bottomed flask equipped with a reflux condenser, magnetic stirrer and nitrogen inlet was charged with ethyl 1-(2-aminoethyl)-4,5,6,7-tetrahydro-1H-indole-2-carboxylate 101k (560 m g, 2.95 mmol), 2,6-dibromotoluene (1.47 g, cesium carbonate (1.92 g, 5.90 mmol), N,N′-dimethylethylenediamine (260 mg, 2.95 mmol) and 1,4-dioxane (25 mL). After bubbling nitrogen through the resulting suspension for 30 min, copper N,N′-dimethylethylenediamine (260 mg, 2.95 mmol) was added, and the reaction mixture was heated at 105° C. (oil bath temperature) for 14 h. After this time, the mixture was cooled to room temperature and filtered. The filtrate was diluted with ethyl acetate (100 mL) and water (20 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3×30 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to afford a 57% yield (600 mg) of 2-(3-bromo-2-methylphenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one 101l as a white solid: mp 163-165° C.; 1H NMR (500 MHz, DMSO-d6) d 7.57 (dd, 1H, J=8.0, 0.5 Hz), 7.32 (d, 1H, J=7.5 Hz), 7.21 (t, 1H, J=8.0 Hz), 6.50 (s, 1H), 4.11 (m, 3H), 3.75 (m, 1H), 2.59 (m, 2H), 2.45 (m, 2H), 2.21 (s, 3H), 1.78 (m, 2H), 1.68 (m, 2H); (APCI+) m/z 358.6 (M+H)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:10]([O-])=O)[C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[OH2:13].O.[Sn](Cl)Cl>CO>[NH2:10][C:4]1[C:5]([C:8]([NH2:9])=[O:13])=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: O
Reactant: N#Cc1ncc(Br)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: CO
Product: NC(=O)c1ncc(Br)cc1N
Temperature: 40 °C

Procedure:
To a solution of 5-bromo-3-nitropyridine-2-carbonitrile (4.71 g, 20.7 mmol) in MeOH (319 mL) under N2 was added tin(II) chloride dihydrate (27.97 g, 123.9 mmol). The reaction was heated to 40° C. for 40 minutes, concentrated in vacuo, and azeotroped with toluene. The residue was dissolved in ethyl acetate, and 10% aqueous sodium bicarbonate was added till the solution was basic. The aqueous layer was extracted 3× with CHCl3 and the combined organics were dried over Na2SO4, filtered and concentrated under vacuum to provide 3-amino-5-bromopyridine-2-carboxamide that gave a mass ion (ES+) of 218.2 for M+H+(81Br).
Reaction SMILES: [CH3:1][C:2]([CH3:33])([CH3:32])[C:3](=[O:31])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[CH:18]=[C:19]([CH3:29])[C:20]3[O:24][C:23]([C:25](O)=[O:26])=[CH:22][C:21]=3[CH:28]=2)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:30].C(Cl)CCl.Cl.C[O:40][C:41](=[O:44])[CH2:42][NH2:43]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:33][C:2]([CH3:1])([CH3:32])[C:3](=[O:31])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[CH:18]=[C:19]([CH3:29])[C:20]3[O:24][C:23]([C:25]([NH:43][CH2:42][C:41]([OH:40])=[O:44])=[O:26])=[CH:22][C:21]=3[CH:28]=2)([CH2:13][CH3:14])[CH2:15][CH3:16])=[CH:8][C:7]=1[CH3:30]
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1cc(C)c2oc(C(=O)O)cc2c1
Reactant: COC(=O)CN
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Solvent: ClCCl
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1cc(C)c2oc(C(=O)NCC(=O)O)cc2c1
Yield: 97.4 %

Procedure:
5-{1-[4-(3,3-Dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-7-methyl-benzofuran-2-carboxylic acid (360 mg, 0.799 mmol) in CH2Cl2 (10 ml) and DMAP (293 mg, 2.40 mmol), EDC (230 mg, 1.20 mmol), and glycine methyl ester hydrochloride (150 mg, 1.20 mmol) are reacted and hydrolyzed analogous to Example 7 to yield title compound (395 mg, 97%).
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:5][CH2:4]1.[OH:6][C@H:7]1[CH2:11][CH2:10][N:9]([C:12]([C:14]2[S:22][C:21]3[C:16](=[N:17][CH:18]=[CH:19][C:20]=3[Cl:23])[CH:15]=2)=[O:13])[CH2:8]1>>[Cl:23][C:20]1[CH:19]=[CH:18][N:17]=[C:16]2[CH:15]=[C:14]([C:12]([N:9]3[CH2:10][CH2:11][C@H:7]([O:6][CH2:2][CH:3]4[CH2:5][CH2:4]4)[CH2:8]3)=[O:13])[S:22][C:21]=12
Reactant: O=C(c1cc2nccc(Cl)c2s1)N1CC[C@H](O)C1
Reactant: BrCC1CC1
Product: O=C(c1cc2nccc(Cl)c2s1)N1CC[C@H](OCC2CC2)C1

Procedure:
The title compound was prepared from bromomethyl-cyclopropane and (3S)-(3-hydroxy-pyrrolidin-1-yl)-[7-chloro-thieno[3,2-b]pyridin-2-yl]-methanone by a procedure analogous to Example 67B. MS: 337.2/339.2 (MH+); HPLC Rf: 5.232 min.; 85%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([N:14]=[CH:15][C:16]=3[C:17]3[CH:18]=[C:19]([NH2:23])[CH:20]=[CH:21][CH:22]=3)[CH:13]=2)=[CH:4][CH:3]=1.CCN(CC)CC.[CH2:31]([N:33]=[C:34]=[O:35])[CH3:32]>COCCOC>[CH2:31]([NH:33][C:34]([NH:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:16]2[CH:15]=[N:14][N:12]3[CH:13]=[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[CH:9]=[CH:10][C:11]=23)[CH:18]=1)=[O:35])[CH3:32]
Reactant: Nc1cccc(-c2cnn3cc(-c4ccc(F)cc4)ccc23)c1
Reactant: CCN=C=O
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: CCNC(=O)Nc1cccc(-c2cnn3cc(-c4ccc(F)cc4)ccc23)c1
Temperature: 60 °C
Yield: 91.8 %

Procedure:
A solution of 3-[6-(4-fluoro-phenyl)-pyrazolo[1,5-a]pyridin-3-yl]-phenylamine (Example 118, 50 mg, 0.16 mmol), Et3N (45 μL, 0.32 mmol) and ethyl isocyanate (26 μL, 0.32 mmol) in dry DME (2 ml) was stirred and heated at 60° C. under N2 for 24 hours [Further ethyl isocyanate (30 μL) was added after 7 hours]. The reaction mixture was evaporated and dried under vacuum to give the title compound (55 mg, solid). 1H NMR (400 MHz, DMSO-d6): 9.09 (1H, s), 8.53 (1H, s), 8.36 (1H, s), 8.02 (1H, d), 7.93-7.83 (3H, m), 7.72 (1H, dd), 7.38-7.29 (3H, m), 7.27-7.22 (2H, m), 6.15 (1H, t), 3.19-3.09 (2H, m), 1.08 (3H, t).