Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:11]2[N:12]([S:21]([N:24]([CH3:26])[CH3:25])(=[O:23])=[O:22])[CH:13]=[C:14]([CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[N:15]=2)=[O:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:33][N:34]1[CH:38]=[C:37](B2OC(C)(C)C(C)(C)O2)[C:36]([NH:48][C:49](=[O:55])[O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[N:35]1.O>CN(C)C=O.O>[C:51]([O:50][C:49](=[O:55])[NH:48][C:36]1[C:37]([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:11]3[N:12]([S:21]([N:24]([CH3:26])[CH3:25])(=[O:22])=[O:23])[CH:13]=[C:14]([CH2:16][C:17]([CH3:18])([CH3:19])[CH3:20])[N:15]=3)=[O:10])=[CH:4][CH:3]=2)=[CH:38][N:34]([CH3:33])[N:35]=1)([CH3:54])([CH3:53])[CH3:52]
Reactant: CN(C)S(=O)(=O)n1cc(CC(C)(C)C)nc1C(=O)Cc1ccc(Br)cc1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)c(NC(=O)OC(C)(C)C)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)S(=O)(=O)n1cc(CC(C)(C)C)nc1C(=O)Cc1ccc(-c2cn(C)nc2NC(=O)OC(C)(C)C)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (23 mg, 0.03 mmol) was added to a degassed, ambient temperature solution of 2-[(4-bromophenyl)acetyl]-4-(2,2-dimethylpropyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide (Intermediate 7) (123 mg, 0.28 mmol), sodium carbonate (89 mg, 0.84 mmol) and tert-butyl [1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-3-yl]carbamate (90 mg, 0.28 mmol) in N,N-dimethylformamide/water (2:1) (7.5 mL). After stirring at 80° C. overnight, the reaction mixture was cooled, poured into water and extracted with diethyl ether. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-30% acetone/methylene chloride afforded tert-butyl[4-(4-{2-[1-[(dimethylamino)sulfonyl]-4-(2,2-dimethylpropyl)-1H-imidazol-2-yl]-2-oxoethyl}phenyl)-1-methyl-1H-pyrazol-3-yl]carbamate.
Reaction SMILES: C([NH:7][C:8]1[N:9]=[C:10]([OH:45])[C:11]2[CH2:17][CH:16]([CH2:18][N:19]([CH2:22][C:23]3[CH:44]=[CH:43][C:26]([C:27]([NH:29][C@H:30]([C:38]([O:40]CC)=[O:39])[CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])=[O:28])=[CH:25][CH:24]=3)[CH:20]=[O:21])[CH2:15][NH:14][C:12]=2[N:13]=1)(=O)C(C)(C)C>[OH-].[Na+]>[NH2:7][C:8]1[N:9]=[C:10]([OH:45])[C:11]2[CH2:17][CH:16]([CH2:18][N:19]([CH2:22][C:23]3[CH:24]=[CH:25][C:26]([C:27]([NH:29][C@H:30]([C:38]([OH:40])=[O:39])[CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:28])=[CH:43][CH:44]=3)[CH:20]=[O:21])[CH2:15][NH:14][C:12]=2[N:13]=1
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(CN(C=O)CC2CNc3nc(NC(=O)C(C)(C)C)nc(O)c3C2)cc1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: Nc1nc(O)c2c(n1)NCC(CN(C=O)Cc1ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1)C2
Yield: 66.8 %

Procedure:
A solution of 0.5 g, (0.8 mmol) of diethyl N-[N-(2-pivaloylamino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-ylmethyl)-N-formyl-4-aminomethylbenzoyl]-glutamate in 0.1N NaOH was stirred at 25° C. for 5 days. The reaction mixture was filtered and the filtrate rendered acidic (pH 4) with 0.5N hydrochloric acid. The solid which formed after 1 h at 0° C. was collected, washed with water, and dried over P2O5 to give 0.26 g (67% yield) of N-[N-(2-amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-ylmethyl)-N-formyl-4-aminomethylbenzoyl]-glutamic acid. An analytical sample was recrystallized from ethanol; mp 178° C. with gradually decomposition; 1H NMR (Me2SO d6) delta 1.75-2.23 (m, 5H), 2.2-2.42 (m, 3H), 2.65.varies.2.83 (m, 1H), 3.0-3.17 (m, 2H), 4.36-4.40 (m, 1H), 4.44-4.60 (m, 2 H), 5.95 (s, 2H), 6.29 (s, 1H), 7.28-7.36 (m, 2H, AA'BB'), 7.69-7.92 (m, 2H, AA'BB'), 8.10 and 8.36 (s, 1H), 8.57 (t, 1H, J=7.78 Hz), 9.8 (br s, 1H). Anal. Calcd for C22H26N6O7 : C, 54.32; H, 5.39; N, 17.28. Found: C, 54.67; H, 5.46; N, 17.02.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([C:18]3[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=3)[NH2:21])=[CH:7][CH:8]=2)[N:3]=1.[C:25]([O:29][C:30]([NH:32][C:33]1[N:38]=[CH:37][C:36](B(O)O)=[CH:35][N:34]=1)=[O:31])([CH3:28])([CH3:27])[CH3:26].P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>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.O>[NH2:21][C:20]1[CH:19]=[C:18]([C:6]2[CH:5]=[C:4]3[C:9]([C:10]([N:12]4[CH2:17][CH2:16][O:15][CH2:14][CH2:13]4)=[N:11][C:2]([C:36]4[CH:37]=[N:38][C:33]([NH:32][C:30](=[O:31])[O:29][C:25]([CH3:27])([CH3:26])[CH3:28])=[N:34][CH:35]=4)=[N:3]3)=[CH:8][CH:7]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: Nc1cccc(-c2ccc3c(N4CCOCC4)nc(Cl)nc3c2)c1
Reactant: CC(C)(C)OC(=O)Nc1ncc(B(O)O)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ncc(-c2nc(N3CCOCC3)c3ccc(-c4cccc(N)c4)cc3n2)cn1
Temperature: 95 °C
Reaction time: 2 h
Yield: 33.4 %

Procedure:
In 50 mL round bottom flask, 3-(2-chloro-4-morpholinoquinazolin-7-yl)aniline (0.6 g, 0.0018 mol), (2-((tert-butoxycarbonyl)amino)pyrimidin-5-yl)boronic acid (0.506 g, 0.0022), potassium phosphate (1.08 g, 0.0054 mol), 1,4-dioxane (20 mL) and water (5 mL) were added. The reaction mixture was degassed with N2 for 5-10 minutes. To the same reaction mixture, Pd (PPh3)4 (0.098 g, 0.00009 mol) was added and degassed with N2 for 5-10 minutes. The reaction mixture was stirred at 95° C. for 2 hours. The reaction mass was cooled to room temperature and water was added. The crude product was extracted with ethyl acetate (3×100 mL). The combined organic layer was washed with brine, dried over sodium sulfate and evaporated under reduced pressure to provide the crude product. The crude product was purified by flash column chromatography (2% methanol in chloroform) to provide the title compound (0.3 g, 34%). 1H NMR (400 MHz, DMSO-d6): δ 10.40 (s, 1H), 9.49 (s, 2H), 8.12 (d, J=8.8 Hz, 1H), 8.01 (d, J=1.6 Hz, 1H), 7.75 (dd, J′=8.8 Hz, J″=1.6 Hz, 1H), 7.20 (t, J=7.6 Hz, 1H), 7.04 (br s, 1H), 6.98 (d, J=7.6 Hz, 1H), 6.66 (d, J=8.4 Hz, 1H), 5.29 (s, 2H), 3.90 (d, J=4.4 Hz, 4H), 3.84 (d, J=4.0 Hz, 4H), 1.49 (s, 9H): LC-MS (ESI): Calculated mass. 499.2, Observed mass [M+H]+: 500.4. (RT=0.78 min).
Reaction SMILES: [NH2:1][NH2:2].O[C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[CH:9]2>O.[Cl-].[Na+].O>[NH:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[CH:9]2)[NH2:2]
Reactant: Oc1cccc2cccnc12
Reactant: NN
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: NNc1cccc2cccnc12
Temperature: 40 °C

Procedure:
A solution of hydrazine in water (equivalent to 250 ml of 100% hydrazine hydrate) was added to the 8-hydroxyquinoline and the mixture was refluxed under nitrogen for 68 hours. After cooling to about 40° C., brine was added and the mixture was extracted with benzene. The benzene solution was washed once with brine, three times with Claisen's alkali (prepared by dissolving 35 g of potassium hydroxide in 25 ml of water, cooling, and adding 100 ml of methanol), twice again with brine, dried over magnesium sulfate, filtered and evaporated to give 60.0 g of an orange oil which crystallized on standing. IR and NMR analysis confirmed the product to be 8-hydrazinoquinoline.
Reaction SMILES: C[O:2][C:3](=[O:24])[CH2:4][C:5]1[CH:10]=[C:9]([Br:11])[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[C:15]([N+:20]([O-])=O)[CH:14]=2)=[C:7]([Br:23])[CH:6]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+].[CH2:33](O)C>CO.O>[Br:23][C:7]1[CH:6]=[C:5]([CH2:4][C:3]([OH:2])=[O:24])[CH:10]=[C:9]([Br:11])[C:8]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]2[N:19]=[CH:33][NH:20][C:15]=2[CH:14]=1
Reactant: COC(=O)Cc1cc(Br)c(Oc2ccc(N)c([N+](=O)[O-])c2)c(Br)c1
Reactant: CCO
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C(O)Cc1cc(Br)c(Oc2ccc3nc[nH]c3c2)c(Br)c1
Temperature: 25 °C
Yield: 42 %

Procedure:
Methyl[3,5-dibromo-4-(4-amino-3-nitrophenoxy)phenyl]acetate (1 g) was dissolved in methanol (10 mL) and hot solution of sodium dithionite (6.1 g) in water (30 mL) was added. The reaction mixture was refluxed for 26 hours, ethanol (255 mL) was added and the formed precipitate filtered off through a pad of celite. The filtrate was concentrated to a constant volyme of 20 mL to which formic acid (16 mL) was added. After reflux for 4 hours, the reaction mixture was cooled down to room temperature, the formed yellow precipitate filtered off and washed with methanol. Recrystallisation from ethanol gave 0.4 g (42%) of 3,5-dibromo-4-(5-benzimidazolyloxy)phenylacetic acid. 1H-NMR (300 MHz, DMSO-d6): δ 12.55 (br s, 1H), 9.47 (s, 1H), 8.27 (s, 1H), 7.88 (d, J=3.0 Hz, 1H), 7.70 (s, 2H), 6.97 (d, J=9 Hz, 1H), 6.34 (dd, J=8.9 Hz, J=3.1 Hz, 1H), 3.68 (s, 2H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:22]3[CH:21]=[CH:20][CH:19]=[C:18]([C:23](O)=O)[C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)=[N:8][CH:9]=1)(=[O:3])[NH2:2].[CH:26]1[C:31]([F:32])=[CH:30][C:29]([NH2:33])=[C:28]([NH2:34])[CH:27]=1.F[B-](F)(F)F.C(OC(C(=NOC(N(C)C)=[N+](C)C)C#N)=O)C.C(N(C(C)C)CC)(C)C>CN(C)C=O.C(O)(=O)C.O>[F:32][C:31]1[CH:26]=[CH:27][C:28]2[N:34]=[C:23]([C:18]3[C:17]4[C:16]5[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=5)[N:10]([C:7]5[CH:6]=[CH:5][C:4]([C:1]([NH2:2])=[O:3])=[CH:9][N:8]=5)[C:22]=4[CH:21]=[CH:20][CH:19]=3)[NH:33][C:29]=2[CH:30]=1
Reactant: NC(=O)c1ccc(-n2c3ccccc3c3c(C(=O)O)cccc32)nc1
Reactant: Nc1ccc(F)cc1N
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(-n2c3ccccc3c3c(-c4nc5ccc(F)cc5[nH]4)cccc32)nc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 41.2 %

Procedure:
In a 50 ml round-bottomed flask, a mixture of 210 mg of 9-(5-carbamoylpyridin-2-yl)-9H-carbazole-4-carboxylic acid, obtained according to the preceding stage, 105 mg of 4-fluoro-O-phenylenediamine, 273 mg of O-((ethoxycarbonyl)cyanomethyleneamino)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TOTU) and 138 μl of diisopropylethylamine in 36 ml of dimethylformamide is stirred at ambient temperature for 12 hours. 300 ml of water are added to the reaction medium and then the aqueous phase is extracted with twice 300 ml of ethyl acetate. The organic phases are combined, washed with 100 ml of a saturated solution of sodium chloride, dried over magnesium sulphate and then evaporated to dryness under vacuum. The crude residue obtained is dissolved with 8.5 ml of glacial acetic acid in a 20 ml tube reactor and heated in a microwave at 110° C. for 1 hour. After return to ambient temperature, the reaction mixture is concentrated under reduced pressure and then 10 ml of water and a 10% aqueous solution of sodium hydrogen carbonate are added in order to bring the pH to around 8. The aqueous phase is extracted with 1×100 ml of ethyl acetate and then the organic phase is concentrated under reduced pressure. The crude residue obtained is purified by silica gel chromatography (15-40 μm), elution being carried out with a mixture of dichloromethane and 7N ammonia in methanol (95/5 by volume). 110 mg of 6-[4-(6-fluoro-1H-benzimidazol-2-yl)-9H-carbazol-9-yl]nicotinamide are thus obtained in the form of an off-beige solid, the characteristics of which are the following:
Reaction SMILES: C([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14](C3C4C(=CC=C(OC(F)F)C=4)NN=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])(C)(C)C.BrCC1CC1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[N:15]1[CH:14]=[CH:13][N:12]=[C:11]2[NH:10][CH:9]=[C:8]([C:6]([NH2:5])=[O:7])[C:16]=12
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3n[nH]c4ccc(OC(F)F)cc34)nc12
Agent: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: NC(=O)c1c[nH]c2nccnc12
Temperature: 70 °C
Reaction time: 18 h
Yield: 92.8 %

Procedure:
To a stirred solution of N-tert-butyl-2-(5-(difluoromethoxy)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (117.1 mg, 221 μmol) and (bromomethyl)cyclopropane (386 mg, 250 μL, 2.86 mmol) in DMF (60 mL) under Ar, cesium carbonate (750 mg, 2.3 mmol) was added in a single portion. The reaction mixture was stirred at 70° C. After 18 h, the reaction was cooled to 25° C. and quenched with water (200 mL). The mixture was extracted with ethyl acetate (3×75 mL) and the organics were washed with brine (100 mL). The organics were dried over sodium sulfate and concentrated to give N-tert-butyl-2-(1-(cyclopropylmethyl)-5-(difluoromethoxy)-1H-indazol-3-yl)-5-(2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (120 mg, 205 μmol, 86%). MS (M)'=585; 1H NMR (DMSO-d6) δ: 9.14 (s, 1H), 8.59 (s, 1H), 8.20 (d, J=2.0 Hz, 1H), 7.93 (s, 1H), 7.87 (s, 1H), 7.41 (dd, J=2.0, 8.8 Hz, 1H), 7.21 (t, J=74.3 Hz, 1H), 5.86 (m, 1H), 5.07 (dd, J=1.5, 17.1 Hz, 1H), 4.98 (d, J=10.3 Hz, 1H), 4.64 (t, J=7.0 Hz, 2H), 3.58 (t, J=8.0 Hz, 2H), 2.70 (m, 2H), 1.51 (s, 9H), 0.86 (t, J=8.0 Hz, 2H), −0.08 (s, 9H).
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[OH:5][C:6]([C:8]([F:11])([F:10])[F:9])=[O:7].[CH2:12]([N:19]1[CH2:28][CH2:27][C:26]2[C:21](=[N:22][C:23](Cl)=[C:24]([N:29]3[CH2:34][CH2:33][CH:32]([O:35][C:36]4[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][C:37]=4[F:44])[CH2:31][CH2:30]3)[N:25]=2)[CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[CH2:12]([N:19]1[CH2:28][CH2:27][C:26]2[C:21](=[N:22][C:23]([NH:4][CH:1]3[CH2:3][CH2:2]3)=[C:24]([N:29]3[CH2:30][CH2:31][CH:32]([O:35][C:36]4[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][C:37]=4[F:44])[CH2:33][CH2:34]3)[N:25]=2)[CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:6]([OH:7])([C:8]([F:11])([F:10])[F:9])=[O:5]
Reactant: COc1ccc(OC2CCN(c3nc4c(nc3Cl)CN(Cc3ccccc3)CC4)CC2)c(F)c1
Reactant: NC1CC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: COc1ccc(OC2CCN(c3nc4c(nc3NC3CC3)CN(Cc3ccccc3)CC4)CC2)c(F)c1
Temperature: 90 °C

Procedure:
A mixture of cyclopropanamine (27.2 mg, 0.477 mmol), 6-benzyl-3-chloro-2-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazine TFA salt (71.2 mg, 0.119 mmol), sodium tert-butoxide (22.9 mg, 0.239 mmol), BINAP (11.1 mg, 0.018 mmol) and Pd2(dba)3 (5.5 mg, 5.96 μmol) in toluene (400 μL) was heated at 90° C. for 14 h. The mixture was directly purified by HPLC Method A to give the title compound as a TFA salt (49.2 mg, 66.8%) as a yellow solid. 1H NMR (400 MHz, methanol-d4) δ ppm 0.50-0.55 (m, 2H), 0.76 (dd, J=7.0, 1.9 Hz, 2H), 1.86-1.96 (m, 2H), 2.01-2.10 (m, 2H), 2.63 (tt, J=7.0, 3.6 Hz, 1H), 2.93-3.01 (m, 2H), 3.07 (br s, 2H), 3.34-3.41 (m, 2H), 3.56 (br s, 2H), 3.75 (s, 3H), 4.23 (br s, 2H), 4.30-4.37 (m, 1H), 4.53 (br s, 2H) 6.63-6.68 (m, 1H), 6.73 (dd, J=12.8, 2.9 Hz, 1H), 7.05 (t, J=9.2 Hz, 1H), 7.52-7.61 (m, 5H); ESI-MS m/z [M+H]+ 504.4.
Reaction SMILES: [C:1]([CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1)#[N:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[NH2:2][CH2:1][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1
Reactant: N#CCCc1ccccn1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: NCCCc1ccccn1

Procedure:
2-(2-Cyanoethyl)pyridine is reduced with lithium aluminium hydride in ether, in the normal way, yielding 2-(3-aminopropyl) pyridine, b.p. 77° C/0.4 mm. (Dihydrochloride, m.p. 175°-177° C).
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].CN(C)CCN(C)C.[Li]C(CC)C.[Br:25][C:26]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:27]=1[CH2:28]Br>C1COCC1>[Br:25][C:26]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:27]=1[CH2:28][CH2:11][C:3]1[C:2]([F:1])=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: Cc1c(F)cccc1C(=O)O
Reactant: COc1ccc(Br)c(CBr)c1
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: COc1ccc(Br)c(CCc2c(F)cccc2C(=O)O)c1
Reaction time: 1 h
Yield: 29.4 %

Procedure:
A solution of 3-fluoro-2-methylbenzoic acid (5.00 g, 32 mmol, 1 equiv) and N,N,N′,N′-tetramethylethylenediamine (TMEDA) (9.7 mL, 64 mmol, 2 equiv) in THF (100 mL) was cooled to −78° C. under an atmosphere of argon. s-BuLi (1.3 M in hexanes, 52 mL, 26 mmol, 2.1 equiv) was added dropwise and the solution was allowed to stir for 1 hr. A solution of 2-bromo-5-methoxybenzylbromide (22 g, 80 mmol, 2.5 equiv) in THF (10 mL) was added dropwise. The solution was allowed stir for 1 hr at −78° C. hr and then quenched by the addition of H2O and 1N HCl. The mixture was extracted with ethyl acetate. The combined organic phases were washed with brine, dried over MgSO4, filtered, and concentrated. After column chromatography (SiO2) followed by trituration from MeOH/DCM, 2-[2-(2-bromo-5-methoxy-phenyl)-ethyl]-3-fluoro-benzoic acid (3.3 g, 9.4 mmol, 80%) was obtained as a white powder. 1H NMR (300 MHz, CDCl3) δ 7.66 (d, J=7.8 Hz, 1H), 7.12-7.33 (m, 4H), 6.78 (d, J=9.0 Hz, 1H), 3.76 (s, 3H), 3.24 (t, J=7.5 Hz, 2H), 2.83 (t, J=7.5 Hz, 2H). LCMS: ES− 351 (M−1), 353 (M+1), 355 (M+3).
Reaction SMILES: O.[OH-].[Li+].C([O:6][P:7]([CH2:14][CH2:15][CH2:16][NH2:17])([CH:9]1[CH2:13][CH2:12][CH2:11][O:10]1)=[O:8])C>O.C(O)C>[NH2:17][CH2:16][CH2:15][CH2:14][P:7]([CH:9]1[CH2:13][CH2:12][CH2:11][O:10]1)(=[O:6])[OH:8]
Reactant: CCOP(=O)(CCCN)C1CCCO1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: NCCCP(=O)(O)C1CCCO1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred solution of 0.57 g of lithium hydroxide monohydrate in 10 ml of water is added a solution of 2.0 g of ethyl-3-aminopropyl(tetrahydrofuran-2-yl)phosphinate in 20 ml of ethanol. A slight exothermic reaction ensues and the reaction mixture becomes turbid. A further 5 ml of water is added and the then clear solution stirred for 3 days at room temperature. After this time, the reaction mixture is concentrated in vacuo at 55°. The residue is re-dissolved in water and washed with 3×10 ml of dichloromethane. The aqueous layer is again evaporated to dryness and the residue dissolved in 10 ml of water and treated with 0.65 ml of 85% phosphoric acid in 2 ml of water. After stirring overnight, the solid is removed by filtration. Evaporation of the filtrate and crystallisation of the residue from methanol/ether affords 3-aminopropyl(tetrahydrofuran-2-yl)phosphinic acid, m.p. 222°-223° (dec.), as a white solid.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]2[C:17](=[CH:18][CH:19]=1)[C:16]1[O:15][C:14]([C:20]3[O:24][N:23]=[C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:21]=3[C:31]([F:34])([F:33])[F:32])=[N:13][C:12]=1[CH2:11][CH2:10]2)(=O)=O.[CH2:37]([Sn](CCCC)(CCCC)C=C)[CH2:38]CC.[Cl-].[Li+]>O1CCOCC1.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>[C:25]1([C:22]2[C:21]([C:31]([F:33])([F:32])[F:34])=[C:20]([C:14]3[O:15][C:16]4[C:17]5[C:9](=[CH:8][C:7]([CH:37]=[CH2:38])=[CH:19][CH:18]=5)[CH2:10][CH2:11][C:12]=4[N:13]=3)[O:24][N:23]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: O=S(=O)(Oc1ccc2c(c1)CCc1nc(-c3onc(-c4ccccc4)c3C(F)(F)F)oc1-2)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: C=Cc1ccc2c(c1)CCc1nc(-c3onc(-c4ccccc4)c3C(F)(F)F)oc1-2
Temperature: 100 °C
Reaction time: 20 h
Yield: 45.8 %

Procedure:
To a solution of 2-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-4,5-dihydronaphtho[2,1-d]oxazol-7-yl trifluoromethanesulfonate (Preparation 48A, 140 mg, 0.264 mmol) in dioxane (1 mL) in a 150 mL sealed tube were sequentially added tributyl(vinyl)tin (0.085 mL, 0.290 mmol), lithium chloride (33.6 mg, 0.792 mmol), and tetrakis(triphenylphosphine)palladium(0) (30.5 mg, 0.026 mmol). The solution was purged with argon for 5 mins. It was stirred for 20 hrs in a 100° C. oil bath. After cooling, the solution was diluted with ˜20 mL of ether and filtered thru CELITE® and evaporated to give an oily residue. The residue was purified by Combiflash (24 g silica gel) eluting with 1:9 followed by 2:8 EtOAc-hexane to give 2-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-7-vinyl-4,5-dihydronaphtho[2,1-d]oxazole (49.4 mg, 46% yield). LC/MS M+1=409.25.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1B(O)O.Br[C:12]1[CH:13]=[C:14]([C:18]([C:23]2[N:24]=[CH:25][N:26]([C:28]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:27]=2)([OH:22])[CH:19]([CH3:21])[CH3:20])[CH:15]=[CH:16][CH:17]=1>>[CH3:20][CH:19]([CH3:21])[C:18]([C:14]1[CH:13]=[C:12]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[CH3:10])[CH:17]=[CH:16][CH:15]=1)([C:23]1[N:24]=[CH:25][N:26]([C:28]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:27]=1)[OH:22]
Reactant: Cc1ccccc1B(O)O
Reactant: CC(C)C(O)(c1cccc(Br)c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Product: Cc1ccccc1-c1cccc(C(O)(c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)C(C)C)c1
Yield: 59.2 %

Procedure:
By the reaction in the same manner as in Example 1-(i) using o-tolylboronic acid (0.69 g) and 1-(3-bromophenyl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol (1.01 g), the amorphous title compound (0.61 g) was obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[N:9]1([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(N(CC)CC)C>CC(O)C>[Cl:8][C:6]1[N:5]=[C:4]([N:12]2[CH2:11][CH2:10][N:9]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][CH2:13]2)[N:3]=[CH:2][CH:7]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(c2nccc(Cl)n2)CC1
Yield: 94.9 %

Procedure:
To a solution (60 ml) of 4,6-dichloropyrimidine (2.00 g, 13.4 mmol) and tert-butyl piperazine-1-carboxylate (3.00 g, 16.1 mmol) in 2-propanol was added triethylamine (4.7 ml, 33.6 mmol), and the mixture was heated under reflux for 2 hrs. The mixture was concentrated under reduced pressure, dichloromethane was added to the residue, and the mixture was washed with water. The aqueous layer was extracted with dichloromethane, and the combined organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2) to give tert-butyl 4-(6-chloropyrimidin-2-yl)piperazine-1-carboxylate (3.80 g, yield 95%) as a white solid.