Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2](=[O:8])[CH2:3][CH2:4][CH2:5]CC.[C:9]1([CH2:15][O:16][CH2:17][C:18]([O:20]C)=O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[C:9]1([CH2:15][O:16][CH2:17][C:18](=[O:20])[CH2:1][C:2](=[O:8])[CH2:3][CH2:4][CH3:5])[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CCCCCC(C)=O
Reactant: COC(=O)COCc1ccccc1
Product: CCCC(=O)CC(=O)COCc1ccccc1

Procedure:
From 2-heptanone and methyl phenylmethoxyacetate according to the method of Intermediate 16.
Reaction SMILES: C1(OC(=O)[N:9]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]4([C:38](=[O:47])[NH:39][C:40]5[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=5)[CH2:37][CH2:36]4)=[O:34])=[CH:28][C:27]=3[F:48])[CH:22]=[CH:21][N:20]=2)[C:10]([O:12]C2C=CC=CC=2)=O)C=CC=CC=1.[CH3:50][N:51]([CH3:60])[CH2:52][CH2:53][N:54]1[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]1>CN(C)C=O>[CH3:50][N:51]([CH3:60])[CH2:52][CH2:53][N:54]1[CH2:59][CH2:58][N:57]([C:10]([NH:9][C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]4([C:38]([NH:39][C:40]5[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=5)=[O:47])[CH2:37][CH2:36]4)=[O:34])=[CH:28][C:27]=3[F:48])[CH:22]=[CH:21][N:20]=2)=[O:12])[CH2:56][CH2:55]1
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1
Reactant: CN(C)CCN1CCNCC1
Solvent: CN(C)C=O
Product: CN(C)CCN1CCN(C(=O)Nc2cc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)ccn2)CC1
Reaction time: 3.5 h
Yield: 35.6 %

Procedure:
To [4-(2-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamic acid phenyl ester (130 mg) was added a solution of 1-[2-(dimethylamino)ethyl]piperazine (123 mg) in N,N-dimethylformamide (2.5 ml) at room temperature, followed by stirring for 3.5 hr. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with a saturated aqueous solution of ammonium chloride and brine in this order, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=95:5). Fractions containing the target compound were concentrated under reduced pressure. A solid was precipitated by addition of diethyl ether:heptane=1:3 to the resultant residue. The solid was collected by filtration and dried under aeration to provide the titled compound as white powder (42.3 mg, 36%).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21](Cl)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:19][N:18]=2)=[CH:12][CH:11]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[NH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35]([N:37]1[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]1)=[O:36]>>[CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21]([NH:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]([N:37]3[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]3)=[O:36])[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:19][N:18]=2)=[CH:12][CH:11]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CN1CCN(C(=O)c2ccccc2N)CC1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccccc3C(=O)N3CCN(C)CC3)n2)cc1)OCC

Procedure:
The title product was prepared according to the procedure for Example 102 using diethyl(4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate and the commercially available (2-aminophenyl)-(4-methylpiperazin-1-yl)methanone. MS (ES+): m/z 607.37 (100) [MH+]; HPLC: tR=0.66 min (UPLC, purity).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:13])([CH3:12])[CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+](=[CH:16][C:17]([O:19]CC)=[O:18])=[N-].C(=O)(O)[O-].[Na+]>ClC(Cl)C.C([O-])(=O)C.[Rh+2].C([O-])(=O)C>[C:1]([O:5][C:6]([NH:8][C:9]([CH3:13])([CH3:12])[CH2:10][O:11][CH2:16][C:17]([OH:19])=[O:18])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: CC(C)(CO)NC(=O)OC(C)(C)C
Agent: [Rh+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Solvent: CC(Cl)Cl
Product: CC(C)(COCC(=O)O)NC(=O)OC(C)(C)C
Yield: 38.2 %

Procedure:
##STR194## A solution of 2-t-butoxycarbonylamino-2-methylpropanol (5.0 g, 26.46 mmol) and rhodium(II)acetate (90 mg) in dichloroethane (500 ml) was heated to 80° C. Then ethyl diazoacetate (4.0 g, 34.78 mmol) was added over a period of 1 h and the mixture was stirred at reflux for 3 h. Another portion of rhodium(II)acetate (90 mg) was added and the mixture was refluxed for another 5 h. The mixture was cooled overnight and saturated sodium bicarbonate (500 ml) was added, the layers were separated and the organic layer was washed twice with saturated sodium bicarbonate (2×200 ml) and dried (magnesium sulfate) and concentrated in vacuo. The obtained product was dissolved in 1M lithium hydroxide in methanol/water 3:1 (200 ml) and stirred overnight. The solvent was removed in vacuo to a minimum, water (50 ml) was added (pH >9) and the mixture was washed with ether (100 ml). Then 1M hydrochloric acid was added until pH <4 and the mixture was extracted with ethyl acetate (100 ml) and the combined organic layers were dried (magnesium sulfate) and concentrated in vacuo to give 2.5 g of (2-t-butoxycarbonylamino-2-methylpropoxy) acetic acid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:2]1.[CH2:15]([O:17][C:18]1[C:19](F)=[C:20]2[C:26]([NH:27][C:28]([CH:30]3[CH2:32][CH2:31]3)=[O:29])=[CH:25][NH:24][C:21]2=[N:22][CH:23]=1)[CH3:16]>C(O)CCC>[CH:30]1([C:28]([NH:27][C:26]2[C:20]3[C:21](=[N:22][CH:23]=[C:18]([O:17][CH2:15][CH3:16])[C:19]=3[N:1]3[CH2:6][CH2:5][CH2:4][C@@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:2]3)[NH:24][CH:25]=2)=[O:29])[CH2:31][CH2:32]1
Reactant: CCOc1cnc2[nH]cc(NC(=O)C3CC3)c2c1F
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Solvent: CCCCO
Product: CCOc1cnc2[nH]cc(NC(=O)C3CC3)c2c1N1CCC[C@@H](NC(=O)OC(C)(C)C)C1
Temperature: 160 °C
Reaction time: 24 h
Yield: 25.9 %

Procedure:
(R)-tert-Butyl piperidin-3-ylcarbamate (205 mg, 1.0 mmol) was added to N-(5-ethoxy-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide (90 mg, 0.34 mmol) in n-butanol (2 mL). The reaction was stirred at 160° C. for 24 hours in a sealed tube. After cooling down and concentration, the residue was purified by reverse phase chromatography (Biotage SP4, C-18 25M+, water/ACN 90/10→10/90, 30CV) to yield (R)-tert-butyl 1-(3-(cyclopropanecarboxamido)-5-ethoxy-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (39 mg) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:21])[N:7]([CH3:20])[C:8]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]3)=[N:9]2)=[CH:4][C:3]=1[CH2:22][N:23]([C:27]1[CH:39]=[CH:38][C:30]([C:31](OC(C)(C)C)=[O:32])=[CH:29][CH:28]=1)[CH2:24][C:25]#[CH:26].[NH2:40][CH2:41][CH2:42][CH2:43][N:44]1[CH:48]=[CH:47][N:46]=[CH:45]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.Cl.[OH-].[Na+]>ClCCl.FC(F)(F)C(O)=O.CN(C=O)C.O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:21])[N:7]([CH3:20])[C:8]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]3)=[N:9]2)=[CH:4][C:3]=1[CH2:22][N:23]([C:27]1[CH:28]=[CH:29][C:30]([C:31]([NH:40][CH2:41][CH2:42][CH2:43][N:44]2[CH:48]=[CH:47][N:46]=[CH:45]2)=[O:32])=[CH:38][CH:39]=1)[CH2:24][C:25]#[CH:26]
Reactant: NCCCn1ccnc1
Reactant: C#CCN(Cc1cc2c(=O)n(C)c(CN3CCN(C)CC3)nc2cc1Cl)c1ccc(C(=O)OC(C)(C)C)cc1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C#CCN(Cc1cc2c(=O)n(C)c(CN3CCN(C)CC3)nc2cc1Cl)c1ccc(C(=O)NCCCn2ccnc2)cc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A solution of tert-butyl 4-[N-[7-chloro-3-methyl-2-(4-methyl-piperazin-1-yl)methyl-4-oxo-3,4-dihydroquinazolin-6-ylmethyl]-N-(prop-2-ynyl)amino]benzoate (0.082 g, 0.15 mmol) (Preparation Example 14) in dichloromethane (1.2 ml) and trifluoroacetic acid (1.6 ml) was stirred at room temperature for 55 min. The solvents were then removed in vacuo, and the residue was treated with dichloromethane/toluene, concentrated in vacuo to leave a pale yellow solid which was dried in vacuo over P2O5. This solid was dissolved in anhydrous DMF (1.8 ml) under argon. The solution was placed in an ice-bath and then a solution of 1-(3-(aminopropyl)imidazole (0.029 g, 0.23 mmol) in anhydrous DMF (0.2 ml) was added followed by PyBOP® (0.083 g, 0.16 mmol), and finally diusopropylethylamine (0.135 g, 1.05 mmol). The solution was stirred at 0° C. for 5 min, then the ice-bath was removed and stirring was continued under argon for 2.5 h. The clear solution was then partitioned between ethyl acetate (150 ml) and saturated aqueous sodium bicarbonate (80 ml). The organic layer was washed with more saturated aqueous sodium bicarbonate (80 ml), brine (80 ml), dried (Na2SO4) and concentrated in vacuo. Purification by column chromatography, on gradient elution with methanol in chloroform (15 to 20%), afforded a white solid. This was suspended in water (6 ml) and the pH was first adjusted to ˜1 with 0.5N HCl and then to ˜12 with 1N NaOH. The white solid was collected by filtration, washed with water, and dried in vacuo over P2O5 (0.036 g, 40%), mp>115° C. (softens); 1H-NMR (DMSO-d6) 1.91 (m, 2H, CONHCH2CH2CH2), 2.14 (s, 3H, N-Me piperazine), 2.30 (br s) and 2.49 br s (obscured)) (8H, N(CH2CH2)2N—), 3.18 (m, 2H, CONHCH2CH2CH2), 3.20 (s, 1H, C≡CH), 3.59, 3.61 (2×s, 5H, N3-Me and 2-CH2), 3.98 (t, J=6.84 Hz, 2H, CONHCH2CH2CH2) 4.37 (s, 2H, CH2C≡C), 4.76 (s, 2H, 6-CH2), 6.78 (d, J=8.5 Hz, 2H, 3,5′-ArH), 6.88, 7.19 (2×s, 2H, imidazole 4-H and 5-H), 7.64 (s, 1H, imidazole 2-H), 7.71 (d, J=8.2 Hz, 2H, 2′,6′-ArH), 7.81, 7.91 (2×s, 2H, 5-H, 8-H), 8.17 (t, J=5.0 Hz, 1H, CONH).
Reaction SMILES: C([O:4][CH2:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([N:18]3[CH2:22][C@H:21]([CH2:23][NH:24][C:25](=[O:27])[CH3:26])[O:20][C:19]3=[O:28])[CH:14]=2)[CH2:9]1)=[O:7])(=O)C.C([O-])([O-])=O.[K+].[K+].Cl>CO>[OH:4][CH2:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([N:18]3[CH2:22][C@H:21]([CH2:23][NH:24][C:25](=[O:27])[CH3:26])[O:20][C:19]3=[O:28])[CH:14]=2)[CH2:9]1)=[O:7]
Reactant: CC(=O)NC[C@H]1CN(c2ccc3c(c2)CCN(C(=O)COC(C)=O)C3)C(=O)O1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(=O)NC[C@H]1CN(c2ccc3c(c2)CCN(C(=O)CO)C3)C(=O)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.1 %

Procedure:
A solution of N-[[(5S)-3-[2-[(acetyloxy)acetyl]-1,2,3,4-tetrahydro-6-isoquinolinyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (Example 3, 230 mg, 0.591 mmol) in MeOH (5.9 mL) is treated with K2CO3 (163 mg, 1.18 mmol), and the resulting mixture is stirred at ambient temperature for 1 hr and is then adjusted to pH 7 with 1M aqueous HCl and concentrated under reduced pressure. The residue is diluted with brine (10 mL) and extracted with CH2Cl2 (3×20 mL), and the combined organic phase is dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product is then chromatographed on a Flash 40S silica gel (40 g, 32-63 μm) cartridge, eluting with a gradient of MeOH/CH2Cl2 (2/98-5/95), and those fractions with an Rf=0.25 by TLC (MeOH/CHCl3, 10/90) are pooled and concentrated and the residue triturated with Et2O to give 146 mg (71%) of the title compound as an amorphous, white solid. MS (ESI+) for C17H21N3O5 m/z 348 (M+H)+; [α]25D=−18° (c 0.96, DMSO); Anal. Calcd for C17H21N3O5: C, 58.78; H, 6.09; N, 12.10. Found: C, 58.59; H, 6.49; N, 11.77.
Reaction SMILES: [CH2:1]1[C:17]2[C:5]([C:6]3[CH:29]=[CH:28][CH:27]=[CH:26][C:7]=3[C:8]3[C:16]=2[CH:15]=[C:14]2[C:9]=3[C:10]3[CH:25]=[CH:24][CH:23]=[CH:22][C:11]=3[C:12]3[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=32)=[CH:4][CH:3]=[CH:2]1.[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH2:48]([O:50][C:51](=[O:70])[C:52]1[CH:57]=[CH:56][C:55]([O:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68]Br)=[CH:54][CH:53]=1)[CH3:49]>O1CCOCC1.C(OCC)C>[CH:18]1[C:13]2[C:12](=[C:11]3[CH:22]=[CH:23][CH:24]=[CH:25][C:10]3=[C:9]3[C:14]=2[CH:15]([CH2:68][CH2:67][CH2:66][CH2:65][CH2:64][CH2:63][CH2:62][CH2:61][CH2:60][CH2:59][O:58][C:55]2[CH:56]=[CH:57][C:52]([C:51]([O:50][CH2:48][CH3:49])=[O:70])=[CH:53][CH:54]=2)[C:16]2[C:8]3=[C:7]3[CH:26]=[CH:27][CH:28]=[CH:29][C:6]3=[C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:17]3=2)[CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)c1ccc(OCCCCCCCCCCBr)cc1
Reactant: C1=CCc2c3c(c4ccccc4c2=C1)=c1c(c2ccccc2c2ccccc12)=C3
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: CCOCC
Solvent: C1COCCO1
Product: CCOC(=O)c1ccc(OCCCCCCCCCCC2c3c(c4ccccc4c4ccccc34)-c3c2c2ccccc2c2ccccc32)cc1

Procedure:
1H-Tetrabenzo[a,c,g,i]fluorene (13) (2.08 g, 5.68 mmol) was suspended in degassed dioxane 80 mL) and heated to reflux under an atmosphere of nitrogen. Tetrabutylammonium hydroxide (40% w/w in H2O, 3.50 g, 5.41 mmol) was added as a solution in dioxane (20 mL) via syringe which was then washed with dioxane (2×5 mL). A yellow precipitate formed immediately which was filtered under nitrogen and washed with warm dioxane (100 mL) and diethyl ether (100 mL). The salt was resuspended in dioxane (100 mL) and to it added 4-(10-bromo-decyloxy)-benzoic acid ethyl ester (10) (2.08 g, 5.40 mmol). The reaction mixture was refluxed under an atmosphere of nitrogen after which time a dark solution had formed. Solvent was removed in vacuo to form a dark brown oil. This was dissolved in diethyl ether and the supernatant removed to leave a yellow slurry. This was washed with diethyl ether (2×30 mL) and all the diethyl ether extracts combined and concentrated. The resulting residue was purified by flash column chromatography using CH2Cl2 /hexane (1:1) as the eluting solvent. The product was isolated as a pale yellow airy solid which was washed with and concentrated from diethyl ether four times. The desired product was precipitated from diethyl ether as a pale yellow powder (2.46 g, 3.67 mmol, 68%).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][N:10]=2)=[CH:5][C:3]=1[NH2:4].[C:17]([O:21][C:22]([NH:24][C:25]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=S)=[O:23])([CH3:20])([CH3:19])[CH3:18].C(N(C(C)C)CC)(C)C.[I-].C[N+]1C=CC=CC=1Cl>ClCCl>[C:31]([O:30][C:28]([NH:27][C:25]([NH:24][C:22]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:23])=[N:4][C:3]1[CH:5]=[C:6]([C:9]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][N:10]=2)[CH:7]=[CH:8][C:2]=1[Cl:1])=[O:29])([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)(C)OC(=O)NC(=S)NC(=O)OC(C)(C)C
Reactant: COc1ccnc(-c2ccc(Cl)c(N)c2)c1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccnc(-c2ccc(Cl)c(N=C(NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c2)c1
Reaction time: 16 h
Yield: 42.9 %

Procedure:
To a suspension of 2-chloro-5-(4-methoxypyridin-2-yl)aniline (165 mg), N,N′-bis(tert-butoxycarbonyl)thiourea (233 mg) and diisopropylethylamine (0.28 ml) in dichloromethane (7 ml) was added 1-methyl-2-chloropyridinium iodide (232 mg), and the mixture was stirred for 16 hours. The mixture was diluted with dichloromethane, washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 30 g, n-hexane:ethyl acetate=2:1) to give N,N′-bis(tert-butoxycarbonyl)-N″-(2-chloro-5-(4-methoxypyridin-2-yl)phenyl)guanidine (144 mg).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].C1(S([N:21]2[C:25]3=[N:26][CH:27]=[CH:28][CH:29]=[C:24]3[C:23]([C:30]3[CH:35]=[CH:34][N:33]=[C:32](Cl)[N:31]=3)=[CH:22]2)(=O)=O)C=CC=CC=1>>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH:5][C:32]1[N:31]=[C:30]([C:23]2[C:24]3[C:25](=[N:26][CH:27]=[CH:28][CH:29]=3)[NH:21][CH:22]=2)[CH:35]=[CH:34][N:33]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2ccnc(Cl)n2)c2cccnc21
Reactant: Nc1ccccc1C(F)(F)F
Product: FC(F)(F)c1ccccc1Nc1nccc(-c2c[nH]c3ncccc23)n1
Yield: 6.3 %

Procedure:
Using the procedure of example 1, 2-trifluoromethylaniline (131 mg) was reacted with compound 1f (100 mg) to provide compound 29 (6 mg, 6%). 1H NMR (400 MHz, CD3OD) δ 8.56 (d, J=8.0 Hz, 1H), 8.27 (t, J=5.6 Hz, 1H), 8.24 (s, 1H), 8.22 (d, J=1.6 Hz, 1H), 8.03 (d, J=8.0 Hz, 1H), 7.75 (d, J=7.8 Hz, 1H), 7.69 (t, J=8.0 Hz, 1H), 7.40 (t, J=8.0 Hz, 1H), 7.27 (d, J=5.6 Hz, 4.8 Hz, 1H), 7.10 (dd, J=8.0 Hz, 4.8 Hz, 1H). MS (ESI) m/z: 356 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:11][CH:12]2[CH2:14][CH2:13]2)[C:5]2[O:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[NH2:15][C:16]1[CH:17]=[CH:18][C:19]2[CH2:25][CH2:24][CH2:23][C:22](=[O:26])[NH:21][C:20]=2[CH:27]=1.C([O-])([O-])=O.[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>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].CC(O)(C)C>[CH:12]1([NH:11][C:4]2[C:5]3[O:10][CH:9]=[CH:8][C:6]=3[N:7]=[C:2]([NH:15][C:16]3[CH:17]=[CH:18][C:19]4[CH2:25][CH2:24][CH2:23][C:22](=[O:26])[NH:21][C:20]=4[CH:27]=3)[N:3]=2)[CH2:14][CH2:13]1
Reactant: Nc1ccc2c(c1)NC(=O)CCC2
Reactant: Clc1nc(NC2CC2)c2occc2n1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(C)(C)O
Product: O=C1CCCc2ccc(Nc3nc(NC4CC4)c4occc4n3)cc2N1
Temperature: 85 °C
Yield: 40.6 %

Procedure:
A flask was charged with 2-chloro-N-cyclopropylfuro[3,2-d]pyrimidin-4-amine (0.50 g, 2.385 mmol, Example #3, Step C), 8-amino-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one (0.420 g, 2.385 mmol, Astatech), K2CO3 (0.989 g, 7.16 mmol) and t-BuOH (9 mL). The flask was purged with N2 for 10 min. Pd2dba3 (0.153 g, 0.167 mmol) and X-Phos (0.159 g, 0.334 mmol) was added. The flask was again purged with N2 for 5 min and the mixture was heated to about 85° C. for about 18 h. The mixture was cooled to rt. The mixture was partitioned between DCM (200 mL) and water (200 mL) and the aqueous layer was extracted with DCM (3×100 mL). The combined organic layers were concentrated under reduced pressure. The resulting residue was suspended in EtOAc (200 mL) and trituated. The suspension was filtered and the solid was collected and washed with EtOAc (50 mL). The solid was suspended in a mixture solvents of DCM (100 mL) and MeOH (10 mL), filtered to give a gray solid, which was purified by preparative reverse phase HPLC (Table 2, method v). The fractions were collected then most of the MeCN was removed under reduced pressure, the resulting suspension was filtered and the solid was collected to give 8-(4-(cyclopropylamino)furo[3,2-d]pyrimidin-2-ylamino)-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one (0.338 g, 40%): LC/MS (Table 2, Method c) Rt=1.80 min; MS m/z: 350 (M+H)+. Syk IC50=A
Reaction SMILES: [CH3:1][CH:2]([CH2:4][N:5]1[CH2:12][C@@H:11]2[C:13]3([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[C@@H:7]([CH2:8][N:9]([CH:19]([CH3:21])[CH3:20])[CH2:10]2)[CH2:6]1)[CH3:3].[C:22]([OH:31])(=[O:30])[C:23]1[C:24](=[CH:26][CH:27]=[CH:28][CH:29]=1)[OH:25]>C(OCC)C>[CH3:3][CH:2]([CH2:4][N:5]1[CH2:6][C@@H:7]2[C:13]3([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]3)[C@@H:11]([CH2:10][N:9]([CH:19]([CH3:21])[CH3:20])[CH2:8]2)[CH2:12]1)[CH3:1].[C:22]([O-:31])(=[O:30])[C:23]1[C:24](=[CH:26][CH:27]=[CH:28][CH:29]=1)[OH:25]
Reactant: O=C(O)c1ccccc1O
Agent: CC(C)CN1C[C@@H]2CN(C(C)C)C[C@H](C1)C21CCCCC1
Solvent: CCOCC
Product: O=C([O-])c1ccccc1O
Reaction time: 0.5 h

Procedure:
10.7 g (=0.037 mole) of bertosamil were dissolved in 40 ml of diethyl ether. A solution of 5.12 g (=0.037 mole) of salicylic acid in 30 ml of diethyl ether was added to the solution, and the reaction mixture was stirred for 30 minutes. The resulting precipitate was filtered out of the mother liquor using a suction filter, and dried at 60° C. in a vacuum drying oven. 14.5 g of bertosamil salicylate having a melting range of 118.4 to 119.5 ° C. were obtained. The base:acid ratio determined by titration was 1:1.0. Thermogravimetric analysis showed no weight loss on drying.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:21][CH2:22]OS(C)(=O)=O.[NH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1>C1COCC1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:21][CH2:22][N:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: Cc1oc(-c2ccc(OCc3ccccn3)cc2)nc1CCOS(C)(=O)=O
Reactant: C1CCNC1
Solvent: C1CCOC1
Product: Cc1oc(-c2ccc(OCc3ccccn3)cc2)nc1CCN1CCCC1

Procedure:
A mixture of methanesulfonic acid 2-{5-methyl-2-[4-(pyridin-2-ylmethoxy)-phenyl]-oxazol-4-yl}-ethyl ester (0.85 mmol) and pyrrolidine (0.71 mL, 8.5 mmol) in THF (4 mL) is heated at reflux overnight. The mixture is partitioned between EtOAc and water. The aqueous phase is extracted with EtOAc (2×), and the combined organic phase is washed with brine and dried (NaSO4). After the solvent is removed, the residue is purified by flash chromatography chromatography [40 g SiO2, elute 20% (10% 2 M NH3 in MeOH/90% CH2Cl2): 80% CH2Cl2 to 70% (10% 2 M NH3 in MeOH/90% CH2Cl2): 30% CH2Cl2] to yield the title compound. MS (m/e): 364.2 (M+1)
Reaction SMILES: [N:1]1[C:2]([C:10]([OH:12])=O)=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:25][CH2:26][C:27]12[CH2:34][CH2:33][CH2:32][N:31]1[CH2:30][CH2:29][CH2:28]2>CN(C)C=O>[CH2:28]1[C:27]2([CH2:26][NH:25][C:10]([C:2]3[N:1]=[C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][N:4]4[CH:3]=3)=[O:12])[N:31]([CH2:32][CH2:33][CH2:34]2)[CH2:30][CH2:29]1
Reactant: NCC12CCCN1CCC2
Reactant: O=C(O)c1cn2ccccc2n1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: O=C(NCC12CCCN1CCC2)c1cn2ccccc2n1

Procedure:
Imidazo[1,2-a]pyridine-2-carboxylic acid is reacted with carbonyldiimidazole in dimethylformamide and subsequently with 7a-aminomethylhexahydro-1H-pyrrolizine to afford the title compound upon workup.
Reaction SMILES: C(O[C:4](=[O:31])[CH:5]([OH:30])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:29])[CH2:15][CH2:16][C:17]2[N:18]=[C:19]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[O:20][C:21]=2[CH3:22])=[CH:10][CH:9]=1)C.[O-:32][C:33]#[N:34].[K+]>C(O)CCC>[CH3:22][C:21]1[O:20][C:19]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[N:18][C:17]=1[CH2:16][CH2:15][C:14]([C:11]1[CH:12]=[CH:13][C:8]([CH2:7][CH2:6][CH:5]2[O:30][C:33](=[O:32])[NH:34][C:4]2=[O:31])=[CH:9][CH:10]=1)=[O:29]
Reactant: CCOC(=O)C(O)CCc1ccc(C(=O)CCc2nc(-c3ccccc3)oc2C)cc1
Reactant: N#C[O-]
Agent: [K+]
Solvent: CCCCO
Product: Cc1oc(-c2ccccc2)nc1CCC(=O)c1ccc(CCC2OC(=O)NC2=O)cc1
Yield: 39.4 %

Procedure:
A mixture of 2-hydroxy-4-[4-[3-(5-methyl-2-phenyl-4-oxazolyl)propionyl]phenyl]butyric acid ethyl ester (1.43 g), powdered potassium cyanate (0.83 g) and butanol (30 ml) was heated under refluxing conditions for 2 days. After the solvent was distilled off under reduced pressure, the residue was acidified with 2N hydrochloric acid and then extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and then concentrated. The residue was purified by silica gel column chromatography. From the fraction eluted with chloroform-methanol (100:2), 5-[2-[4-[3-(5-methyl-2-phenyl-4-oxazolyl)propionyl]phenyl]ethyl]-2,4-oxazolidinedione (0.56 g, 39%) was obtained, which was then recrystallized from dichloromethane-methanol to yield colorless prisms having a melting point of 173°-174° C.