Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].C([N:12]1[C:24]2[CH:23]=[CH:22][C:21]([CH:25]=[O:26])=[CH:20][C:19]=2[C:18]2[C:13]1=[CH:14][CH:15]=[CH:16][CH:17]=2)C1C=CC=CC=1>ClCCCl>[CH:23]1[C:24]2[NH:12][C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:19]=2[CH:20]=[C:21]([CH:25]=[O:26])[CH:22]=1
Reactant: O=Cc1ccc2c(c1)c1ccccc1n2Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: O=Cc1ccc2[nH]c3ccccc3c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 39.9 %

Procedure:
A 250-mL round-bottomed flask was charged with a solution of AlCl3 (9.26 g, 69.45 mmol, 20.00 equiv, 99%) in 1,2-dichloroethane (150 mL). To this was added 9-benzyl-9H-carbazole-3-carbaldehyde (1 g, 3.47 mmol, 1.00 equiv, 99%) in several batches at room temperature over 5 minutes. The resulting mixture was stirred for 2 hours at room temperature. The reaction was then quenched by the addition of H2O/ice (100 mL). The solids were filtered out. The resulting solution was extracted with DCM (3×100 mL) and the combined organic layers were concentrated on a rotary evaporator to give a residue that was purified by silica gel column chromatography eluted with PE:EtOAc (10:1) to afford 9H-carbazole-3-carbaldehyde as green solid (270 mg, 40%). LCMS: [M+H]+: 196
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=O)[CH2:7][CH2:6]2.Cl.[NH2:14][OH:15].C([O-])(=O)C.[Na+]>O.CO.C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[N:14][OH:15])[CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCC2=O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CCC2=NO
Temperature: 70 °C
Reaction time: 1.5 h

Procedure:
5-Methoxy-2,3-dihydromden-1-one (Ig, 6.17 mmol) was added to a solution of hydroxylamine HCl (730 mg, 10.5 mmol) in 10 ml of water. The mixture was brought up to 70° C. and a solution of sodium acetate (1.4 g, 16.7 mmol) in 7 mL of H2O, 14 ml of MeOH, 3 ml of THF was added. After stirring for 1.5 h at 70° C., 10 ml of H2O was added to produce a precipitate and the suspension was allowed to stir for 2 h. The precipitate was collected by filtration to give 5-methoxy-2,3-dihydroinden-1-one oxime almost quantitatively and was used in the next step without further purification. The oxime (0.5 g, 2.82 mmol) was dissolved in MeOH and a catalytic amount of Raney nickel and 25 mL of ammonia solution in MeOH (7N) was added. The reaction was stirred at r.t. overnight under H2. The slurry was filtered over celite and concentrated in vacuo, diluted with EtOAc, washed with water and brine, dried over MgSO4, filtered, and concentrated in vacuo to give the crude title amine (yield, 45%). The crude amine was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:15]2[CH2:14][CH2:13][C@H:12]3[C@H:8]([CH2:9][CH2:10][NH:11]3)[C:7]=2[CH:6]=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].Br[CH2:25][CH2:26][CH2:27][CH2:28][N:29]1[C:33](=[O:34])[C:32]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:31]2[C:30]1=[O:39]>CC(CC)=O.O>[CH3:1][O:2][C:3]1[C:15]2[CH2:14][CH2:13][C@H:12]3[C@H:8]([CH2:9][CH2:10][N:11]3[CH2:25][CH2:26][CH2:27][CH2:28][N:29]3[C:33](=[O:34])[C:32]4=[CH:35][CH:36]=[CH:37][CH:38]=[C:31]4[C:30]3=[O:39])[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2c1CC[C@@H]1NCC[C@H]21
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: COc1cccc2c1CC[C@H]1[C@@H]2CCN1CCCCN1C(=O)c2ccccc2C1=O
Yield: 103.8 %

Procedure:
A solution of 1.00 g (0.005 mol) of rac-cis-2,3,3a,4,5,9b-hexahydro-6-methoxy-1H-benzo[e]indole in 60 ml of ethyl methyl ketone was treated with 0.86 g (0.006 mol) of potassium carbonate, 0.29 g (0.002 mol) of sodium iodide and 1.40 g (0.005 mol) of N-(4-bromobutyl)phthalimide. The mixture was boiled under reflux for 24 hours and, after cooling, treated with water. The mixture was extracted with ethyl acetate, the extracts were dried with sodium sulphate and the solvent was distilled off in a vacuum. Chromatography over silica gel with methylene chloride/methanol 20:1 gave 2.10 g (quant.) of crude rac-cis-N-[4-(1,2,3a,4,5,9b-hexahydro-6-methoxy-3H-benzo[e]indol-3-yl)butyl]phthalimide as pale yellow crystals. A small sample was recrystallized from ethyl acetate/ether and then exhibited a m.p. of 103°-105°.
Reaction SMILES: C([N:8]1[CH2:15][C@@H:14]([F:16])[CH2:13][C@H:9]1[C:10](O)=O)(OC(C)(C)C)=O.[C:17]([C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[C:23]([NH2:28])[CH:22]=1)([CH3:20])([CH3:19])[CH3:18]>>[C:17]([C:21]1[CH:26]=[CH:25][C:24]2[NH:27][C:10]([C@@H:9]3[CH2:13][C@H:14]([F:16])[CH2:15][NH:8]3)=[N:28][C:23]=2[CH:22]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)c1ccc(N)c(N)c1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](F)C[C@H]1C(=O)O
Product: CC(C)(C)c1ccc2[nH]c([C@@H]3C[C@H](F)CN3)nc2c1

Procedure:
The title compound was prepared according to Method 4 using N-Boc-cis-4-fluoro-L-proline and 4-tert-butyl-1,2-diaminobenzene. The final residue was washed with ethyl acetate and diluted with water, basified with saturated lithium hydroxide solution (pH=8), extracted with ethyl acetate and dried over anhydrous Na2SO4 and concentrated under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[CH:11]=[C:12]([N:16]3[C:20]([CH2:21][O:22][CH3:23])=[C:19]([C:24](O)=[O:25])[C:18]([CH2:27][O:28][CH3:29])=[N:17]3)[CH:13]=[CH:14][CH:15]=2)=[CH:4][CH:3]=1.[N:30]1([CH:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[CH2:34][CH2:33][CH2:32][CH2:31]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[CH:11]=[C:12]([N:16]3[C:20]([CH2:21][O:22][CH3:23])=[C:19]([C:24]([N:38]4[CH2:39][CH2:40][CH:35]([N:30]5[CH2:34][CH2:33][CH2:32][CH2:31]5)[CH2:36][CH2:37]4)=[O:25])[C:18]([CH2:27][O:28][CH3:29])=[N:17]3)[CH:13]=[CH:14][CH:15]=2)=[CH:4][CH:3]=1
Reactant: COCc1nn(-c2cccc(/C=C/c3ccc(Cl)cc3)c2)c(COC)c1C(=O)O
Reactant: C1CCN(C2CCNCC2)C1
Product: COCc1nn(-c2cccc(/C=C/c3ccc(Cl)cc3)c2)c(COC)c1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for example 1, 1-{3-[(E)-2-(4-chloro-phenyl)-vinyl]-phenyl}-3,5-bis-methoxymethyl-1H-pyrazole-4-carboxylic acid (intermediate 3) and 4-pyrrolidin-1-yl-piperidine gave the title compound as brown solid. MS: 549.3 (MH+, 1 Cl).
Reaction SMILES: CO[CH:3](OC)[CH2:4][N:5]([CH3:38])[C:6]([C:8]1[N:9]([CH2:35][CH:36]=[CH2:37])[CH:10]=[C:11]([C:13]([C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[N:24]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[N:23]=[CH:22]3)([OH:18])[C:14]([F:17])([F:16])[F:15])[CH:12]=1)=[O:7].OS(O)(=O)=O>CCOCC>[CH2:35]([N:9]1[C:8]2[C:6](=[O:7])[N:5]([CH3:38])[CH:4]=[CH:3][C:12]=2[C:11]([C:13]([C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[N:24]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[N:23]=[CH:22]3)([OH:18])[C:14]([F:15])([F:16])[F:17])=[CH:10]1)[CH:36]=[CH2:37]
Reactant: C=CCn1cc(C(O)(c2ccc3c(cnn3-c3ccc(F)cc3)c2)C(F)(F)F)cc1C(=O)N(C)CC(OC)OC
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: C=CCn1cc(C(O)(c2ccc3c(cnn3-c3ccc(F)cc3)c2)C(F)(F)F)c2ccn(C)c(=O)c21
Reaction time: 13 h
Yield: 95.1 %

Procedure:
A room temperature solution of 1-allyl-4-{2,2,2-trifluoro-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-1-hydroxyethyl}-1H-pyrrole-2-carboxylic acid (2,2-dimethoxyethyl)methylamide (100 mg, 0.178 mmol) in ether (2 mL) was added H2SO4 (50 μL). After 13 hours, the mixture was carefully quenched with saturated aqueous sodium bicarbonate (3 mL) and extracted with three 10 mL portions of ethyl acetate. The combined organic layers were washed with brine (10 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by chromatography on SiO2 (0-80% ethyl acetate in hexanes, gradient) to give 84 mg (95%) of the title compound. MS m/z 497.36 (MH+), m.p. 91° C.-93° C.
Reaction SMILES: C([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[O:10][C:9]([C:18]2[N:19]=[CH:20][C:21]3[N:22]([CH:24]=[CH:25][CH:26]=3)[CH:23]=2)=[CH:8]1)(C)(C)C.Cl.[Cl:28][CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][C:34]([F:38])([F:37])[CH2:33][CH2:32]1>>[ClH:28].[F:37][C:34]1([F:38])[CH2:35][CH2:36][N:31]([CH2:30][CH2:29][O:17][C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[O:10][C:9]([C:18]2[N:19]=[CH:20][C:21]4[N:22]([CH:24]=[CH:25][CH:26]=4)[CH:23]=2)=[CH:8][C:7]3=[N:6][OH:5])[CH2:32][CH2:33]1
Reactant: CC(C)(C)ON=c1cc(-c2cn3cccc3cn2)oc2ccc(O)cc12
Reactant: FC1(F)CCN(CCCl)CC1
Agent: Cl
Product: ON=c1cc(-c2cn3cccc3cn2)oc2ccc(OCCN3CCC(F)(F)CC3)cc12

Procedure:
6-[2-(4,4-Difluoro-piperidin-1-yl)-ethoxy]-2-pyrrolo[1,2-a]pyrazin-3-yl-chromen-4-one oxime, hydrochloride was prepared in 50% overall yield using the method described in example 123, starting from 6-Hydroxy-2-pyrrolo[1,2-a]pyrazin-3-yl-chromen-4-one O-tert-butyl-oxime (example 123B) and 1-(2-Chloro-ethyl)-4,4-difluoro-piperidine hydrochloride.
Reaction SMILES: C1(P(C2CCCCC2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2C=CC=CC=2N(C)C)CCCCC1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[F:39][C:40]([F:50])([F:49])[CH:41]([CH3:48])[CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44].BrC1C=CC(C)=CC=1>C1(C)C=CC=CC=1.C1COCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1CCCCC1.ClCCl>[F:39][C:40]([F:49])([F:50])[CH:41]([CH3:48])[CH:42]([C:12]1[CH:11]=[CH:10][C:9]([CH3:14])=[CH:8][CH:13]=1)[C:43]([O:45][CH2:46][CH3:47])=[O:44]
Reactant: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Reactant: CCOC(=O)CC(C)C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: C1CCCCC1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOC(=O)C(c1ccc(C)cc1)C(C)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Under argon, 196.9 mg (0.88 mmol) of palladium(II) acetate and 724.8 mg (1.84 mmol) of 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl were initially charged in 50 ml of anhydrous toluene. 43.8 ml (43.8 mmol) of a 1 M solution of lithium hexamethyldisilazide in THF were then added slowly to the reaction solution, and the mixture was stirred at room temperature for 10 min. The reaction solution was then cooled to −10° C., 7 g (38.0 mmol) of ethyl 4,4,4-trifluoro-3-methylbutanoate were added slowly and the mixture was stirred at −10° C. for 10 min. 5 g (29.2 mmol) of 4-bromotoluene, dissolved in 50 ml of toluene, were then added dropwise, and the reaction solution was warmed first to room temperature and then to 80° C. The mixture was stirred at this temperature for 2 h and then cooled to room temperature and stirred overnight. After the reaction had ended (monitored by TLC; mobile phase cyclohexane/dichloromethane 2:1), the reaction mixture was filtered through kieselguhr, the residue was washed repeatedly with ethyl acetate and dichloromethane and the combined filtrates were concentrated under reduced pressure. The crude product obtained was purified chromatographically on silica gel (mobile phase petroleum ether/dichloromethane 4:1→3:1). This gave 3.91 g (14.3 mmol, 48.8% of theory) of the title compound as a colorless liquid.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:33][C:34]([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)([C:41]1[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:32])[CH2:9][NH:10][C:11](=[O:31])[CH2:12][NH:13]C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O.N1CCCCC1>C(#N)C>[CH3:1][O:2][CH:3]([O:33][C:34]([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)([C:41]1[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:32])[CH2:9][NH:10][C:11](=[O:31])[CH2:12][NH2:13]
Reactant: COc1ccc(C(OC(CCCNC(=O)CNC(=O)CNC(=O)OCC2c3ccccc3-c3ccccc32)OC)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Solvent: CC#N
Product: COc1ccc(C(OC(CCCNC(=O)CNC(=O)CN)OC)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.2 %

Procedure:
To compound 13 (3.00 g, 4.12 mmol) were added acetonitrile (5 mL) and piperidine (2.4 mL) at room temperature, and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (eluent: dichloromethane-methanol (9:1)+0.05% pyridine) to give glycylglycine-4,4′-dimethoxytrityloxybutylamide (14) (1.13 g, 54%). The instrumental analysis values of glycylglycine-4,4′-dimethoxytrityloxybutylamide (14) are shown below.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C@:10]3([CH2:23][C:13]4=[N:14][CH:15]=[C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:17]=[C:12]4[CH2:11]3)[C:9](=[O:24])[N:8](COCC[Si](C)(C)C)[C:5]2=[N:6][CH:7]=1.Cl.C(N)CN.[OH-].[Na+]>CO.O>[F:1][C:2]1[CH:3]=[C:4]2[C@:10]3([CH2:23][C:13]4=[N:14][CH:15]=[C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:17]=[C:12]4[CH2:11]3)[C:9](=[O:24])[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CCOC(=O)c1cnc2c(c1)C[C@@]1(C2)C(=O)N(COCC[Si](C)(C)C)c2ncc(F)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: NCCN
Solvent: O
Product: CCOC(=O)c1cnc2c(c1)C[C@@]1(C2)C(=O)Nc2ncc(F)cc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of ethyl (6S)-5′-fluoro-2′-oxo-1′-{[2-(trimethylsilyl)ethoxy]methyl}-1′,2′,5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridine]-3-carboxylate (300 mg, 0.656 mmol) in MeOH (15 mL) was saturated with HCl (g) and aged for 30 min at ambient temperature. The resulting mixture was concentrated to dryness in vacuo. The residue was dissolved in MeOH (10 mL), ethylenediamine (0.044 mL, 0.656 mmol) was added, and the solution was adjusted to pH 10 by addition of 1 N sodium hydroxide. The resulting mixture was stirred at ambient temperature for 30 min, poured into water (20 mL) and extracted with CHCl3 (2×25 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated to dryness in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:MeOH-100:0 to 90:10, to give the title compound, which contained some of the corresponding methyl ester. MS: m/z=328.2 (M+1).
Reaction SMILES: Br[C:2]1[C:3]([F:14])=[CH:4][N:5]=[C:6]2[C:11]=1[N:10]=[C:9]([O:12][CH3:13])[CH:8]=[CH:7]2.[C:15]1(/[CH:21]=[CH:22]/B(O)O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>>[F:14][C:3]1[C:2](/[CH:22]=[CH:21]/[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([O:12][CH3:13])=[N:10]2)=[N:5][CH:4]=1
Reactant: COc1ccc2ncc(F)c(Br)c2n1
Reactant: OB(O)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc2ncc(F)c(/C=C/c3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 94.4 %

Procedure:
8-bromo-7-fluoro-2-methoxy-[1,5]naphthyridine (prepared as in WO 2004/058144; 7 g, 27.2 mmol), trans-phenylvinyl boronic acid (4.23 g, 1.05 eq) and K2CO3 (4.9 g) were introduced in a two-necked flask. The atmosphere was flushed with nitrogen and dioxane (40 ml) and water (10 ml) were added. The mixture was stirred at rt for 5 min and Pd(PPh3)4 (1.56 g, 5 mol %) was added. The mixture was heated at reflux overnight. After cooling, the solvent was evaporated in vacuo and the residue was extracted with EA (2×150 ml). The combined extracts were washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was chromatographed (Hept-EA 2-1) to afford the title compound (7.2 g, 94% yield) as a white solid.
Reaction SMILES: [CH2:1]([N:19]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:20][CH2:21][CH2:22][NH2:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH:42](OC)=[O:43]>C(O)C>[CH2:24]([N:19]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:20][CH2:21][CH2:22][NH:23][CH:42]=[O:43])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]
Reactant: CCCCCCCCCCCCCCCCCCN(CCCN)CCCCCCCCCCCCCCCCCC
Reactant: COC=O
Solvent: CCO
Product: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)CCCNC=O
Reaction time: 8 h

Procedure:
A mixture of N,N-dioctadecyl-1,3-propanediamine (4.88 g.), ethanol (15 ml.) and methyl formate (35 ml.) is heated at reflux for one-half four. By-product methanol is distilled off and additional methyl formate (20 ml.) added. The mixture is refluxed for a half hour and allowed to stand overnight. It is taken to dryness under reduced pressure and the white solid residue recrystallized from ethyl acetate, Yield= quantitative: m.p. 42°-46° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[C:15]#[N:16])=[CH:4][CH:3]=1>[Ti](Cl)(Cl)(Cl)Cl.[OH-].[Na+]>[NH2:16][C:15]1[C:6]2[C:5]([N:8]=[C:9]3[C:10]=1[CH2:11][CH2:12][CH2:13][CH2:14]3)=[CH:4][CH:3]=[C:2]([F:1])[CH:7]=2
Reactant: N#CC1=C(Nc2ccc(F)cc2)CCCC1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1c2c(nc3ccc(F)cc13)CCCC2
Temperature: 140 °C

Procedure:
Under nitrogen, titanium tetrachloride (0.9 ml, 8.2 mmol) was added to the above enamine (Example 33) (1.5 g, 7.5 mmol) and the stirred mixture was heated at 140° C. for 1 hour. After cooling, 10M-sodium hydroxide solution (20 ml) was added and the mixture heated under reflux for 1 hour. After being allowed to cool, this mixture was filtered and the solids washed with dichloromethane. Any organics in the filtrate were also extracted into dichloromethane. All extracts were combined, dried (Na2SO4), filtered and the solvent evaporated. Kugelrohr distillation (175° C., 0.05 mmHg) gave the product as a pale yellow powder.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([N:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[CH:27]1[C:36]2[CH:35]=[CH:34][CH:33]=[C:32](B(O)O)[C:31]=2[CH:30]=[CH:29][N:28]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[CH:27]1[C:36]2[C:31](=[C:32]([C:2]3[N:3]=[C:4]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[C:5]4[S:10][C:9]([CH2:11][N:12]5[CH2:17][CH2:16][CH:15]([N:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]5)=[CH:8][C:6]=4[N:7]=3)[CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][N:28]=1
Reactant: OB(O)c1cccc2cnccc12
Reactant: CN(C)C1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CN(C)C1CCN(Cc2cc3nc(-c4cccc5cnccc45)nc(N4CCOCC4)c3s2)CC1
Temperature: 130 °C
Yield: 49.7 %

Procedure:
A sealable tube was charged with [1-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperidin-4-yl]-dimethyl-amine (0.630 g, 1.59 mmol), isoquinoline-5-boronic acid (0.331 g, 1.91 mmol), dichlorobis(triphenylphosphine) palladium(II) (0.056 g, 0.08 mmol), 1 N aqueous sodium carbonate solution (2.5 mL) and acetonitrile (7.5 mL). The vessel was evacuated and back-filled with argon three times then sealed and heated at 130° C. for 90 min. The reaction mixture was cooled, concentrated, redissolved in methanol and filtered through celite. The filtrates were concentrated then purified by chromatography (C-18 reverse phase column, 5 to 95% acetonitrile in water containing 0.1% TFA). The fractions containing the desired product were concentrated then dissolved in MeOH/dichloromethane, basified with solid sodium carbonate then filtered and concentrated to furnish 109 (0.386 g, 50%) as a white foam. MS m/e 489 [M+H]; 1H NMR (300 MHz, MeOH-d4) δ ppm 1.61-1.91 (m, 2 H) 1.99-2.15 (m, 2 H) 2.17-2.36 (m, 2 H) 2.88 (s, 6 H) 3.04-3.28 (m, 3 H) 3.73-3.87 (m, 4 H) 3.91 (s, 2 H) 3.96-4.07 (m, 4 H) 7.33 (s, 1 H) 7.69-7.83 (m, 1 H) 8.18 (d, J=8.3 Hz, 1 H) 8.30 (d, J=7.2 Hz, 1 H) 8.43 (d, J=6.4 Hz, 1 H) 8.57 (d, J=6.0 Hz, 1 H) 9.28 (s, 1 H)
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[N:9][S:10][C:6]=2[CH:5]=[C:4]([C:11]([NH:13][O:14][CH2:15][CH2:16][O:17]C=C)=[O:12])[C:3]=1[NH:20][C:21]1[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][C:22]=1[Cl:28].Cl.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:1][C:2]1[C:7]2[N:8]=[N:9][S:10][C:6]=2[CH:5]=[C:4]([C:11]([NH:13][O:14][CH2:15][CH2:16][OH:17])=[O:12])[C:3]=1[NH:20][C:21]1[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][C:22]=1[Cl:28]
Reactant: C=COCCONC(=O)c1cc2snnc2c(F)c1Nc1ccc(Br)cc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(NOCCO)c1cc2snnc2c(F)c1Nc1ccc(Br)cc1Cl
Reaction time: 1 h
Yield: 83.3 %

Procedure:
To a solution of compound 4-fluoro-5-((4-bromo-2-chlorophenyl)amino)-N-(2-(vinyloxy)ethoxy)benzo[d][1,2,3]thiadiazole-6-carboxamide (191 mg, 0.39 mmol) in CH2Cl2 (10 mL) was added 1.0 N HCl (aq., 1.5 mL, 1.5 mmol). After stirring for 1 h, the reaction mixture was neutralized with saturated NaHCO3 (aq.). The aqueous layer was washed with CH2Cl2 (10 mL×2). The combined organic layer was washed with water (30 mL×2) and brine (30 mL), dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (CH2Cl2/MeOH, 20:1, v/v) and gave the desired product as a yellow solid (150 mg, 66.5% yield for two steps). 1H NMR (400 MHz, CD3OD): δ 8.53 (s, 1H), 7.69 (s, 1H), 7.34 (d, 1H), 6.74 (m, 1H), 3.91 (m, 2H), 3.62 (m, 2H). MS APCI (+) m/z: 462.5 [M+H].
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH3:10])[N:5]=[C:4]([NH:18][C:19]2[CH:24]=[N:23][CH:22]=[CH:21][N:20]=2)[CH:3]=1.C([Sn](CCCC)(CCCC)[C:30]1[O:34][C:33]([Si:35]([CH:42]([CH3:44])[CH3:43])([CH:39]([CH3:41])[CH3:40])[CH:36]([CH3:38])[CH3:37])=[N:32][CH:31]=1)CCC.CN(C)C=O>O.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>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C@@H:9]([NH:8][C:6]2[N:5]=[C:4]([NH:18][C:19]3[CH:24]=[N:23][CH:22]=[CH:21][N:20]=3)[CH:3]=[C:2]([C:30]3[O:34][C:33]([Si:35]([CH:39]([CH3:41])[CH3:40])([CH:42]([CH3:44])[CH3:43])[CH:36]([CH3:37])[CH3:38])=[N:32][CH:31]=3)[N:7]=2)[CH3:10])=[CH:12][CH:13]=1
Reactant: C[C@H](Nc1nc(Cl)cc(Nc2cnccn2)n1)c1ccc(F)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc([Si](C(C)C)(C(C)C)C(C)C)o1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)[Si](c1ncc(-c2cc(Nc3cnccn3)nc(N[C@@H](C)c3ccc(F)cc3)n2)o1)(C(C)C)C(C)C
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 65.9 %

Procedure:
150 mg of (S)-6-chloro-N2-[1-(4-fluorophenyl)ethyl]-N4-(pyrazin-2-yl)pyrimidine-2,4-diamine (Example 9), 246 mg of 5-(tributylstannyl)-2-(triisopropylsilyl)oxazole (synthesized according to the method described in WO2007/17096), and 25 mg of tetrakis(triphenylphosphine)palladium were added in turn to 5 ml of degassed dimethylformamide, and then the mixture was stirred at 100° C. for 2.5 hours under argon atmosphere. 246 mg of 5-(tributylstannyl)-2-(triisopropylsilyl)oxazole was added thereto, and the mixture was further stirred for four hours. The reaction solution was diluted with water, and then subjected to extraction with ethyl acetate. The organic layer was washed in turn with water and brine, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 153 mg of (S)—N2-[1-(4-fluorophenyl)ethyl]-N4-(pyrazin-2-yl)-6-[2-(triisopropylsilyl)oxazol-5-yl]pyrimidine-2,4-diamine as pale orange oil.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Br[CH2:6][C:7]1([CH2:11][OH:12])[CH2:10][O:9][CH2:8]1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[N:1]([CH2:6][C:7]1([CH2:11][OH:12])[CH2:10][O:9][CH2:8]1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: OCC1(CBr)COC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Product: [N-]=[N+]=NCC1(CO)COC1
Yield: 47.9 %

Procedure:
A solution of sodium azide (2.07 g, 0.0317 mol), 3-bromomethyl-3-hydroxymethyloxetane (5.0 g, 0.028 mol) and tetra-n-butylammonium bromide (0.0978 g, 0.3 mmol) in water (14 mL) was heated for 3 h at 104°-107° C. The solution was cooled and was extracted with ethyl ether (5×20 mL). The combined extracts were evaporated to give 1.92 g (49%) of 3-azidomethyl-3-hydroxymethyloxetane, essentially pure by glc analysis, as an oil. NMR: 1H NMR: 3.70 (s, 2H), 3.84 (d, J=4.9 Hz, 2H), 4.44 (s, 4H); 13C NMR: 44.283, 53.852, 64.073, 76.227.