Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-].[CH:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([CH3:4])[CH3:3].C([Li])CCC.[CH:29]([C:31]1[CH:32]=[CH:33][C:34]([N:37]([CH2:55][C:56]2[CH:61]=[CH:60][C:59]([O:62][C:63]([F:66])([F:65])[F:64])=[CH:58][CH:57]=2)[CH2:38][CH2:39][C:40]2[CH:54]=[CH:53][C:43]([O:44][C:45]([CH3:52])([CH3:51])[C:46]([O:48][CH2:49][CH3:50])=[O:47])=[CH:42][CH:41]=2)=[N:35][CH:36]=1)=O>C1COCC1.CCCCCC>[CH3:52][C:45]([O:44][C:43]1[CH:53]=[CH:54][C:40]([CH2:39][CH2:38][N:37]([C:34]2[CH:33]=[CH:32][C:31]([CH:29]=[C:2]([CH3:4])[CH3:3])=[CH:36][N:35]=2)[CH2:55][C:56]2[CH:61]=[CH:60][C:59]([O:62][C:63]([F:65])([F:64])[F:66])=[CH:58][CH:57]=2)=[CH:41][CH:42]=1)([CH3:51])[C:46]([O:48][CH2:49][CH3:50])=[O:47]
Reactant: CC(C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCN(Cc2ccc(OC(F)(F)F)cc2)c2ccc(C=O)cn2)cc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)Oc1ccc(CCN(Cc2ccc(OC(F)(F)F)cc2)c2ccc(C=C(C)C)cn2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 33.1 %

Procedure:
A solution of isopropyltriphenylphosphonium bromide (326 mg; 0.75 mmol) in 1.5 ml of dry THF was treated in an ice bath, under nitrogen, with n-butyl lithium (0.425 ml of a 1.6M solution in hexane; 0.68 mmol), dropwise. After stirring for 15 minutes, this mixture was added, via syringe, into an ice-cold solution of ethyl 2-[4-(2-{(5-formylpyridin-2-yl)[4-(trifluoromethoxy)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate (200 mg; 0.38 mmol) in 2 ml of dry THF. After stirring at rt overnight, the reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with water and brine, dried over sodium sulfate, filtered and concentrated. Purification by radial chromatography using ethyl acetate-hexane mixtures (5–20% gradient) afforded ethyl 2-methyl-2-[4-(2-{[5-(2-methylprop-1-enyl)pyridin-2-yl][4-(trifluoromethoxy)benzyl]amino}ethyl)phenoxy]propanoate (70 mg; 33% yield).
Reaction SMILES: Cl.[C:2]1([C@@H:8]2[CH2:10][C@H:9]2[NH2:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:12]([C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1)#[N:13].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.O>[C:2]1([C@@H:8]2[CH2:10][C@H:9]2[NH:11][CH2:18][C:17]2[CH:20]=[CH:21][C:14]([C:12]#[N:13])=[CH:15][CH:16]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(C=O)cc1
Reactant: N[C@@H]1C[C@H]1c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: N#Cc1ccc(CN[C@@H]2C[C@H]2c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 18.8 %

Procedure:
A mixture of (trans)-2-phenylcyclopropanamine hydrochloride (0.25 g, 1.50 mmol) and 4-cyanobenzaldehyde (0.22 g, 1.65 mmol) in CH2Cl2 (8 mL) and water (0.5 mL) was vigorously stirred at room temperature for 10 min. Then, NaBH(OAc)3 (0.41 g, 1.95 mmol) was slowly added and stirring continued for 1.5 h. The reaction mixture was washed with an aqueous saturated solution of NaHCO3 (10 mL), the organic layer was dried over anhydrous Na2SO4, filtered and, after removal of the solvent, the residual oil was purified by column chromatography on silica gel (1% MeOH/CH2Cl2) affording 0.07 g of 4-({[(trans)-2-phenylcyclopropyl]amino}methyl)benzonitrile [Rf=0.6 (5% MeOH/CH2Cl2), colorless oil, 19% yield].
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]3[CH2:15][C:16]4[S:17][CH:18]=[CH:19][C:20]=4[C:13]=3[NH:12][N:11]=2)=[CH:6][CH:5]=1.[CH3:21][Si:22]([CH2:25][CH2:26][O:27][CH2:28]Cl)([CH3:24])[CH3:23]>C1COCC1>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]3[CH2:15][C:16]4[S:17][CH:18]=[CH:19][C:20]=4[C:13]=3[N:12]([CH2:28][O:27][CH2:26][CH2:25][Si:22]([CH3:24])([CH3:23])[CH3:21])[N:11]=2)=[CH:6][CH:5]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Brc1ccc(-c2n[nH]c3c2Cc2sccc2-3)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1nc(-c2ccc(Br)cc2)c2c1-c1ccsc1C2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69.1 %

Procedure:
At 0° C., NaH (60 percent, 0.48 g, 12 mmol) was added to a THF solution (15 mL) containing 6-(4-Bromo-phenyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (3.1 g, 9.7 mmol). Then SEM-Cl (90% pure, 2.4 mL, 12 mmol) was added to the reaction mixture and the resulting mixture was stirred at 0° C. for 30 min, warmed up to 80° C. and stirred for 2 hr. The solution was cooled to room temperature and poured into ice water. The resulting mixture was extracted with ethyl acetate. The organic layer was collected and washed with saturated aqueous NH4Cl, dried over MgSO4(s), and concentrated under reduced pressure. The oily residue was purified by gravity column chromatography (20% EtOAc in hexane) to give 6-(4-Bromo-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (3.0 g, 6.7 mmol) as brown solid in 69% yield.
Reaction SMILES: Br.Br[CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)=O.[C:12]1([CH2:18][CH2:19][NH:20][C:21]([NH2:23])=[S:22])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])(=O)C.[Na+].C(O)C>O>[C:12]1([CH2:18][CH2:19][NH:20][C:21]2[S:22][CH:3]=[C:4]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=3)[N:23]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(CBr)c1ccccn1
Reactant: NC(=S)NCCc1ccccc1
Agent: Br
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: c1ccc(CCNc2nc(-c3ccccn3)cs2)cc1
Yield: 67.6 %

Procedure:
A mixture of 2-bromo-1-pyridin-2-ylethanone hydrobromide (4.00 g), N-(2-phenylethyl)thiourea (3.60 g), sodium acetate (1.60 g) and ethanol (30 mL) was stirred with heating under reflux for 1 hr. After cooling, the reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:9-2:1 in volume ratio) to give the title compound (2.71 g, yield 48%) as a yellow oil.
Reaction SMILES: [C:1]([N:4]1[C:8](=[O:9])[CH2:7][C:6](=[O:10])[N:5]1[C:11]1[CH:16]=[C:15]([S:17][CH2:18][C:19]([F:22])([F:21])[F:20])[C:14]([CH3:23])=[CH:13][C:12]=1[F:24])(=[O:3])[CH3:2].CO.[CH2:27](OCC)C.C[Si](C=[N+]=[N-])(C)C>ClCCl>[C:1]([N:4]1[C:8](=[O:9])[CH:7]=[C:6]([O:10][CH3:27])[N:5]1[C:11]1[CH:16]=[C:15]([S:17][CH2:18][C:19]([F:20])([F:21])[F:22])[C:14]([CH3:23])=[CH:13][C:12]=1[F:24])(=[O:3])[CH3:2]
Reactant: CC(=O)N1C(=O)CC(=O)N1c1cc(SCC(F)(F)F)c(C)cc1F
Reactant: CCOCC
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: ClCCl
Solvent: CO
Product: COc1cc(=O)n(C(C)=O)n1-c1cc(SCC(F)(F)F)c(C)cc1F
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Then, 1.50 g of 1-acetyl-2-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}pyrazolidine-3,5-dione was dissolved in 50 mL of dichloromethane, 5 mL of methanol was added, and 2.1 mL of a diethyl ether solution (2.0 mol/L) of trimethylsilyldiazomethane was added under cooling with ice, followed by stirring at room temperature for 5 hours. Then, the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (developing solvent ethyl acetate:hexane=1:2) to obtain 0.69 g of 2-acetyl-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-5-methoxypyrazol-3-one.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[C:16]2[CH2:15][CH2:14][C:13]3[C:17]4[C:23]([NH:24][C:25]5[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]6[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=6)=[C:27]([Cl:40])[CH:26]=5)=[N:22][CH:21]=[N:20][C:18]=4[S:19][C:12]=3[C:11]=2[CH:10]=[N:9]1)(=O)=O.[NH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1.C(N(C(C)C)CC)(C)C>CC#N>[Cl:40][C:27]1[CH:26]=[C:25]([NH:24][C:23]2[N:22]=[CH:21][N:20]=[C:18]3[S:19][C:12]4[C:11]5[CH:10]=[N:9][N:8]([CH2:7][CH2:6][N:41]6[CH2:46][CH2:45][O:44][CH2:43][CH2:42]6)[C:16]=5[CH2:15][CH2:14][C:13]=4[C:17]=23)[CH:30]=[CH:29][C:28]=1[O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=1
Reactant: C1COCCN1
Reactant: CS(=O)(=O)OCCn1ncc2c1CCc1c-2sc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c12
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Fc1cccc(COc2ccc(Nc3ncnc4sc5c(c34)CCc3c-5cnn3CCN3CCOCC3)cc2Cl)c1
Temperature: 70 °C
Yield: 58.6 %

Procedure:
To 2 mL CH3CN were sequentially added 2-[6-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-4,5-dihydro-3H-pyrimido[5′,4′:4,5]thieno[2,3-e]indazol-3-yl]ethyl methanesulfonate (80 mg, 0.13 mmol), morpholine (18 mg, 0.20 mmol), and diisopropylethylamine (35 mg, 0.27 mmol). The reaction mixture was then heated up to 70° C. for 14 h. Upon cooling down, the crude was purified by HPLC to afford the desired product as an off-white solid (45 mg, 54%). 1H-NMR (DMSO-d6) δ 8.38 (s, 1H), 7.80 (d, 1H), 7.53 (s, 1H), 7.44 (dd, 1H), 7.38 (m, 1H), 7.24 (m, 2H), 7.04 (td, 1H), 6.98 (d, 1H), 6.95 (s, 1H), 5.13 (s, 2H), 4.18 (t, 2H), 3.63 (t, 4H), 3.35 (t, 2H), 3.14 (t, 2H), 2.78 (t, 2H), 2.45 (t, 4H); LCMS RT=2.72 min; [M+H]+=591.2.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[N:14]=[CH:13][C:12]([O:15][C:16]2[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:17]=2[C:18]([O:20][CH3:21])=[O:19])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:30]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]([CH3:30])[C:9]1[N:14]=[CH:13][C:12]([O:15][C:16]2[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:17]=2[C:18]([O:20][CH3:21])=[O:19])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: COC(=O)c1ccc(F)cc1Oc1ccc(NC(=O)OC(C)(C)C)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(F)cc1Oc1ccc(N(C)C(=O)OC(C)(C)C)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of EXAMPLE 377B (0.750 g) in N,N-dimethylformamide (5 mL) was added sodium hydride (0.091 g). The reaction was stirred for 30 minutes at room temperature and then iodomethane (0.142 mL) was added to the reaction and stirring was continued at room temperature for 2 hours. The reaction was quenched with water (25 mL) and extracted with ethyl acetate (75 mL). The organic layer was separated, washed with brine (50 mL), dried over magnesium sulfate, filtered, and concentrated. The residue was loaded onto silica gel (Reveleris 40 g) and eluted with a gradient of 5-15% ethyl acetate/hexanes over 30 minutes (flow=40 ml/min) to provide the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1F)[N:8]1[CH:14]([CH3:16])[S:15][C:7]1=[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:5]2=[O:22].Cl.[F:24][C:25]([F:35])([F:34])[C:26]([NH:28][C@H:29]1[CH2:33][CH2:32][NH:31][CH2:30]1)=[O:27].C1CCN2C(=NCCC2)CC1>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1[N:31]1[CH2:32][CH2:33][C@H:29]([NH:28][C:26](=[O:27])[C:25]([F:35])([F:34])[F:24])[CH2:30]1)[N:8]1[CH:14]([CH3:16])[S:15][C:7]1=[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:5]2=[O:22]
Reactant: CCOC(=O)c1c2n(c3c(F)c(F)c(F)cc3c1=O)C(C)S2
Reactant: O=C(N[C@H]1CCNC1)C(F)(F)F
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1c2n(c3c(F)c(N4CC[C@H](NC(=O)C(F)(F)F)C4)c(F)cc3c1=O)C(C)S2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 1.34 g of ethyl 6,7,8-trifluoro-1-methyl-4-oxo-1H,4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate, 2.66 g of (S)-3-trifluoroacetylaminopyrrolidine hydrochloride [[α]D20 -28.6° (c=1, MeOH)], 1.80 g of 1.8-diazabicyclo[5,4,0]-7-undecene and 30 ml of N,N-dimethylformamide was stirred at room temperature for 5 hours. The reaction mixture was concentrated in vacuo, and water was added to the residue. The precipitate was collected by filtration and was chromatographed on silica gel using chloroform-methanol (8:2) to give the desired compound, which was recrystallized from methanol to give 0.80 g of pale yellow needles, m.p. 219°-224° C.
Reaction SMILES: [CH3:1][N:2]([CH3:31])[C:3]1[CH:8]=[C:7]([C:9]2[O:13][N:12]=[C:11]([C:14]3[CH:25]=[C:24]([CH3:26])[C:17]([O:18][CH2:19][CH:20]([OH:23])[CH2:21]O)=[C:16]([CH2:27][CH3:28])[CH:15]=3)[N:10]=2)[CH:6]=[C:5]([CH2:29][CH3:30])[N:4]=1.CC[N:34](C(C)C)C(C)C.CS(Cl)(=O)=O.S([O-])(=O)(=O)C.N>C1COCC1.CO>[NH2:34][CH2:21][CH:20]([OH:23])[CH2:19][O:18][C:17]1[C:24]([CH3:26])=[CH:25][C:14]([C:11]2[N:10]=[C:9]([C:7]3[CH:6]=[C:5]([CH2:29][CH3:30])[N:4]=[C:3]([N:2]([CH3:31])[CH3:1])[CH:8]=3)[O:13][N:12]=2)=[CH:15][C:16]=1[CH2:27][CH3:28]
Reactant: CCc1cc(-c2nc(-c3cc(C)c(OCC(O)CO)c(CC)c3)no2)cc(N(C)C)n1
Reactant: CCN(C(C)C)C(C)C
Agent: CS(=O)(=O)Cl
Agent: CS(=O)(=O)[O-]
Agent: N
Solvent: C1CCOC1
Solvent: CO
Product: CCc1cc(-c2nc(-c3cc(C)c(OCC(O)CN)c(CC)c3)no2)cc(N(C)C)n1
Temperature: 65 °C
Reaction time: 16 h

Procedure:
To a solution of rac-3-{4-[5-(2-dimethylamino-6-ethyl-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl-phenoxy}-propane-1,2-diol (78 mg, 0.183 mmol) and DIPEA (47 mg, 0.365 mmol) in THF (5 mL) is added methanesulfonylchloride (23 mg, 0.201 mmol) at 0° C. The mixture is stirred at 0° C. for 3 h (Mesylate: LC-MS: tR=0.88 min; [M+1]+=505.12) before it is added to 7 N NH3 in methanol (10 mL). The mixture is stirred at 65° C. for 16 h. The solvent is removed in vacuo and the crude product is purified on prep. TLC plates with DCM containing 5% of methanol and 10% of 7 N NH3 in methanol to give rac-1-amino-3-{4-[5-(2-dimethylamino-6-ethyl-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl-phen-oxy}-propan-2-ol as a yellow resin. This material is dissolved in DCM and to the solution glycolic acid (29 mg, 0.375 mmol) and DIPEA (70 mg, 0.540 mmol) is added. The mixture is cooled to 0° C. before TBTU (71 mg, 0.221 mmol) is added. The mixture is stirred at 0° C. for 1 h before it is diluted with EA (100 mL), washed twice with sat. aq. NaHCO3-solution (25 mL), dried over Na2SO4, filtered and concentrated. The crude product is purified on prep. TLC plates with heptane:EA 7:3 to give rac-N-(3-{4-[5-(2-dimethylamino-6-ethyl-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl-phenoxy}-2-hydroxy-propyl)-2-hydroxy-acetamide (32 mg) as a yellow resin; LC-MS: tR=0.76 min; [M+1]+=484.19.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([Cl:10])[CH:3]=1.[Cl:11][C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[C:16]([O:18][CH3:19])[CH:17]=1>>[Cl:10][C:4]1[CH:3]=[C:2]([C:14]2[CH:15]=[C:16]([O:18][CH3:19])[CH:17]=[C:12]([Cl:11])[CH:13]=2)[CH:8]=[C:7]([F:9])[C:5]=1[NH2:6]
Reactant: COc1cc(Cl)cc(B(O)O)c1
Reactant: Nc1c(F)cc(Br)cc1Cl
Product: COc1cc(Cl)cc(-c2cc(F)c(N)c(Cl)c2)c1
Yield: 32.6 %

Procedure:
The title compound (41 mg) was prepared from 4-bromo-2-chloro-6-fluoroaniline (100 mg, 0.44 mmol) and 3-chloro-5-methoxyphenylboronic acid (107 mg, 0.57 mmol) as a pale-yellow solid.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[O:21][CH3:22].CN(C)[CH:25]=[O:26]>O1CCCC1>[Br:13][C:14]1[C:15]([O:21][CH3:22])=[C:16]([C:17]([F:20])=[CH:18][CH:19]=1)[CH:25]=[O:26]
Reactant: CN(C)C=O
Reactant: COc1cc(F)ccc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COc1c(Br)ccc(F)c1C=O
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 63.7 %

Procedure:
1.6 M Solution of n-butyllithium in hexanes (3.35 mL, 5.36 mmol) was added dropwise to a solution of N,N-diisopropylamine (0.960 mL, 6.85 mmol) in tetrahydrofuran (10 mL) at −78° C. and the resultant reaction mixture was stirred at −78° C. for 10 min. A solution of 1-bromo-4-fluoro-2-methoxybenzene (1.0 g, 4.9 mmol) in tetrahydrofuran (2 mL) was added to the reaction mixture dropwise at −78° C. and the reaction mixture was stirred at −78° C. for 1 h. N,N-dimethylformamide (0.412 mL, 5.32 mmol) was added to the reaction mixture dropwise at −78° C. and the reaction mixture was stirred at −78° C. for 1 h. Reaction mixture was quenched with saturated ammonium chloride, warmed to 20° C., and diluted with ether and 1M aqueous solution of HCl. Layers were separated and the aqueous layer was and re-extracted with ether. The combined organic layers were washed with brine, dried with magnesium sulfate, filtered, and concentrated in vacuo to give a crude residue. Purification by flash column chromatography (100% hexanes to 30% EtOAc/hexanes) gave the desired product (727 mg, 64%) as a yellow solid. LCMS calculated for C8H7BrFO2 (M+H)+: m/z=233.0, 235.0. found: 233.0, 234.8.
Reaction SMILES: Br[C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[CH:8]=[C:9]3[C:14](=[C:15]4[CH:20]=[CH:19][N:18]=[CH:17][C:16]=24)[N:13]=[CH:12][N:11]([C@H:21]2[CH2:26][CH2:25][CH2:24][CH2:23][C@@H:22]2[OH:27])[C:10]3=[O:28])=[CH:4][CH:3]=1.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.CC(C)([O-])C.[K+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[OH:27][C@H:22]1[CH2:23][CH2:24][CH2:25][CH2:26][C@@H:21]1[N:11]1[C:10](=[O:28])[C:9]2[C:14](=[C:15]3[CH:20]=[CH:19][N:18]=[CH:17][C:16]3=[C:7]([CH2:6][C:5]3[CH:29]=[CH:30][C:2]([N:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)=[CH:3][CH:4]=3)[CH:8]=2)[N:13]=[CH:12]1
Reactant: C1COCCN1
Reactant: O=c1c2cc(Cc3ccc(Br)cc3)c3cnccc3c2ncn1[C@H]1CCCC[C@@H]1O
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=c1c2cc(Cc3ccc(N4CCOCC4)cc3)c3cnccc3c2ncn1[C@H]1CCCC[C@@H]1O
Temperature: 100 °C

Procedure:
To a solution of 6-(4-bromobenzyl)-3-[(1S,2S)-2-hydroxycyclohexyl]pyrido[3,4-h]quinazolin-4(3H)-one (0.050 g, 0.11 mmol) in 1 mL of toluene under an atmosphere of nitrogen was added morpholine (0.038 g, 0.43 mmol), bis(tri-tert-butylphosphine)palladium(0) (2.8 mg, 0.0054 mmol), and potassium tert-butoxide (0.030 g, 0.27 mmol). The mixture was heated to 100° C. for 18 h, cooled to rt, and diluted with ethyl acetate. The organic solution was washed with saturated aqueous sodium bicarbonate and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via preparative reverse phase HPLC to provide the title compound that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 471.0 for [M+H]+: 1H NMR (400 MHz, d6-DMSO) δ 9.70 (s, 1H), 9.20 (d, J=6.1 Hz, 1H), 8.77 (d, J=6.2 Hz, 1H), 8.65 (s, 1H), 8.28 (s, 1H), 7.22 (d, J=8.6 Hz, 2H), 7.02 (d, J=8.6 Hz, 2H), 4.64 (s, 2H), 4.22 (br s, 1H), 3.84 (t, J=4.8 Hz, 4H), 3.18 (t, J=4.6 Hz, 4H), 2.20 (br s, 1H), 2.03-1.87 (m, 1H), 1.87-1.72 (m, 4H), 1.56-1.47 (m, 3H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:11]1(=[O:17])[O:16][C:14](=[O:15])[CH2:13][CH2:12]1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClCCl>[CH:9]1[C:10]2[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=2)[CH:6]=[CH:7][C:8]=1[C:11](=[O:17])[CH2:12][CH2:13][C:14]([OH:16])=[O:15]
Reactant: O=C1CCC(=O)O1
Reactant: c1ccc2ccccc2c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(O)CCC(=O)c1ccc2ccccc2c1
Yield: 59.3 %

Procedure:
To 900 ml of dichloromethane contained in a 3 liter, 3-neck flask equipped with a mechanical stirrer, drying tube and thermometer and surrounded by an ice water bath was added 290.0 g (2.26 moles) naphthalene. To the stirred suspension was added 145.2 g (1.44 moles) of succinic anhydride. A total of 400 g of aluminum chloride was then added in small increments over the next 41/2 hours while stirring and cooling in an ice water bath. The resulting amber brown-yellow reaction mixture was stirred at room temperature overnight. Next morning it was poured on crushed ice and acidified with conc. hydrochloric acid. The aqueous portion was decanted and the organic layer was filtered to collect white solids. The solids were washed with dichloromethane containing 20% hexanes and slurried in 700 ml of boiling ethyl acetate. After cooling in a cold water bath, the solids were collected by filtration and washed with fresh ethyl acetate. Then the solids were recrystallized from 500 ml of glacial acetic acid and dried under vacuum to give 195.0 g (59.4% yield) of 4-(2-naphthyl)4-oxobutyric acid as an off-white solid. M.P. 171°-175° C.; M/e 229; λmax 282 nm (7,260) in ethanol.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][N:8]2[CH:16]=[C:15]3[C:10]([CH:11]=[CH:12][C:13]([NH2:17])=[CH:14]3)=[N:9]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[O:18]([C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1>[O:18]([C:25]1[CH:26]=[CH:27][C:28]([NH:31][C:32]([NH:17][C:13]2[CH:12]=[CH:11][C:10]3[C:15](=[CH:16][N:8]([CH2:7][CH2:6][N:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)[N:9]=3)[CH:14]=2)=[O:33])=[CH:29][CH:30]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Nc1ccc2nn(CCN3CCCC3)cc2c1
Reactant: O=C=Nc1ccc(Oc2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Oc2ccccc2)cc1)Nc1ccc2nn(CCN3CCCC3)cc2c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A mixture of 2-(2-pyrrolidin-1-yl-ethyl)-2H-indazol-5-ylamine (0.100 g, 0.434 mmol), 4-phenoxyphenyl isocyanate (0.0917 g, 0.434 mmol) and 6 mL of THF was stirred at 50° C. for 1 hour. The mixture was cooled to room temperature and the solvents removed under vacuo. The resultant solid was triturated in ether and collected by filtration to provide the titled product. 1H NMR (300 MHz, DMSO-D6) δ ppm 1.66 (m, 4 H), 2.50 (m, 4 H), 2.96 (m, 2 H), 4.48 (t, J=5.93 Hz, 2 H), 6.97 (m, 4 H), 7.11 (m, 2 H), 7.36 (m, 2 H), 7.50 (m, 3 H), 7.88 (m, 1 H), 8.26 (s, 1 H), 8.54 (s, 1 H), 8.64 (s, 1 H); MS (DCI/NH3) m/z 441 [M+H]+.
Reaction SMILES: [OH:1]OS([O-])=O.[K+].[C:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[C:17]3[C:22]([S:23][CH2:24][CH3:25])=[C:21]([C:26]([NH2:28])=[O:27])[CH:20]=[N:19][N:18]3[CH:29]=2)=[CH:11][CH:10]=1)#[N:8]>O.CC(C)=O>[C:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[C:17]3[C:22]([S:23]([CH2:24][CH3:25])=[O:1])=[C:21]([C:26]([NH2:28])=[O:27])[CH:20]=[N:19][N:18]3[CH:29]=2)=[CH:11][CH:10]=1)#[N:8]
Reactant: O=S([O-])OO
Reactant: CCSc1c(C(N)=O)cnn2cc(-c3ccc(C#N)cc3)cc12
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCS(=O)c1c(C(N)=O)cnn2cc(-c3ccc(C#N)cc3)cc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of oxone (3.30 g, 5.37 mmol) in water (Volume: 40 mL) was added dropwise to a yellow suspension of impure 6-(4-cyanophenyl)-4-(ethylthio)pyrrolo[1,2-b]pyridazine-3-carboxamide (0.787 g, 2.441 mmol) in acetone (Ratio: 1.000, Volume: 40 mL) at rt. The resulting suspension was stirred at rt for 3 h. LCMS and HPLC showed that the starting material was consumed and the desired product was formed. The suspension was filtered, washed with water (2×10 mL), and dried under high vacuum to give a green-yellow solid. 1H NMR and HPLC indicated that the desired product was the major component, but the material was impure. The amount of the material is more than theoretical weight and the material is not totally soluble when making NMR solution, indicating the possible presence of inorganic salt. The material was treated with water (10 mL), stirred for 15 min, filtered, washed with H2O (2×5 mL), and dried under high vacuum to give a green-yellow solid (591.3 mg; 44% yield over 2 steps). 1H NMR, LCMS and HPLC indicated that the material was not pure, but the major component is consistent with the desired product. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.83 (1 H, d, J=1.54 Hz), 8.54 (1 H, s), 8.28 (1 H, br. s.), 8.07 (1 H, d, J=1.54 Hz), 8.03 (2 H, d, J=8.36 Hz), 7.89 (2 H, d, J=8.36 Hz), 7.80 (1 H, br. s.), 3.31-3.46 (2 H, m), 1.35 (3 H, t, J=7.48 Hz).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([O:10]O)=O)[CH:3]=1.[CH3:12][O:13][C:14]([C:16]1[N:20]([CH:21]2C3C(=CC=CC=3)C[CH2:23][C:22]2([CH3:32])[CH3:31])[CH:19]=[N:18][CH:17]=1)=[O:15].C(=O)([O-])O.[Na+]>C(Cl)Cl.O>[CH3:12][O:13][C:14]([C:16]1[N:20]([CH:21]2[C:3]3[C:4](=[CH:5][CH:6]=[CH:7][CH:2]=3)[C:8](=[O:10])[CH2:23][C:22]2([CH3:32])[CH3:31])[CH:19]=[N:18][CH:17]=1)=[O:15]
Reactant: COC(=O)c1cncn1C1c2ccccc2CCC1(C)C
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1cncn1C1c2ccccc2C(=O)CC1(C)C
Temperature: 25 °C
Reaction time: 72 h
Yield: 4 %

Procedure:
10.6 g of 3-chloroperbenzoic acid are added to a solution, cooled to 0° C., of 7.1 g of 1-(2,2-dimethyltetralin-1-yl)-5-imidazolecarboxylic acid methyl ester in 200 ml of methylene chloride. The mixture is stirred at room temperature for a further 72 hours. A solution of 7.5 g of sodium hydrogen carbonate in 100 ml of water is then added. The organic phase is separated off, washed with water, dried and concentrated by evaporation. The residue is purified by column chromatography on silica gel using chloroform as eluant. The product-containing fraction is again chromatographed on silica gel using a chloroform/methanol mixture (99.5:0.5). 0.3 g of 1-(2,2-dimethyl-4-oxotetralin-1-yl)-5-imidazolecarboxylic acid methyl ester is obtained in the form of a solid.