Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[NH:13][C:12]3[CH:11]=[N:10][CH:9]=[CH:8][C:7]=3[C:5]=2[CH:6]=1.Cl.[Cl:15]N1C(=O)CCC1=O.C([O-])([O-])=O.[K+].[K+]>O>[Cl:15][C:2]1[CH:3]=[C:4]2[C:5]([C:7]3[CH:8]=[CH:9][N:10]=[CH:11][C:12]=3[NH:13]2)=[CH:6][CH:1]=1
Reactant: c1ccc2c(c1)[nH]c1cnccc12
Reactant: O=C1CCC(=O)N1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Clc1ccc2c(c1)[nH]c1cnccc12
Temperature: 25 °C
Reaction time: 6 h
Yield: 85 %

Procedure:
To a solution of norharmane (2.0 g, 11.9 mmol) in water (89 ml) and 1M aqueous HCl (29.8 ml, 29.8 mmol) was added N-chlorosuccinimide (3.17 g, 23.8 mmol) portionwise. The resulting solution was stirred at RT for 6 h, and then at 0° C. to 5° C. for 12 h. The reaction was diluted with water (100 ml) and basified cautiously with solid K2CO3 (4.3 g). After stirring at RT for 1 h, the product was collected and washed with water. The crude product was refluxed in chloroform for 1 h and filtered after cooling to 15° C. to provide 2.05 g of 7-chloro-β-carboline.
Reaction SMILES: Cl[C:2]1[C:3](=[O:16])[NH:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[O:17]1[C:21]2=[CH:22][C:23]3[CH2:24][CH2:25][CH2:26][NH:27][C:28]=3[CH:29]=[C:20]2[O:19][CH2:18]1>CN1C(=O)CCC1>[O:17]1[C:21]2=[CH:22][C:23]3[CH2:24][CH2:25][CH2:26][N:27]([C:2]4[C:3](=[O:16])[NH:4][C:5]5[C:10]([N:11]=4)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=5)[C:28]=3[CH:29]=[C:20]2[O:19][CH2:18]1
Reactant: COC(=O)c1ccc2[nH]c(=O)c(Cl)nc2c1
Reactant: c1c2c(cc3c1OCO3)NCCC2
Solvent: CN1CCCC1=O
Product: COC(=O)c1ccc2[nH]c(=O)c(N3CCCc4cc5c(cc43)OCO5)nc2c1
Temperature: 140 °C
Reaction time: 1 h
Yield: 55.1 %

Procedure:
To a solution of methyl 3-chloro-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (161 mg, 0.67 mmol) in NMP (5 ml) was added the 2H,5H,6H,7H,8H-[1,3]dioxolo[4,5-g]quinoline (180 mg, 1.02 mmol) and the reaction was stirred for 1 h at 140° C. The reaction mixture was cooled to room temperature, and the product was precipitated by the addition of water and filtered off to afford methyl 3-[2H,5H,6H,7H,8H-[1,3]dioxolo[4,5-g]quinolin-5-yl]-2-oxo-1,2-dihydroquinoxaline-6-carboxylate as a brown solid (140 mg, 55%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:12])[C:9]([OH:11])=O)[CH:5]=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[O:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]1[O:25][CH2:26][CH2:27][C:28](=[N:30]O)[NH2:29]>>[F:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:8]([C:9]1[O:11][N:30]=[C:28]([CH2:27][CH2:26][O:25][CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][O:19]2)[N:29]=1)[CH3:12]
Reactant: CC(C(=O)O)c1ccc(-c2ccccc2)c(F)c1
Reactant: NC(CCOC1CCCCO1)=NO
Product: CC(c1ccc(-c2ccccc2)c(F)c1)c1nc(CCOC2CCCCO2)no1

Procedure:
According to substantially the same procedure as that of Example 1, treatment of 5.38 g of 2-(2-fluoro-4-biphenylyl)propionic acid with 4.56 g of 3-tetrahydropyranyloxypropionamidoxime yielded 5-(3-fluoro-4-phenyl-α-methylbenzyl)-3-(2-tetrahydropyranyloxyethyl)-1,2,4-oxadiazole.
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:15]2[C:14]([Cl:16])=[N:13][CH:12]=[N:11][C:10]=2[N:9]([CH:17]([CH3:19])[CH3:18])[CH:8]=1.CON(C)[C:23](=[O:34])[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-:32])=[O:31])[C:25]=1[CH3:33]>C(OCC)C>[Cl:16][C:14]1[C:15]2[C:7]([C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-:32])=[O:31])[C:25]=3[CH3:33])=[O:34])=[CH:8][N:9]([CH:17]([CH3:19])[CH3:18])[C:10]=2[N:11]=[CH:12][N:13]=1
Reactant: CON(C)C(=O)c1cccc([N+](=O)[O-])c1C
Reactant: CC(C)n1cc(Br)c2c(Cl)ncnc21
Agent: [Li]CCCC
Solvent: CCOCC
Product: Cc1c(C(=O)c2cn(C(C)C)c3ncnc(Cl)c23)cccc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 37.7 %

Procedure:
n-Butyllithium (2.5 M in hexanes, 14.3 mmol) was added dropwise to a suspension of 5-Bromo-4-chloro-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine (3.7 g, 13.6 mmol) and ethyl ether (75 mL), cooled to −78 C, and stirred for 1 h. N-Methoxy-2,N-dimethyl-3-nitro-benzamide (4.0 g, 17.7 mmol) was added to the reaction mixture, stirred for 2 h, quenched with aqueous NH4Cl (100 mL), and extracted with EtOAc (3×100 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated in vacuo. Purification by flash column chromatography (silica, 3:7 EtOAc:hexanes) provided the title compound as an yellow solid (1.84 g, 38%). MS: 357.5 (MH−); HPLC Rf: 2.0 min. (HPLC method 2); HPLC purity: 100%.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.Cl.[F:18][C:19]([F:53])([F:52])[C:20]1[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)[N:23]=[C:22]([C:36]2[CH:41]=[CH:40][N:39]=[C:38]([C:42]3[CH:43]=[C:44]([S:48](Cl)(=[O:50])=[O:49])[CH:45]=[CH:46][CH:47]=3)[CH:37]=2)[N:21]=1>C1COCC1>[CH2:1]([NH:9][S:48]([C:44]1[CH:45]=[CH:46][CH:47]=[C:42]([C:38]2[CH:37]=[C:36]([C:22]3[N:21]=[C:20]([C:19]([F:18])([F:52])[F:53])[CH:25]=[C:24]([C:26]4[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:28][CH:27]=4)[N:23]=3)[CH:41]=[CH:40][N:39]=2)[CH:43]=1)(=[O:49])=[O:50])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: NCCc1ccccc1
Reactant: O=S(=O)(Cl)c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)ccn2)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=S(=O)(NCCc1ccccc1)c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)ccn2)c1
Temperature: 0 °C
Yield: 90.7 %

Procedure:
To a cooled (ice-water bath) and stirred mixture of phenethylamine (0.36 g, 3.0 mmol), triethylamine (0.29 ml, 2.1 mmol) and THF (4 ml) was added drop wise a solution of 3-{4-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-pyridin-2-yl}-benzenesulfonyl chloride hydrochloride (example I.1) (0.58 g, 1.0 mmol) in THF (6 ml). The mixture was allowed to stir at room temperature for 16 h. Purification of the reaction mixture by flash chromatography on silica gel (ethyl acetate/heptane) and crystallization (dichloromethane/MeOH/hexane) yielded the title compound as a white solid (0.57 g, 97%). MS (ISP) 628.8 [(M+H)+]; mp 201° C.
Reaction SMILES: [CH:1]1([CH2:4][C:5]2([C:22]#[N:23])[CH2:10][CH2:9][C:8]([S:11][Si](C(C)C)(C(C)C)C(C)C)=[CH:7][CH2:6]2)[CH2:3][CH2:2]1.Br[CH2:25][CH:26]1[CH2:28][CH2:27]1.[F-].[Cs+]>CN(C)C=O.O>[CH:1]1([CH2:4][C:5]2([C:22]#[N:23])[CH2:10][CH2:9][C:8]([S:11][CH2:25][CH:26]3[CH2:28][CH2:27]3)=[CH:7][CH2:6]2)[CH2:2][CH2:3]1
Reactant: BrCC1CC1
Reactant: CC(C)[Si](SC1=CCC(C#N)(CC2CC2)CC1)(C(C)C)C(C)C
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Solvent: O
Product: N#CC1(CC2CC2)CC=C(SCC2CC2)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 73.9 %

Procedure:
To a solution of 1-cyclopropylmethyl-4-triisopropylsilanylsulfanylcyclohex-3-enecarbonitrile (20.5 g, 58.5 mmol) and (bromomethyl)cyclopropane (15.8 g, 117 mmol) in anhydrous N,N-dimethylformamide (65 ml) was added cesium fluoride (17.8 g, 117 mmol) and the mixture left to stir at ambient temperature for 15 hours. The mixture was diluted with water (500 ml) and extracted with diethyl ether (3×200 ml). The combined organic layer was washed with water (2×300 ml) and brine (200 ml), dried over anhydrous magnesium sulphate, filtered and evaporated to give an orange oil. The oil was purified by dry flash column chromatography on silica eluting with isohexane on a gradient of dichloromethane (10-40%). Collecting appropriate fractions gave a colourless oil (10.7 g, 74%). 1H NMR δ (ppm) (CDCl3): 5.53 (1H, t, J=1.6 Hz), 2.69-2.51 (4H, m), 2.30-2.11 (3H, m), 1.71-1.67 (1H, m), 1.60-1.45 (2H, m), 1.05-0.99 (1H, m), 0.92-0.88 (1H, m), 0.60-0.56 (4H, m), 0.26-0.18 (4H, m).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:44]=[C:45]([F:47])[CH:46]=1)[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2[NH:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]2)=[CH:20][C:19]=1[NH:37][CH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1)=[O:17].[C:48](Cl)(=[O:52])[O:49][CH2:50][CH3:51]>O1CCCC1.ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:44]=[C:45]([F:47])[CH:46]=1)[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([C:48]([O:49][CH2:50][CH3:51])=[O:52])[N:10]=[C:9]2[NH:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:20][C:19]=1[NH:37][CH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1)=[O:17]
Reactant: CCOC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)Nc3n[nH]c4ccc(Cc5cc(F)cc(F)c5)cc34)c(NC3CCOCC3)c2)CC1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOC(=O)n1nc(NC(=O)c2ccc(N3CCNCC3)cc2NC2CCOCC2)c2cc(Cc3cc(F)cc(F)c3)ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl 4-[4-{[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]carbamoyl}-3-(tetrahydro-2H-pyran-4-ylamino)phenyl]piperazine-1-carboxylate (0.013 mmol) in anhydrous tetrahydrofurane (1.0 mL) maintained at −50° C. under argon atmosphere a 1M solution of LiHMSD in anhydrous tetrahydrofurane (0.015 mL) was added. After stirring at that temperature for 5 minutes ethyl chlorocarbonate (0.002 mL, 1.63 mg, 0.015 mmol) was added. After 30 minutes at −50° C. the reaction was completed. After diluting with dichloromethane, the solution was washed with brine, dried over sodium sulphate and evaporated to dryness. The crude was dissolved in dichloromethane (1 mL), trifluoroacetic acid (0.1 mL) was added and the mixture was stirred at room temperature overnight. After diluting with dichloromethane, the solution was washed with sodium hydrogencarbonate, with brine, dried over sodium sulphate and evaporated to dryness.
Reaction SMILES: Cl[C:2]1[S:3][CH:4]=[C:5]([Cl:7])[N:6]=1.C(=O)([O-])[O-].[K+].[K+].[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>C(#N)C>[Cl:7][C:5]1[N:6]=[C:2]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[S:3][CH:4]=1
Reactant: C1COCCN1
Reactant: Clc1csc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Clc1csc(N2CCOCC2)n1
Temperature: 40 °C
Yield: 76.6 %

Procedure:
To a mixture of 2,4-dichlorothiazole (34 g, 0.22 mol) in acetonitrile (425 mL) add potassium carbonate (60.9 g, 0.44 mol) and then morpholine (21.2 mL, 0.225 mol) dropwise over 30 min. Reflux the mixture at 40° C. and then cool to 22° C. Filter the mixture and evaporate the filtrate. Triturate the residue with i-propyl alcohol (60 mL) at 22° C. for one hour. Filter the solids and dry under vacuum to a constant weight to afford the title compound (34.5 g, 76%). ES/MS m/z (35Cl) 205 (M+1)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[S:9]([C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([CH2:21][CH2:22][C:23]#[N:24])[C:16](=O)[C:15]12[O:30][CH2:29][CH2:28][CH2:27][O:26]1)(=[O:11])=[O:10].N.C1COCC1.[H][H]>[Ni].CCO>[CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[S:9]([C:12]1[CH:20]=[CH:19][C:18]2[N:17]3[CH2:21][CH2:22][CH2:23][N:24]=[C:16]3[C:15]3([O:26][CH2:27][CH2:28][CH2:29][O:30]3)[C:14]=2[CH:13]=1)(=[O:11])=[O:10]
Reactant: [H][H]
Reactant: COC[C@@H]1CCCN1S(=O)(=O)c1ccc2c(c1)C1(OCCCO1)C(=O)N2CCC#N
Agent: [Ni]
Agent: N
Solvent: CCO
Solvent: C1CCOC1
Product: COC[C@@H]1CCCN1S(=O)(=O)c1ccc2c(c1)C1(OCCCO1)C1=NCCCN12
Temperature: 135 °C
Yield: 14.5 %

Procedure:
A mixture of 3-[5′-{[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]sulfonyl}-2′-oxospiro[1,3-dioxane-2,3′-indol]-1′ (2′H)-yl]propanenitrile (4.48 g, 10.3 mmol), and wet Raney nickel (4.1 g) in 2M EtOH.NH3 (100 mL) and THF (100 mL) was hydrogenated in a Parr Hydrogenation Bottle (2L) at 45 lb/in2 hydrogen for 24 hours. The Raney nickel was removed by filtration through Sulka Floc. The filtrate was poured into a steel pressure vessel and heated to 135° C. for 51 hours. The reaction was cooled and the solvents were removed. The residue was taken up in CH2Cl2 and combined with silica gel. The solvent was removed and the adsorbate was flash chromatographed (Biotage KP silica gel, and step gradient of CH2Cl2/CH3OH/NH4OH (98.5/1.0/0.5-98/01.5/0.5)) to give the title compound as a white solid (0.63 g, 14.5% yield). Anal: Calc'd. for C20H27N3O5S: C, 56.99; H, 6.46; N, 9.97; Found: C, 56.80, H, 6.45, N, 9.87; NMR (400 MHz, DMSO-d6): consistent. MS: (ES+) m/z 422 [M+H]. Opt. Rotation: 94.1(calculated) at 25° C. in CH3OH (1% concentration), wavelength 589; m.p. 129-130°.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:29]/[O:30][CH3:31])/[C:8]([NH:10][CH:11]2[C:27](=[O:28])[N:13]3[C:14]([C:24]([O-:26])=[S:25])=[C:15]([CH:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+].[C:33]([O:39][CH2:40]I)(=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35]>>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:29]/[O:30][CH3:31])/[C:8]([NH:10][CH:11]2[C:27](=[O:28])[N:13]3[C:14]([C:24]([O:26][CH2:40][O:39][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])=[S:25])=[C:15]([CH:18]4[CH2:19][CH2:20][O:21][CH2:22][CH2:23]4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C(C([O-])=S)=C(C3CCOCC3)CS[C@H]12)c1csc(N)n1
Reactant: CC(C)(C)C(=O)OCI
Agent: [Na+]
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=S)OCOC(=O)C(C)(C)C)=C(C3CCOCC3)CS[C@H]12)c1csc(N)n1
Yield: 77.1 %

Procedure:
Sodium 7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-(tetrahydropyran-4-yl)thio-3-cephem-4-carboxylate (90 mg) was reacted with iodomethyl pivalate (84 mg), followed by purifying the reaction product in accordance with the procedure of Example 2, affording the titled compound (82 mg; 77%).
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH2:7][NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[F:23][C:24]1[CH:25]=[CH:26][C:27]([CH3:42])=[C:28]([CH:41]=1)[C:29]([NH:31][C:32]1[N:37]=[CH:36][C:35]([C:38](Cl)=[O:39])=[CH:34][CH:33]=1)=[O:30]>ClCCl>[CH:1]1[C:11]2[CH2:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH2:7][N:6]([C:38]([C:35]3[CH:34]=[CH:33][C:32]([NH:31][C:29](=[O:30])[C:28]4[CH:41]=[C:24]([F:23])[CH:25]=[CH:26][C:27]=4[CH3:42])=[N:37][CH:36]=3)=[O:39])[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)Cl)cn1
Reactant: c1ccc2c(c1)CNc1ccccc1C2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cn1

Procedure:
As described for Example 1, 6,11-dihydro-5H-dibenz[b,e]azepine is reacted in dichloromethane in the presence of triethylamine, with 6-[(5-fluoro-2-methylbenzoyl)amino]pyridine-3-carbonyl chloride to give the product as a solid.
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)(=O)C.O.[OH-].[Li+]>C1COCC1>[CH:11]1[C:10]2[N:9]([CH2:8][CH2:7][CH2:6][CH2:5][OH:4])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]=2[CH:14]=[CH:13][CH:12]=1
Reactant: CC(=O)OCCCCn1c2ccccc2c2ccccc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: OCCCCn1c2ccccc2c2ccccc21
Temperature: 80 °C
Reaction time: 12 h
Yield: 86.9 %

Procedure:
Compound 9 (35.1 g, 0.125 mol) and lithium hydroxide monohydrate (13.0 g, 0.31 mol) were dissolved in 200 mL THF. The reaction mixture was stirred at 80° C. for 12 hours. The mixture was filtered and the homogeneous solution was evaporated to give the crude product. The resulting product was purified by silica gel column chromatography (eluent: ethyl acetate:methylene chloride=1:10 v/v) to yield 26 g (86%) of 4-(9H-carbazol-9-yl)butan-1-ol (Compound 10).
Reaction SMILES: Br[C:2]1[C:11]([CH3:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:13])[CH:8]=2)[C:3]=1[OH:14].CCN(CC)CC>CCO.[Pd]>[CH3:12][C:11]1[CH:2]=[C:3]([OH:14])[C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([CH3:13])=[CH:6][CH:5]=2
Reactant: Cc1ccc2c(O)c(Br)c(C)cc2c1
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1ccc2c(O)cc(C)cc2c1
Reaction time: 6 h

Procedure:
A solution of 2-bromo-3,6-dimethylnaphthalen-1-ol (31.9 g, 127 mmol) in EtOH (1.3 L) was treated with Et3N (26.6 mL, 191 mmol) at room temperature. Pd/C (13.5 g, 12.7 mmol, 10% wt on C) was added in one portion and the atmosphere replaced with H2. The reaction was left under balloon pressure of H2 for 6 hours. After replacing the atmosphere with air, Celite (20 g) was added and the slurry stirred for 15 minutes before filtering the solution through a pad of Celite. The volatiles were removed in vacuo, and the residue was taken up in EtOAc/water (250 mL each). The organics were washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The resulting residue was purified on Isco silica gel column chromatography (0-35% EtOAc/hex) to afford 3,6-dimethylnaphthalen-1-ol. LCMS-ESI+ (m/z): [M+H]+ calcd for C12H13O: 173.1. found: 173.4.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[C:11](Cl)[N:10]=[C:9]([Cl:14])[CH:8]=2)[CH2:3][CH2:2]1.[OH:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.[H-].[Na+]>O1CCCC1>[Cl:14][C:9]1[CH:8]=[C:7]([N:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)[N:12]=[C:11]([O:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[N:10]=1
Reactant: Clc1cc(N2CCOCC2)nc(Cl)n1
Reactant: OCCN1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1cc(N2CCOCC2)nc(OCCN2CCOCC2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.4 %

Procedure:
6-Morpholino-2,4-dichloropyrimidine (4.6 g; 20 mmol) and 4-(2-hydroxyethyl)-morpholine (3.3 g; 25 mmol) were dissolved in tetrahydrofuran (200 mL), and chilled in an ice bath. To the solution was added sodium hydride (600 mg; 25 mmol), and it was stirred overnight at room temperature. The solvents were evaporated, and the solid was dissolved in dichloromethane (200 mL) which was then washed with water (2×10 mL). The organic layer was dried over magnesium sulfate, evaporated, and purified by column chromatography to give 4-[2-(4-Chloro-6-(morpholin-4-yl)-pyrimidin-2-yloxy)-ethyl]-morpholine (4.5 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][CH:20]=1)[C:7]([C:9]1[C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=[CH:11][N:10]=1)=[O:8])([O-:3])=[O:2].[N+](=[CH2:23])=[N-]>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][CH:20]=1)[C:7]([C:9]1[C:14]([C:15]([O:17][CH3:23])=[O:16])=[CH:13][CH:12]=[CH:11][N:10]=1)=[O:8])([O-:3])=[O:2]
Reactant: C=[N+]=[N-]
Reactant: O=C(O)c1cccnc1C(=O)c1cccc([N+](=O)[O-])c1
Solvent: ClCCl
Product: COC(=O)c1cccnc1C(=O)c1cccc([N+](=O)[O-])c1
Reaction time: 2 h

Procedure:
2-(3-Nitrobenzoyl)-3-carboxypyridine was dissolved in 20 ml of methylene chloride and the solution was cooled in an ice/water bath. Diazomethane (25 ml, 0.33M) was added to the solution and stirred for 2 hours. The solvent was removed and the residue chromatographed (methylene chloride) yielding 0.26 g of 2-(3-nitrobenzoyl)-3-methoxycarbonylpyridine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[NH:4][C:5]1[N:6]=[C:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19](=[O:22])[NH:20][CH3:21])[CH:14]=3)[CH:10]=[N:9][N:8]2[CH:23]=1.C1C(=O)N([Br:32])C(=O)C1>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:24])[NH:4][C:5]1[N:6]=[C:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19](=[O:22])[NH:20][CH3:21])[CH:14]=3)[CH:10]=[N:9][N:8]2[C:23]=1[Br:32]
Reactant: O=C1CCC(=O)N1Br
Reactant: CNC(=O)c1cccc(-c2cnn3cc(NC(=O)OC)nc3c2)c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CNC(=O)c1cccc(-c2cnn3c(Br)c(NC(=O)OC)nc3c2)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
[7-(3-Methylcarbamoyl-phenyl)-imidazo-[1,2-b]-pyridazin-2-yl]-carbamic acid methyl ester (1 eq, 0.167 mmol, 55 mg) is dissolved in DMF (1 ml) at 0° C. and NBS (1.1 eq, 0.184 mmol, 33.8 mg) is added. The reaction mixture is stirred for 1 h at 0° C. and then is diluted with EtOAc. The reaction is washed with NaHCO3 and brine, dried over MgSO4, filtered and evaporated to yield [3-Bromo-7-(3-Methylcarbamoyl-phenyl)-imidazo-[1,2-b]-pyridazin-2-yl]-carbamic acid methyl ester as a brown solid which did not require further purification; [M+H]+=406
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH2:9]Cl)=[CH:4][N:3]=1.[C:11]([N:14]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH:19]=[CH:18]C2N=C(Cl)C(F)=CC=2C1)(=[O:13])[CH3:12]>>[C:11]([N:14]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH:19]=[CH:18][C:6]2[N:7]=[C:2]([Cl:1])[N:3]=[CH:4][C:5]=2[CH2:9]1)(=[O:13])[CH3:12]
Reactant: ClCc1cnc(Cl)nc1Cl
Reactant: CC(=O)N1Cc2cc(F)c(Cl)nc2C=Cc2ccccc21
Product: CC(=O)N1Cc2cnc(Cl)nc2C=Cc2ccccc21
Yield: 46 %

Procedure:
Compound 64B (66.1 mg, 46%) was prepared from 64A (0.10 g, 0.5 mmol) and bb (82 mg, 0.5 mmol) in two steps by a route analogous to that used for the preparation of 1D. HPLC Rt=2.286 min; LCMS Found: (M+H)+=286.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH:9]([OH:11])[CH3:10].N1C=CN=C1.[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>CN(C=O)C.CCOCC>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH:9]([O:11][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH3:10]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(O)c1c(F)cccc1Cl
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(O[Si](C)(C)C(C)(C)C)c1c(F)cccc1Cl
Yield: 94.6 %

Procedure:
1-(2-Chloro-6-fluorophenyl)ethanol (8.5 g), imidazole (8.1 g) and t-butyldimethylsilylchloride (8.71 g) were stirred in DMF for 24 hours. The mixture was diluted with ether and washed with water, dried (anhydrous magnesium sulphate) and filtered. The filtrate was evaporated to dryness to give 1-(2-chloro-6-fluorophenyl)ethyl (t-butyldimethylsilyl)ether (13.3 g) as a clear oil, NMR (CDCl3) -0.1(s,3H), 0.05(s,3H), 0.85(s,9H), 1.5(d,3H), 5.4(q,1H), 6.9(m,1H), 7.05(m,2H).
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][C:4](=[O:12])[N:3]=1.Cl.Cl.[NH2:15][CH:16]([CH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)[C:17]([NH:19][C:20]1([C:27]#[N:28])[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]1)=[O:18]>>[C:27]([C:20]1([NH:19][C:17](=[O:18])[CH:16]([NH:15][C:2]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[O:5][C:4](=[O:12])[N:3]=2)[CH2:29][CH:30]2[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]2)[CH2:21][CH2:22][N:23]([CH3:26])[CH2:24][CH2:25]1)#[N:28]
Reactant: O=c1nc(Cl)c2ccccc2o1
Reactant: CN1CCC(C#N)(NC(=O)C(N)CC2CCCCC2)CC1
Agent: Cl
Product: CN1CCC(C#N)(NC(=O)C(CC2CCCCC2)Nc2nc(=O)oc3ccccc23)CC1

Procedure:
The title compound was prepared starting from 4-chloro-benzo[e][1,3]oxazin-2-one (prepared from benzo[e][1,3]oxazin-2,4-dione and PCl5 in refluxing toluene) and 2-amino-N-(4-cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-propionamide bis hydrochloride salt according to the procedure from Example 81. MS, m/z 438=M+1.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][NH:8]2)=[CH:4][CH:3]=1.[Cl:11][C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][N:13]=1.Cl>CC(O)C>[ClH:11].[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:4][CH:3]=1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: Brc1ccc2c(c1)NCC2
Agent: Cl
Solvent: CC(C)O
Product: COc1cc2ncnc(N3CCc4ccc(Br)cc43)c2cc1OC
Yield: 88 %

Procedure:
Utilizing a procedure analogous to that described in Example 1, this product was prepared in 88% yield from 6-bromo-indoline (1.1 eq.) and 4-chloro-6,7-dimethoxy-quinazoline (1.0 eq) in i-PrOH. The HCl salt was generated from the purified free base according to a procedure analogous to that given in Example 2. (M.P. 245°-248° C.(dec); LC-MS: 386, 388 (MH+); anal. RP18-HPLC RT: 4.95 min.).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][CH:17]([O:20][CH3:21])[O:18][CH3:19].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[CH3:19][O:18][CH:17]([O:20][CH3:21])[CH2:16][S:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1
Reactant: Oc1ccc(S)cc1
Reactant: COC(CBr)OC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(CSc1ccc(O)cc1)OC
Reaction time: 2 h
Yield: 115.8 %

Procedure:
To a solution of 4-mercaptophenol (3.81 g) in DMF (80 ml) is added potassium carbonate (8.3 g) and 1-bromo-2,2-dimethoxyethane (3.55 g). The mixture is stirred at 70° under nitrogen for 2 hr, then cooled and poured into 0.1N citric acid (600 ml). The product is extracted with ether, and the ether extracts are concentrated and distilled in vacuo (140°-145°, 0.01 torr), to provide 4-((2,2-dimethoxyethyl)thio)phenol as a pale yellow viscous oil (5.21 g, 81%).