Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:20][C:19]2[S:18][C:17]3[N:16]=[CH:15][N:14]=[C:13]([NH:21][CH:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:23][OH:24])[C:12]=3[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(=O)(O)[O-].[Na+]>ClCCl>[C:25]1([CH:22]([NH:21][C:13]2[C:12]3[C:11]4[CH2:10][CH2:9][NH:8][CH2:20][C:19]=4[S:18][C:17]=3[N:16]=[CH:15][N:14]=2)[CH2:23][OH:24])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(sc3ncnc(NC(CO)c4ccccc4)c23)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: OCC(Nc1ncnc2sc3c(c12)CCNC3)c1ccccc1
Reaction time: 4 h
Yield: 76.2 %

Procedure:
To a mixture of 4-(2-hydroxy-1-phenyl-ethylamino)-5,8-dihydro-6H-9-thia-1,3,7-triaza-fluorene-7-carboxylic acid tert-butyl ester (0.6 g) in dichloromethane (2 mL) at room temperature was added TFA (1 mL). The reaction mixture was stirred for 4 h, then neutralized by slow addition of sodium bicarbonate solution. The precipitate formed was collected by filtration and washed with water then dichloromethane to give the title compound (0.350 g, 76%). 1H NMR (400 MHz, CDCl3): δ 8.28 (s, 1H), 7.26-7.38 (m, 5H), 6.04 (d, 1H, J=6.4 Hz), 5.38 (d, 1H, J=4.8 Hz), 4.01 (d, 2H, J=7.6 Hz), 3.99 (d, 2H, J=3.2 Hz), 3.20 (t, 2H, J=4.4 Hz), 2.84-3.04 (m, 2H). LC-MS (ESI) m/z 327.1 (M+H).
Reaction SMILES: Br.[NH2:2][CH:3]1[CH2:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([Cl:16])[CH:10]=2)[C:4]1=[O:17].C(N(CC)CC)C.[C:25](Cl)(=O)/[CH:26]=[CH:27]/[CH3:28]>O1CCCC1>[CH2:25]([NH:2][CH:3]1[CH2:7][C:6](=[O:8])[N:5]([C:9]2[CH:10]=[C:11]([Cl:16])[CH:12]=[C:13]([Cl:15])[CH:14]=2)[C:4]1=[O:17])[CH:26]=[CH:27][CH3:28]
Reactant: C/C=C/C(=O)Cl
Reactant: NC1CC(=O)N(c2cc(Cl)cc(Cl)c2)C1=O
Agent: Br
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC=CCNC1CC(=O)N(c2cc(Cl)cc(Cl)c2)C1=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To 13.6 g of 3-amino-1-(3,5-dichlorophenyl)pyrrolidine-2,5-dione hydrobromide in 100 ml of tetrahydrofurane are added, at 0° C., 12 ml of triethylamine. Then 6 ml of crotonyl chloride are added dropwise and the reaction mixture is stirred for a further 12 hours at room temperature. The solution is then filtered and the filtrate is concentrated. The residue is purified by column chromatography over silica gel with dichloromethane/petroleum ether (85:15) as eluant. The solvent is removed and the residue is recrystallised from ethyl acetate/petroleum ether. The colourless crystals melt at 107°-110° C.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[C:5]([Cl:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:15][C:16]1[CH:21]=[CH:20][N:19]=[C:18]([Sn](CCCC)(CCCC)CCCC)[CH:17]=1>C1(C)C=CC=CC=1>[Cl:13][C:10]1[C:9]2[C:4](=[C:5]([Cl:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([C:18]2[CH:17]=[C:16]([CH3:15])[CH:21]=[CH:20][N:19]=2)[C:11]=1[CH3:12]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(C)ccn1
Reactant: Cc1c(Cl)nc2c(Cl)cccc2c1Cl
Solvent: Cc1ccccc1
Product: Cc1ccnc(-c2nc3c(Cl)cccc3c(Cl)c2C)c1

Procedure:
The Stille coupled product was prepared according to Procedure E using 2,4,8-trichloro-3-methylquinoline (0.15 g, 0.61 mmol), 4-methyl-2-(tributylstannyl)-pyridine (0.26 g, 0.67 mmol), palladium tetrakistriphenylphosphine (0.070 g, 0.06 mmol) in toluene (1.2 mL) to give 4,8-dichloro-3-methyl-2-(4-methylpyridin-2-yl)quinoline as a light yellow solid. Mass Spectrum (ESI) m/e=303.0 (M+1).
Reaction SMILES: [N+](C1C=CC(C([O:10][C@@:11]([C:18]2[N:19]=[N:20][N:21]([CH2:23][C:24]3[CH:33]=[C:32]4[C:27]([C:28](Cl)=[CH:29][C:30]([C:34]#[N:35])=[N:31]4)=[CH:26][CH:25]=3)[CH:22]=2)([C:14]([F:17])([F:16])[F:15])[CH2:12][CH3:13])=O)=CC=1)([O-])=O.[Cl:39][C:40]1[CH:41]=[C:42](B(O)O)[CH:43]=[C:44]([Cl:46])[CH:45]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[Cl:39][C:40]1[CH:41]=[C:42]([C:28]2[C:27]3[C:32](=[CH:33][C:24]([CH2:23][N:21]4[CH:22]=[C:18]([C@:11]([OH:10])([C:14]([F:16])([F:17])[F:15])[CH2:12][CH3:13])[N:19]=[N:20]4)=[CH:25][CH:26]=3)[N:31]=[C:30]([C:34]#[N:35])[CH:29]=2)[CH:43]=[C:44]([Cl:46])[CH:45]=1
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Reactant: CC[C@](OC(=O)c1ccc([N+](=O)[O-])cc1)(c1cn(Cc2ccc3c(Cl)cc(C#N)nc3c2)nn1)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC[C@](O)(c1cn(Cc2ccc3c(-c4cc(Cl)cc(Cl)c4)cc(C#N)nc3c2)nn1)C(F)(F)F
Reaction time: 1.5 h

Procedure:
To a solution of (S)-1-{1-[(4-chloro-2-cyanoquinolin-7-yl)methyl]-1H-1,2,3-triazol-4-yl}-1-(trifluoromethyl)propyl 4-nitrobenzoate (150 mg, 0.28 mmol) in DME (3 mL) was added tetrakis(triphenylphosphine)palladium (16 mg, 0.014 mmol), 3,5-dichlorophenylboronic acid (80 mg, 0.42 mmol) and aq. 2M Na2CO3 (0.42 mL, 0.84 mmol). After 1.5 h at 100° C., the reaction was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduce pressure. To this crude product was added THF (4 mL) and LiOH IM (1.4 mL, 1.4 mmol). After 2 h at rt, the reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduce pressure. Purification on silica gel (eluting with EtOAc/hexanes, 3:7) gave the title compound. MS (+ESI): 506 (M+H)+.
Reaction SMILES: [OH:1][C@:2]1([C:20](OC)=[O:21])[CH2:11][C:10]2([S:15][CH2:14][CH2:13][S:12]2)[C:9]2[C:4](=[C:5]([O:18][CH3:19])[CH:6]=[CH:7][C:8]=2[O:16][CH3:17])[CH2:3]1.[BH4-].[Na+]>O1CCCC1>[OH:1][C@@:2]1([CH2:20][OH:21])[CH2:3][C:4]2[C:9](=[C:8]([O:16][CH3:17])[CH:7]=[CH:6][C:5]=2[O:18][CH3:19])[C:10]2([S:12][CH2:13][CH2:14][S:15]2)[CH2:11]1
Reactant: COC(=O)[C@]1(O)Cc2c(OC)ccc(OC)c2C2(C1)SCCS2
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(OC)c2c1C[C@@](O)(CO)CC21SCCS1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
2.0 g of methyl (S)-1',2',3',4'-tetrahydro-2'-hydroxy-5',8'-dimethoxyspiro[1,3-dithiolane-2,4'-naphthalene]-2'-carboxylate were dissolved in 200 ml of dry tetrahydrofuran and 2.0 g of sodium borohydride were added to the solution. The resulting mixture was stirred at room temperature under nitrogen for 20 hours. The solvent was removed by evaporation and 100 ml of 10% ammonium chloride solution were added. The mixture was extracted with three 30 ml portions of ethyl acetate. The extracts were dried and evaporated to give (S)-1',2',3',4'-tetrahydro-3'-hydroxy-3'-hydroxymethyl-5',8'-dimethoxyspiro[1,3-dithiolane-2,1'-naphthalene] in the form of a colourless gum which was used directly in the next step.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][NH:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[NH:25][C:24](=[O:29])[CH:23]=[CH:22]3)[CH2:7][CH2:6]1.[CH:30]1([CH2:36][S:37](Cl)(=[O:39])=[O:38])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.C(N(CC)CC)C>ClCCl>[CH3:1][O:2][CH2:3][O:4][CH:5]1[CH2:6][CH2:7][N:8]([CH2:11][CH2:12][N:13]([CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[NH:25][C:24](=[O:29])[CH:23]=[CH:22]3)[S:37]([CH2:36][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)(=[O:39])=[O:38])[CH2:9][CH2:10]1
Reactant: COCOC1CCN(CCNCCCCOc2ccc3[nH]c(=O)ccc3c2)CC1
Reactant: O=S(=O)(Cl)CC1CCCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCOC1CCN(CCN(CCCCOc2ccc3[nH]c(=O)ccc3c2)S(=O)(=O)CC2CCCCC2)CC1
Yield: 17.8 %

Procedure:
A solution of 2.5 g of 6-{4-[2-(4-methoxymethoxy-1-piperidinyl)ethyl]aminobutoxy}carbostyril, 1.5 g of cyclohexylmethanesulfonyl chloride and 1.35 ml of triethylamine in 30 ml of dichloromethane was stirred at room temperature for 16 hours. The reaction mixture was washed with water and dried with magnesium sulfate. The solvent was removed by distillation. The resulting residue was purified by a silica gel column chromatography (eluant: 3% methanol/chloroform)-to obtain 620 mg of 6-[4-{N-[2-(4-methoxymethoxy-1-piperidinyl)ethyl]-N-cyclohexylmethylsulfonylamino}butoxy]carbostyril.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[OH:15][CH2:16][C@@H:17]1[O:21][C:20](=[O:22])[N:19]([C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH2:30][CH2:31][O:32][CH2:33][CH:34]=3)=[C:25]([F:35])[CH:24]=2)[CH2:18]1.O[C:37]1[CH:41]=[CH:40][O:39][N:38]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[O:39]1[CH:40]=[CH:41][C:37]([O:15][CH2:16][C@@H:17]2[O:21][C:20](=[O:22])[N:19]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH2:30][CH2:31][O:32][CH2:33][CH:34]=4)=[C:25]([F:35])[CH:24]=3)[CH2:18]2)=[N:38]1
Reactant: Oc1ccon1
Reactant: O=C1O[C@@H](CO)CN1c1ccc(C2=CCOCC2)c(F)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1O[C@@H](COc2ccon2)CN1c1ccc(C2=CCOCC2)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.6 %

Procedure:
Diisopropylazodicarboxylate (248 mg, 1.22 mmol) was added dropwise, at ambient temperature, to a stirred solution of 5(R)-hydroxymethyl-3-(3-fluoro-4-(3,6-dihydro-(2H)-pyran-4-yl)phenyl)oxazolidin-2-one (International Patent Application Publication WO 97/09328) (300 mg, 1.02 mmol), 3-hydroxyisoxazole (104 mg, 1.22 mmol) and triphenylphosphine (340 mg, 1.30 mmol) in THF (8.0 ml). The resulting solution was stirred at ambient temperature for 30 minutes before evaporating the solvent to give an oil which was purified by flash chromatography (Merck 9385 silica, EtOAc/iso-hexane (7:3) eluant) to give the title product (219 mg, 59%) as a crystalline solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C@@H:8]([CH2:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[NH:27][CH:26]=1)[CH2:9][O:10][C:11]1[CH:12]=[N:13][CH:14]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[CH:18]=2)[CH:16]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:36]1[CH:41]=[CH:40][N:39]=[C:38]([NH2:42])[N:37]=1>CCO>[C:1]([O:5][C:6](=[O:34])[NH:7][C@@H:8]([CH2:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[NH:27][CH:26]=1)[CH2:9][O:10][C:11]1[CH:12]=[N:13][CH:14]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:36]3[CH:41]=[CH:40][N:39]=[C:38]([NH2:42])[N:37]=3)[CH:18]=2)[CH:16]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H](COc1cncc(-c2cccc(N)c2)c1)Cc1c[nH]c2ccccc12
Reactant: Nc1nccc(Cl)n1
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@H](COc1cncc(-c2cccc(Nc3ccnc(N)n3)c2)c1)Cc1c[nH]c2ccccc12
Temperature: 80 °C

Procedure:
A mixture of Example 121A (0.07 g, 0.153 mmol) and 4-chloro-2-pyrimidinylamine (0.021 g, 0.163 mmol) was dissolved in EtOH (1 mL). The mixture was heated to 80° C. overnight then cooled and evaporated. The product was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:21])[CH2:17][C:18]([OH:20])=O)=[CH:11][C:10]=2[F:22])[CH:5]=[CH:4][N:3]=1.[ClH:23].[NH2:24][C@@H:25]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:26]([NH2:28])=[O:27]>>[ClH:23].[NH2:28][C:26](=[O:27])[C@@H:25]([NH:24][C:18](=[O:20])[CH2:17][C:16]([NH:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH2:1])[CH:7]=2)=[C:10]([F:22])[CH:11]=1)=[O:21])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: Nc1cc(Oc2ccc(NC(=O)CC(=O)O)cc2F)ccn1
Reactant: NC(=O)[C@@H](N)c1ccccc1
Agent: Cl
Product: NC(=O)[C@@H](NC(=O)CC(=O)Nc1ccc(Oc2ccnc(N)c2)c(F)c1)c1ccccc1
Yield: 52.8 %

Procedure:
3-(4-(2-Aminopyridin-4-yloxy)-3-fluorophenylamino)-3-oxopropanoic acid (30 mg, 0.10 mmol) was coupled with (S)-2-amino-2-phenylacetamide hydrochloride (Acros, 28 mg, 0.15 mmol) in a manner similar to that which is described in Step C of Example 1 to give (S)—N1-(2-amino-2-oxo-1-phenylethyl)-N3-(4-(2-aminopyridin-4-yloxy)-3-fluorophenyl)malonamide, hydrochloride salt (25 mg, 53% yield). 1H NMR (DMSO-d6) δ 10.68 (s, 1H), 8.80 (d, 1H, J=8.0 Hz), 7.96 (d, 1H, J=7.5 Hz), 7.77-7.90 (m, 4H), 7.20-7.45 (m, 8H), 6.70 (m, 1H), 6.12 (s, 1H), 5.39 (d, 1H, J=7.5 Hz), 3.48 (d, 1H, J=15.0 Hz), 3.41 (d, 1H, J=15.0 Hz); MS (ESI+) m/z 438.26 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([C:6]1[O:10][N:9]=[C:8]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[N:22]=[C:23]4[N:27]([CH:28]=3)[C:26]3[CH:29]=[CH:30][C:31]([O:33][CH2:34][CH2:35][N:36]5[CH2:41][CH2:40][O:39][CH2:38][CH2:37]5)=[CH:32][C:25]=3[S:24]4)=[CH:17][CH:16]=2)=[O:13])[CH:7]=1)([CH3:5])[CH:3]=[O:4].S(N)(=O)(=O)[OH:43].Cl([O-])=O.[Na+].[OH-].[Na+]>C(O)(=O)C.O>[CH3:5][C:2]([C:6]1[O:10][N:9]=[C:8]([NH:11][C:12]([NH:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[N:22]=[C:23]4[N:27]([CH:28]=3)[C:26]3[CH:29]=[CH:30][C:31]([O:33][CH2:34][CH2:35][N:36]5[CH2:37][CH2:38][O:39][CH2:40][CH2:41]5)=[CH:32][C:25]=3[S:24]4)=[CH:19][CH:20]=2)=[O:13])[CH:7]=1)([CH3:1])[C:3]([OH:43])=[O:4]
Reactant: NS(=O)(=O)O
Reactant: CC(C)(C=O)c1cc(NC(=O)Nc2ccc(-c3cn4c(n3)sc3cc(OCCN5CCOCC5)ccc34)cc2)no1
Agent: [Na+]
Agent: [O-][Cl+][O-]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C(=O)O)c1cc(NC(=O)Nc2ccc(-c3cn4c(n3)sc3cc(OCCN5CCOCC5)ccc34)cc2)no1
Temperature: 25 °C

Procedure:
Alternatively final compound 2-methyl-2-[3-(3-{4-[7-(2-morpholin-4-yl-ethoxy)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-ureido)-isoxazol-5-yl]-propionic acid (I-5) is prepared by following a general procedure given in US 2005/0070549 A1. To a stirred solution of 1-[5-(1,1-dimethyl-2-oxo-ethyl)-isoxazol-3-yl]-3-{4-[7-(2-morpholin-4-yl-ethoxy)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-urea (I-4a) (1 equivalent) in a mixture of acetic acid and water at rt is added a solution of amidosulfuric acid (1.5 equivalents) and sodium chlorite (1.5 equivalents) in water, and the mixture is stirred at rt until the reaction is substantially complete as monitored by LCMS or TLC. The mixture is neutralized with 30% aq sodium hydroxide and partitioned between water and either dichloromethane or a mixture of isopropanol and dichloromethane. The separated aqueous layer is further extracted with dichloromethane or a mixture of isopropanol and dichloromethane, and the combined organic layers are washed with water or brine dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by preparative reverse-phase HPLC or silica gel flash chromatography to afford 2-methyl-2-[3-(3-{4-[7-(2-morpholin-4-yl-ethoxy)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-ureido)-isoxazol-5-yl]-propionic acid (I-5).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH:8](Br)Br)=[N:4][CH:5]=[CH:6][CH:7]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)[OH:14]>N1CCOCC1.CCOC(C)=O>[Br:1][C:2]1[C:3]([CH:8]=[O:14])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Brc1cccnc1C(Br)Br
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1COCCN1
Solvent: CCOC(C)=O
Product: O=Cc1ncccc1Br
Temperature: 60 °C

Procedure:
A suspension of 3-bromo-2-dibromomethyl-pyridine (10.0 g, 30.32 mmole) in morpholine (30.0 mL) was heated to 60° C. for 1 h. The reaction mixture was cooled to rt and diluted with EtOAc (200 mL). The pH was adjusted to 4.0 by adding citric acid (40.0 g). The reaction mixture was then extracted with EtOAc (3×200 mL) and the combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography using silica (100-200 mesh) using 3% EtOAc in hexane as eluent to give 3-bromo-pyridine-2-carbaldehyde. 1H-NMR (400 MHz, CDCl3): δ 10.23 (s, 1H), 8.74-8.76 (d, 1H), 8.02-8.04 (d, 1H), 7.26-7.38 (t, 1H).
Reaction SMILES: [CH:1]([N-:4]C(C)C)(C)[CH3:2].[Li+].[CH3:9][C:10]1([C:13]([O:15]C)=O)[CH2:12][CH2:11]1.CC#N>C1COCC1>[CH3:9][C:10]1([C:13](=[O:15])[CH2:2][C:1]#[N:4])[CH2:12][CH2:11]1
Reactant: COC(=O)C1(C)CC1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC#N
Product: CC1(C(=O)CC#N)CC1
Temperature: 25 °C
Yield: 72.8 %

Procedure:
Combine lithium diisopropylamide (LDA, 2.0 M/heptanes; Aldrich; 2.2 eq, 88 mmol, 44 mL) with THF (1.5 mL/mmol; 60 mL) and cool to −78° C. Combine methyl 1-methylcyclopropane carboxylate (TCI US; 4.56 g, 40 mmol) and CH3CN (4.20 mL, 80 mmol) in THF (10 mL) and add slowly with stirring. Stir the mixture at −65 to −78° C. for 1 hour, then remove the bath and warm the mixture to room temperature. Concentrate the reaction mixture to a slurry under reduced pressure. Add hexanes (150 mL) to form a precipitate from the slurry. Collect the solid by vacuum filtration and wash with hexanes (2×50 mL). Replace the catch flask with a clean one, and dissolve the solid on the frit in 50 mL 2.5 M HCl and collect in the flask. Rinse with 20 mL 2.5 M HCl followed by 200 mL Et2O. Separate the layers in the filtrate and extract the acidic phase with Et2O (150 mL). Combine the Et2O organic phases, dry with MgSO4, filter and concentrate under reduced pressure to yield 3-(1-Methyl-cyclopropyl)-3-oxo-propionitrile as a clear amber oil (3.58 g, 29.1 mmol, 73%). Use without purification in reaction with tolylhydrazine hydrochloride (5.23 g, 33.0 mmol) and ethanol (2 mL/mmol) at reflux for 20 hr. Cool the reaction mixture to room temperature and concentrate under reduced pressure. Dilute the residue with ethyl acetate (250 mL) and wash with water (2×60 mL), saturated aq. NaHCO3 (60 mL) and saturated aq. sodium chloride (60 mL). Dry the organic phase with MgSO4, filter and concentrate by rotary evaporation. Subject residue to silica gel chromatography eluting with a gradient of ethyl acetate and hexane to provide 5-(1-methyl-cyclopropyl)-2-p-tolyl-2H-pyrazol-3-ylamine (4.2238 g, 18.5 mmol, 46%). LCMS (ES+): m/z=228.2 [M+H].
Reaction SMILES: [CH:1](=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]2[C:22](=[O:23])[C:21]([CH3:25])([CH3:24])[CH2:20][O:19]2)=[C:13]([Cl:26])[CH:12]=1.O>C(O)C>[Cl:26][C:13]1[CH2:12][C:11](=[N:10][CH2:1][C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[OH:4])[CH:16]=[CH:15][C:14]=1[CH2:17][N:18]1[C:22](=[O:23])[C:21]([CH3:25])([CH3:24])[CH2:20][O:19]1
Reactant: CC1(C)CON(Cc2ccc(N)cc2Cl)C1=O
Reactant: O=Cc1ccccc1O
Solvent: CCO
Solvent: O
Product: CC1(C)CON(CC2=C(Cl)CC(=NCc3ccccc3O)C=C2)C1=O

Procedure:
A warmed solution of 0.48 gram (0.004 mole) of salicylaldehyde in 35 mL of ethanol was stirred, and 1.0 gram (0.004 mole) of 2-[(4-amino-2-chlorophenyl)methyl]-4,4-dimethyl-3-isoxazolidinone was added in one portion. The reaction mixture was heated an additional 30 minutes and then 15 mL of water was added. The mixture was filtered, and the filtrate was cooled. The resultant oily suspension solidified when abraded. The solid was collected by filtration to yield, when dried, 0.87 gram of 2-[[2-chloro-4-[(2-hydroxyphenyl)methylimino]phenyl]-methyl]-4,4-dimethyl-3-isoxazolidinone; m.p. 105°-107° C.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10](N)[C:9]2[C:4](=[C:5]3[CH:20]=[CH:19][CH:18]=[CH:17][C:6]3=[C:7]3[CH:16]=[CH:15][CH:14]=[CH:13][C:8]3=2)[N:3]=1.[NH4+].[OH-:22]>Cl>[NH2:1][C:2]1[NH:11][C:10](=[O:22])[C:9]2[C:4](=[C:5]3[CH:20]=[CH:19][CH:18]=[CH:17][C:6]3=[C:7]3[CH:16]=[CH:15][CH:14]=[CH:13][C:8]3=2)[N:3]=1
Reactant: [OH-]
Reactant: Nc1nc(N)c2c3ccccc3c3ccccc3c2n1
Agent: Cl
Agent: [NH4+]
Product: Nc1nc2c3ccccc3c3ccccc3c2c(=O)[nH]1
Reaction time: 0.33 h

Procedure:
A suspension of 2,4-diaminodibenzo[f,h]quinazoline (0.20 g, 0.76 mmol) in 1 N HCl (150 ml) was stirred at reflux for 24 h, then neutralized with NH4OH. The resulting solid was filtered, washed with water and methanol, then suspended in warm methanol (50 ml) for 20 minutes, filtered and dried at 90° C. under reduced pressure. The solid was nearly dissolved in ethanol (100 ml) and 1 N NaOH (˜1.5 ml), filtered, and the filtrate neutralized with acetic acid to give a precipitate which was filtered, washed with ethanol, and dried at 90° C. under reduced pressure. The solid was briefly heated to reflux in pivalic anhydride (4 ml), the solution concentrated in vacuo, and the residue subjected to chromatography on silica gel, eluting with methylene chloride containing a small precentage of ethyl acetate. The pivalamide (not characterized) was hydrolyzed in a solution of methanol (9 ml) and 1 N NaOH (1 ml) at reflux for 1.5 hours. The solution was neutralized with acetic acid, and the precipitate filtered, washed with methanol and dried at 90° C. under reduced pressure to give 2-aminodibenzo[f,h]quinazolin-4-(3H)-one as a beige solid (0.10 g). 1H NMR (DMSO-d6, 200 MHz) δ: 6.69 (br s, 2H, NH2), 7.47-7.84 (m, 4H, Ar), 8.66-8.80 (m, 2H, Ar), 8.96 (dd, J=8, 1 Hz, 1H, Ar), 9.75-9.83 (m, 1H, Ar), 11.26 (br s, 1H, NH). Mass spectrum (CI-CH4) 262 (M+1, 100%). Anal. Calculated for C16H11N3O: C, 73.55; H, 4.24; N, 16.08. Found: C, 73.52; H, 4.27; N, 16.03.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[NH2:10][OH:11]>CO>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[N:10][OH:11])=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=Cc1ccc(O)cc1
Solvent: CO
Product: ON=Cc1ccc(O)cc1
Reaction time: 2 h

Procedure:
Into a 500 ml round bottom flask equipped with a magnetic stirring bar, 40.49 g (331.6 mmol) of 4-hydroxybenzaldehyde were added. The aldehyde was dissolved in 240 ml methanol. To the stirred solution, 22.99 g (348.1 mmol) of 50% aqueous solution of hydroxylamine were added over a 15 min. period. The mixture was stirred for an additional 2 hr, at which time it was judged to be complete by the disappearance of the starting aldehyde as observed by thin layer chromatography (SiO2/CH3OH:CH2CL2 5:95). The solvent was removed in vacu to give the product 4-hydroxybenzaldehyde oxime as a dark tan oil, which was recrystallized from water.
Reaction SMILES: Cl.[CH:2]([N:5]1[CH:13]=[C:12]2[C:7]([C:8](=[O:19])[NH:9][C:10]3([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[CH2:11]2)=[N:6]1)([CH3:4])[CH3:3].Br[C:21]1[C:25](CI)=CN(C(CC)(C)C)N=1>>[C:2]([N:5]1[CH:13]=[C:12]2[C:7]([C:8](=[O:19])[NH:9][C:10]3([CH2:14][CH2:15][NH:16][CH2:17][CH2:18]3)[CH2:11]2)=[N:6]1)([CH2:21][CH3:25])([CH3:4])[CH3:3]
Reactant: CC(C)n1cc2c(n1)C(=O)NC1(CCNCC1)C2
Reactant: CCC(C)(C)n1cc(CI)c(Br)n1
Agent: Cl
Product: CCC(C)(C)n1cc2c(n1)C(=O)NC1(CCNCC1)C2

Procedure:
The title compound was prepared by a method analogous to that described for Intermediate 3 in Steps 4-8, using 3-bromo-4-(iodomethyl)-1-tert-pentyl-1H-pyrazole. +ESI (M+H) 277.3; 1H NMR (400 MHz, CD3OD, δ): 7.67 (s, 1H), 3.22-3.37 (m, 4H), 2.93 (s, 2H), 1.92 (q, J=7.61 Hz, 2H), 1.88-2.05 (m, 4H), 1.57 (s, 6H), 0.67 (t, J=7.41 Hz, 3H).
Reaction SMILES: [OH:1][C:2]([C:5]1[O:9][N:8]=[C:7]([CH:10]=[C:11]([C:14]#[N:15])[C:12]#[N:13])[CH:6]=1)([CH3:4])[CH3:3].[CH2:16]([Mg]Cl)[CH:17]=C.Cl>O1CCOCC1.O1CCCC1.[Cu]I>[OH:1][C:2]([C:5]1[O:9][N:8]=[C:7]([CH:10]([CH:11]([C:12]#[N:13])[C:14]#[N:15])[CH:16]=[CH2:17])[CH:6]=1)([CH3:4])[CH3:3]
Reactant: C=CC[Mg]Cl
Reactant: CC(C)(O)c1cc(C=C(C#N)C#N)no1
Agent: [Cu]I
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: C=CC(c1cc(C(C)(C)O)on1)C(C#N)C#N
Reaction time: 1 h

Procedure:
2.26 g of {[5-(1-hydroxy-1-methylethyl)-isoxazol-3-yl]methylidene}malononitrile was dissolved in 50 ml of 1,4-dioxane. Thereto, 0.08 g of copper(I) iodide was added and 18.6 ml of a 1.4 M solution of allylmagnesium chloride in tetrahydrofuran was then added under ice-cooling. The mixture was stirred for 1 hour under ice-cooling. The reaction mixture was added to 0.1 M hydrochloric acid and then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.56 g of {1-[5-(1-hydroxy-1-methylethyl)-isoxazol-3-yl]allyl}malononitrile.