Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].[H-].[Na+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1>[CH2:19]([N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)CCc1nc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CCc1nc2ccccc2n1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 82.2 %

Procedure:
To a stirred solution of ethyl 3-(1H-benzo[d]imidazol-2-yl)propanoate 6a (2.85 g, 13.1 mmol, 1.0 eq.) in tetrahydrofuran (100 mL) at 0° C., was added 60% sodium hydride in mineral oil (784 mg, 19.6 mmol, 1.5 eq.), and the reaction was stirred at 0° C. for 20 minutes. Benzyl bromide (4.47 g, 26.1 mmol, 2.0 eq.) was added at 0° C., and the reaction was stirred, with warming to room temperature, for 16 hours. The mixture was concentrated in vacuo and water (100 mL) was carefully added. The aqueous layer was extracted with dichloromethane (3×75 mL), and the combined organic extracts were washed with 1M hydrochloric acid (100 mL) and brine (100 mL). The organic layer was dried over magnesium sulfate and concentrated in vacuo. Purification by flash chromatography (5% MeOH:95% EtOAc) gave 6b as an orange oil (3.32 g, 82%).
Reaction SMILES: [N:1]([CH:4]([CH3:20])[CH2:5][N:6]1[C:10]2=[CH:11][C:12]3[C:17]([CH2:16][CH:15]=[CH:14][C:13]=3[O:18][CH3:19])=[C:9]2[CH:8]=[N:7]1)=[N+]=[N-].[C:21]([OH:28])(=[O:27])/[CH:22]=[CH:23]/[C:24]([OH:26])=[O:25]>C(O)C.C(OCC)C.CO.[Pt]=O>[C:21]([OH:28])(=[O:27])/[CH:22]=[CH:23]/[C:24]([OH:26])=[O:25].[CH3:19][O:18][C:13]1[CH:14]=[CH:15][CH2:16][C:17]2[C:12]=1[CH:11]=[C:10]1[C:9]=2[CH:8]=[N:7][N:6]1[CH2:5][CH:4]([NH2:1])[CH3:20]
Reactant: COC1=C2C=c3c(cnn3CC(C)N=[N+]=[N-])=C2CC=C1
Agent: O=[Pt]
Agent: O=C(O)/C=C/C(=O)O
Solvent: CO
Solvent: CCO
Solvent: CCOCC
Product: COC1=C2C=c3c(cnn3CC(C)N)=C2CC=C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 78.3 %

Procedure:
0.85 g (3.2 mmol) of (RS)-1-(2-azido-propyl)-7-methoxy-1,4-dihydro-indeno[2,1-c]pyrazole dissolved in 50 ml of anhydrous ethanol was hydrogenated on 85 mg of platinum oxide for 2 hours. The catalyst was subsequently filtered off, rinsed with ethanol and the solvent was removed in a vacuum. The colorless oil obtained was dissolved in 70 ml of anhydrous diethyl ether, filtered and treated while stirring with a solution of 371 mg (3.2 mmol) of fumaric acid in 10 ml of methanol. The mixture was stirred at room temperature for 15 hours and the white crystals were subsequently filtered off. 0.9 g (78%) of (RS)-2-(7-methoxy-1,4-dihydro-indeno[2,1-c]pyrazol-1-yl)-1-methyl-ethylamine fumarate (1:1) with m.p. 182° was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[S:23][C:22]3[C:21]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[N:20][C:19]([Cl:30])=[N:18][C:17]=3[CH:16]=2)([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:34]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([C:15]2[S:23][C:22]3[C:21]([N:24]4[CH2:25][CH2:26][O:27][CH2:28][CH2:29]4)=[N:20][C:19]([Cl:30])=[N:18][C:17]=3[CH:16]=2)([O:14][CH3:34])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1(c2cc3nc(Cl)nc(N4CCOCC4)c3s2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (335 mg) in DMF (3 ml) was added sodium hydride (60% w/w suspension in mineral oil, 41 mg) at 0° C. After 30 min, iodomethane (56 ul) was added and the reaction mixture was warmed slowly to room temperature overnight. Ethyl acetate/brine extraction and purification on silica afforded 4-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-4-methoxy-piperidine-1-carboxylic acid tert-butyl ester (219 mg).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][C:3]=1[CH3:10].C(N(CC)CC)C.[CH:18](OCC)=[O:19]>>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][CH:18]=[O:19])=[CH:4][C:3]=1[CH3:10]
Reactant: CCOC=O
Reactant: Cc1cc(CN)ccc1Br
Solvent: CCN(CC)CC
Product: Cc1cc(CNC=O)ccc1Br

Procedure:
To a solution of 4-bromo-3-methyl-benzylamine (15.11 g) (Example I1) in ethyl formate (150 ml) was added triethylamine (1.5 ml) at ambient temperature. The reaction mixture was stirred at reflux for 16 hours. The reaction mixture was concentrated and the residue was triturated with diisopropyl ether/heptane (1:1) (100 ml) to give N-(4-bromo-3-methyl-benzyl)-formamide (14.04 g) as a white solid. 1H-NMR (400 MHz, CDCl3): 8.28 (s, 1H), 7.49 (m, 1H), 7.16 (s, 1H), 6.97 (m, 1H), 5.85 (s, 1H), 4.42 (m, 2H), 2.39 (s, 3H) ppm.
Reaction SMILES: OO.FC(F)(F)C(OC(=O)C(F)(F)F)=[O:6].P([O-])([O-])(O)=O.[Na+].[Na+].[Cl:23][C:24]([Cl:35])([Cl:34])[CH2:25][O:26][C:27]([N:29]1[CH2:33][CH:32]=[CH:31][CH2:30]1)=[O:28]>C(Cl)Cl.O>[O:6]1[CH:31]2[CH:32]1[CH2:33][N:29]([C:27]([O:26][CH2:25][C:24]([Cl:23])([Cl:34])[Cl:35])=[O:28])[CH2:30]2
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: O=C(OCC(Cl)(Cl)Cl)N1CC=CC1
Agent: O=P([O-])([O-])O
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: O=C(OCC(Cl)(Cl)Cl)N1CC2OC2C1
Reaction time: 0.25 h

Procedure:
12 ml of 90% strength hydrogen peroxide (0.48 mol) are dissolved in 40 ml of methylene chloride and the solution is treated at 0° with 63.5 ml (0.45 mol) of trifluoroacetic anhydride. After stirring for 15 minutes at 0°, the solution is added dropwise to a suspension, which is kept at 0°, of 196 g of anhydrous disodium hydrogen phosphate in 800 ml of methylene chloride, in which 41.8 g (0.17 mol) of N-(β,β,β-trichloroethoxycarbonyl)-3-pyrroline has been dissolved. Subsequently, the reaction mixture is stirred for 2 hours at room temperature and then stirred into 900 ml of water and the resulting mixture is stirred for a further one hour. The organic phase is separated off and the aqueous phase is extracted by shaking with 3 times 200 ml of methylene chloride; the combined organic phases are washed successively with aqueous sodium chloride solution, aqueous iron-II sulphate solution and then with water, dried over sodium sulphate and evaporated under a water pump vacuum, whereupon 3,4-epoxy-1-(β,β,β-trichloroethoxycarbonyl)-pyrrolidine is obtained in the form of white crystals with a melting point of 52°-55°.
Reaction SMILES: [NH2:1][C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.N[C:16](N)=[O:17]>COCCOCCOC>[NH:1]1[C:2]2[C:3]3[CH:4]=[CH:5][CH:6]=[N:7][C:8]=3[CH:9]=[CH:10][C:11]=2[NH:12][C:16]1=[O:17]
Reactant: Nc1c([N+](=O)[O-])ccc2ncccc12
Reactant: NC(N)=O
Solvent: COCCOCCOC
Product: O=c1[nH]c2ccc3ncccc3c2[nH]1
Yield: 91 %

Procedure:
Quinolino[5,6-d]imidazolinone (2f) was prepared from 5-amino-6-nitroquinoline by hydrogenation and subsequent treatment with urea in diglyme. Overall yield: 91%.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:28](=[O:29])[N:13]3[CH:14]([C:20]([O:22][CH2:23][C:24]([Cl:27])([Cl:26])[Cl:25])=[O:21])[C:15]([CH3:19])([CH2:17]Br)[S:16][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(Cl)Cl>N1C=CC=CC=1>[C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:28](=[O:29])[N:13]3[C:14]([C:20]([O:22][CH2:23][C:24]([Cl:26])([Cl:27])[Cl:25])=[O:21])=[C:15]([CH3:17])[CH2:19][S:16][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC1(CBr)S[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC1=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2SC1
Yield: 73.9 %

Procedure:
A mixture of 2,2,2-trichloroethyl 6-(2-phenylacetamido)-2-methyl-2-bromomethylpenam-3-carboxylate (0.54 g.), chloroform (5 cc) and pyridine (0.16 g.) was heated under reflux for 2.5 hours. The reaction mixture was washed with water, dried over magnesium sulfate and then concentrated. The residue was crystallized from ether to yield crystals (0.34 g.) of 2,2,2-trichloroethyl 7-(2-phenylacetamido)-3-methyl-3-cephem-4-carboxylate, m.p. 161°-162° C.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([O:11][CH2:12][CH2:13][CH3:14])[N:3]=1.[F:15][C@@H:16]1[C@H:20]([OH:21])[C@@H:19]([CH2:22][OH:23])[O:18][C@H:17]1N1C=CC(=O)NC1=O.[N-]=[N+]=[N-].[K+].[OH-].[K+].[C@@H]1(N2C=C(C)C(=O)NC2=O)O[C@H](CO)[C@@H](O)C1>P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:17]2[O:18][C@H:19]([CH2:22][OH:23])[C@@H:20]([OH:21])[C@H:16]2[F:15])=[C:4]([O:11][CH2:12][CH2:13][CH3:14])[N:3]=1
Reactant: CCCOc1nc(N)nc2nc[nH]c12
Reactant: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2F)c(=O)[nH]1
Agent: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: CCCOc1nc(N)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1F
Temperature: 37 °C

Procedure:
2-Amino-6-propoxypurine (0.3 g, 1.6 mmoles) which may be prepared according to R. W. Balsiger and J. A. Montgomery (J. Org. Chem. 25:1573, 1960) and 1-(2-deoxy-2-fluoro-β-D-ribofuranosyl)uracil (0.52 g, 2.1 mmoles) which may be prepared according to J. F. Codington et al. (J. Org. Chem. 29:558, 1964) were suspended in 50 ml of 2 mM potassium phosphate buffer, pH 7.0, which contained 0.04% (w/v) potassium azide. The pH of the suspension was adjusted to 7.0 with KOH. Thymidine phosphorylase (4,000 I.U.) and purine nucleoside phosphorylase (14,000 I.U.) (T. A. Krenitsky et al., Biochemistry 20:3615, 1981 and U.S. Pat. No. 4,381,344) were added and the reaction stirred at 37° C. On day 6, the reaction was diluted to 250 ml with 5 mM potassium phosphate buffer, pH 7.0, which contained 0.04% (w/v) potassium azide, and 4,000 I.U. of thymidine phosphorylase and 14,000 I.U. of purine nucleoside phosphorylase were added. On day 14, the solvent was removed under vacuum. The residue was suspended in methanol/water and the suspension was filtered. The filtrate was evaporated. The residue was dissolved in hot water and applied to a 2.5×13 cm column of anion exchange resin (Bio-Rad AG1X2 hydroxide form). After washing the column with water, the product was eluted with methanol/water (1/1). Product-containing fractions were combined and the solvent removed under vacuum. The residue was dissolved in water and lyophilized to obtain title compound that analyzed as 0.9 hydrate.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[C:10]1[NH:15][C:14](=[O:16])[N:13]2[N:17]=[C:18]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[N:19]=[C:12]2[CH:11]=1.[CH2:26]=O.[Na]>CO>[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[C:10]1[NH:15][C:14](=[O:16])[N:13]2[N:17]=[C:18]([CH:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)[N:19]=[C:12]2[CH:11]=1
Reactant: C=O
Reactant: O=c1[nH]c(-c2ccc(Cl)cc2Cl)cc2nc(C3CCNCC3)nn12
Agent: Cl
Agent: [Na]
Solvent: CO
Product: CN1CCC(c2nc3cc(-c4ccc(Cl)cc4Cl)[nH]c(=O)n3n2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
At 0° C., 500 mg (1.25 mmol) of 7-(2,4-dichlorophenyl)-2-(piperidin-4-yl)[1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one hydrochloride were initially charged in methanol (4 ml), and 3 Å molecular sieve (50 mg), formalin (210 μl, 7.50 mmol) and sodium cyanoborhydride (470 mg, 7.50 mmol) were added. The mixture was stirred at 0° C. for 1 h and then stirred at RT for another 12 h. The reaction mixture was filtered, and dichloromethane (100 ml) and water (75 ml) were added to the filtrate. The mixture was extracted and the organic phase was dried (magnesium sulfate) and concentrated. This gave 274 mg (58% of theory) of the crude product.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[NH2:25])[CH2:12][CH2:11]2)=[N:2]1.[S:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[CH2:31][C:32](Cl)=[O:33]>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[NH:25][C:32](=[O:33])[CH2:31][C:27]3[S:26][CH:30]=[CH:29][CH:28]=3)[CH2:12][CH2:11]2)=[N:2]1
Reactant: Nc1ccccc1CCCN1CCN(c2nsc3ccccc23)CC1
Reactant: O=C(Cl)Cc1cccs1
Product: O=C(Cc1cccs1)Nc1ccccc1CCCN1CCN(c2nsc3ccccc23)CC1

Procedure:
N-{2-[3-(4-1,2-Benzoisothiazol-3-yl-piperazin-1-yl)-propyl]-phenyl}-2-thiophen-2-yl-acetamide was prepared according to the procedure outlined in Example 1, starting with 2-[3-(4-1,2-benzisothiazol-3-yl-piperazin-1-yl)-propyl]-phenylamine (200 mg) and 2-thiopheneacetyl chloride (0.069 mL). The resultant white solid was purified using an ISCO autocolumn eluting with 80% ethyl acetate in hexanes. N-{2-[3-(4,1,2-Benzoisothiazol-3-yl-piperazin-1-yl)-propyl]-phenyl}-2-(4-chloro-phenyl)-acetamide was isolated in 100% purity @ 254 nm; LCMS (APCI): 477 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]1[NH:15][CH2:14][CH2:13][N:12]([S:16]([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)(=[O:18])=[O:17])[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:25]1[CH:30]=[CH:29][C:28]([C:31]([OH:37])([CH3:36])[C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=1.CC(C)([O-])C.[Na+].C1(C)C=CC=CC=1>CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC(C)C)=CC=CC=2OC(C)C)CCCCC1>[CH2:1]([O:8][CH2:9][CH:10]1[CH2:11][N:12]([S:16]([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)(=[O:17])=[O:18])[CH2:13][CH2:14][N:15]1[C:25]1[CH:30]=[CH:29][C:28]([C:31]([OH:37])([CH3:36])[C:32]([F:34])([F:35])[F:33])=[CH:27][CH:26]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(O)(c1ccc(Br)cc1)C(F)(F)F
Reactant: O=S(=O)(c1cccs1)N1CCNC(COCc2ccccc2)C1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)CC2COCc2ccccc2)cc1)C(F)(F)F
Temperature: 100 °C
Yield: 87.3 %

Procedure:
A mixture of 3-(benzyloxymethyl)-1-(thiophen-2-ylsulfonyl)piperazine (2.95 g, 8.37 mmol), 2-(4-bromophenyl)-1,1,1-trifluoropropan-2-ol (2.70 g, 10.04 mmol, Example 27, step 1), dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine (RuPhos) (0.156 g, 0.335 mmol, Strem Chemicals, Newburyport, Mass.), tris(dibenzylideneacetone)dipalladium (0) (0.153 g, 0.167 mmol, Strem Chemicals, Newburyport, Mass.), sodium tert-butoxide (2.011 g, 20.92 mmol) and toluene (50 mL) was added to a high-pressure reaction vessel. The vessel was sealed and heated at 100° C. for 16 h. The solution was then diluted with EtOAc (200 mL). The organic solution was washed with water (100 mL) and brine (100 mL) then dried (MgSO4), filtered and concentrated. The crude material was subjected to flash chromatography on silica gel (120 g, 5-80% (10% MeOH-EtOAc) in hexanes) to give 2-(4-(2-((benzyloxy)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol (3.95 g) as a mixture of four isomers.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.Cl[C:13]1[CH:18]=[C:17]([C:19]([OH:22])([CH3:21])[CH3:20])[CH:16]=[C:15]([C:23]([F:26])([F:25])[F:24])[N:14]=1.[H-].[Na+]>O1CCCC1>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([O:11][C:13]3[CH:18]=[C:17]([C:19]([OH:22])([CH3:21])[CH3:20])[CH:16]=[C:15]([C:23]([F:24])([F:26])[F:25])[N:14]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: CC(C)(O)c1cc(Cl)nc(C(F)(F)F)c1
Reactant: OC1CCC2(CC1)OCCO2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(O)c1cc(OC2CCC3(CC2)OCCO3)nc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 60 h

Procedure:
1,4-Dioxaspiro[4.5]decan-8-ol (0.25 g, 1.58 mmol) and 2-[2-chloro-6-(trifluoromethyl)pyridin-4-yl]propan-2-ol (0.2 g, 0.835 mmol) were dissolved in tetrahydrofuran (2 mL) and cooled to 0° C. and a 60% mixture of sodium hydride (70.0 mg, 1.75 mmol) in mineral oil was added and the reaction was stirred for 30 minutes at 0° C. and at 25° C. for 60 hours at which time TLC analysis indicated the presence of some product. The reaction was quenched with water, and was extracted with ethyl acetate and the organic extracts were washed with water, saturated NaCl, dried (MgSO4), and evaporated in vacuo. The residue was purified by LC (pH 2) to give the product. MS (ES): 362 (M+1).
Reaction SMILES: [F:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([CH2:15][OH:16])=[C:5]([OH:14])[CH:6]=[N:7]2.C(OCC)(=O)C.CCCCCC>CC(C)=O.[O-2].[O-2].[Mn+4]>[F:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([CH:15]=[O:16])=[C:5]([OH:14])[CH:6]=[N:7]2
Reactant: COc1ccc2ncc(O)c(CO)c2c1F
Agent: [Mn+4]
Agent: [O-2]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1ccc2ncc(O)c(C=O)c2c1F
Temperature: 35 °C
Reaction time: 17 h
Yield: 42.1 %

Procedure:
Manganese dioxide (299 mg, 4.3 mmol, 10.0 eq) is added at room temperature to a stirred solution of 5-fluoro-4-hydroxymethyl-6-methoxy-quinolin-3-ol (120 mg, 0.43 mmol, 1.0 eq) in acetone (12 mL) and the resulting mixture is stirred at 35° C. for 17 hours. The solid is filtered off, washed with acetone (3×10 mL) and the filtrate is concentrated to give a residue that is purified by column chromatography (silica gel, eluent: ethyl acetate:hexane, 1:3, v/v) to afford 5-fluoro-3-hydroxy-6-methoxy-quinoline-4-carbaldehyde as a yellow solid (40 mg, 42% yield).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][CH2:10][C:11]1[O:15][N:14]=[C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH:12]=1>C(Cl)Cl>[N:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:13]1[CH:12]=[C:11]([CH2:10]/[N:9]=[CH:1]/[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[O:15][N:14]=1
Reactant: O=Cc1ccccc1
Reactant: NCc1cc(-c2ccccn2)no1
Solvent: ClCCl
Product: C(=N/Cc1cc(-c2ccccn2)no1)\c1ccccc1
Reaction time: 20 h
Yield: 97.7 %

Procedure:
Freshly distilled benzaldehyde (373 mg, 3.5 mmol) was added to a solution of 5-aminomethyl-3-(pyrid-2-yl)isoxazole (Method 70 of WO 03/048133) (0.614 mg, 3.5 mmol) in dry DCM (18 ml). 4 Å molecular sieve (1.75 g) was then added and the mixture stirred gently under nitrogen for 20 hours. The molecular sieve was removed by filtration and the filtrate evaporated. The residue was dissolved in toluene and the solution concentrated by evaporation. The product crystallised and was collected by filtration to give the title compound (900 mg, 97%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][N:15]=3)[N:10]([S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)(=[O:19])=[O:18])[CH:9]=2)[CH:5]=[C:4](Cl)[N:3]=1.[C:27]([NH2:35])(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:35][C:27](=[O:34])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:5]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][N:15]=3)[N:10]([S:17]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)(=[O:18])=[O:19])[CH:9]=2)[CH:7]=1
Reactant: NC(=O)c1ccccc1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cc(Cl)nc(Cl)c2)c2nccnc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: O=C(Nc1cc(-c2cn(S(=O)(=O)c3ccccc3)c3nccnc23)cc(Cl)n1)c1ccccc1
Yield: 32.2 %

Procedure:
A mixture of EXAMPLE 14A (290.0 mg, 0.716 mmol), benzamide (95 mg, 0.787 mmol), cesium carbonate (233 mg, 0.716 mmol), palladium (II) acetate (8.03 mg, 0.036 mmol), and Xantphos (31.1 mg, 0.054 mmol) in dioxane (7 mL) and N,N-dimethylformamide (0.6 mL) was heated in a Biotage Initiator microwave reactor at 170° C. for 10 min. The solids were filtered and the filtrate concentrated and purified by flash chromatography eluted with a gradient of 97:5:2.5 to 95:5 dichloromethane/ethyl acetate to give 113 mg (32%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH2:19]OS(C)(=O)=O)[C:11](=[O:18])[N:12]([CH2:14][CH:15]([CH3:17])[CH3:16])[N:13]=2)=[CH:4][C:3]=1[CH3:25].[N:26]1([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[C:35]([O:34][C:32]([N:26]1[CH2:31][CH2:30][N:29]([CH2:19][C:10]2[C:11](=[O:18])[N:12]([CH2:14][CH:15]([CH3:17])[CH3:16])[N:13]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[C:3]([CH3:25])[CH:4]=3)[CH:9]=2)[CH2:28][CH2:27]1)=[O:33])([CH3:38])([CH3:36])[CH3:37]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1cc(-c2cc(COS(C)(=O)=O)c(=O)n(CC(C)C)n2)ccc1F
Product: Cc1cc(-c2cc(CN3CCN(C(=O)OC(C)(C)C)CC3)c(=O)n(CC(C)C)n2)ccc1F

Procedure:
Following the procedure of Example 1(10), 6-(4-fluoro-3-methylphenyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and tert-butyl 1-piperazinecarboxylate were reacted to yield the title compound as a slightly yellow oil (yield: 97.5%).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:19][C:20]3[CH:21]=[C:22]([CH:28]=[C:29]([N:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)[CH:30]=3)[C:23]([N:25]([CH3:27])[CH3:26])=O)=[C:7]([CH3:18])[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)=[N:9]2)=[CH:4][CH:3]=1.B>C1COCC1>[CH3:27][N:25]([CH2:23][C:22]1[CH:21]=[C:20]([NH:19][C:6]2[C:5]3[C:10](=[CH:11][C:2]([F:1])=[CH:3][CH:4]=3)[N:9]=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[C:7]=2[CH3:18])[CH:30]=[C:29]([N:31]2[CH2:32][CH2:33][O:34][CH2:35][CH2:36]2)[CH:28]=1)[CH3:26]
Reactant: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1Nc1cc(C(=O)N(C)C)cc(N2CCOCC2)c1
Agent: B
Solvent: C1CCOC1
Product: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1Nc1cc(CN(C)C)cc(N2CCOCC2)c1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
To a stirring solution of 3-(7-fluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-ylamino)-N,N-dimethyl-5-morpholinobenzamide (0.074 g, 0.152 mmol) in THF (1.5 mL) was added 1M borane:THF complex (0.76 mL, 0.762 mmol). The reaction was stirred at 60° C. for 18 h, then cooled to 23° C., quenched with 0.7 mL concd HCl, and concd. To the resulting residue, 5 mL water was added as the reaction was stirred at 90° C. for one hour. The reaction was then basified with 1M sodium hydroxide, and the product was extracted twice with EtOAc. The combined organics were dried over magnesium sulfate and concd, affording a crude material that was purified by reverse-phase HPLC (0-70% acetonitrile in water). This yielded N-(3-((dimethylamino)methyl)-5-(4-morpholinyl)phenyl)-7-fluoro-3-methyl-2-(2-pyridinyl)-4-quinolinamine as a yellow amorphous solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.65-8.72 (1H, m), 8.47 (1H, s), 8.08 (1H, dd, J=9.2, 6.3 Hz), 7.96-8.01 (1H, m), 7.83-7.87 (1H, m), 7.69-7.73 (1H, m), 7.42-7.50 (2H, m), 6.38 (1H, s), 6.27-6.30 (1H, m), 6.09-6.11 (1H, m), 3.69 (4H, dd, J=5.6, 4.0 Hz), 3.23 (1H, br. s.), 2.99-3.05 (4H, m), 2.18 (3H, s), 2.10 (5H, br. s.). Mass Spectrum (ESI) m/e=472.2 (M+1).
Reaction SMILES: [C:1]([O:14]C)(=[O:13])[CH2:2][C:3]1[C:4](=[CH:9][CH:10]=[CH:11][CH:12]=1)[C:5]([O:7]C)=O.Br[C:17]1[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=[CH:21][C:18]=1[CH:19]=O>>[N+:25]([C:23]1[CH:24]=[C:17]2[C:18](=[CH:21][CH:22]=1)[CH:19]=[C:2]1[C:1]([O:14][C:5](=[O:7])[C:4]3[C:3]1=[C:12]2[CH:11]=[CH:10][CH:9]=3)=[O:13])([O-:27])=[O:26]
Reactant: COC(=O)Cc1ccccc1C(=O)OC
Reactant: O=Cc1ccc([N+](=O)[O-])cc1Br
Product: O=C1OC(=O)c2cc3ccc([N+](=O)[O-])cc3c3cccc1c23

Procedure:
As described in example 50, the following compounds were prepared from dimethyl homophthalate and 2-bromo-4-nitrobenzaldehyde (Dandegaonker, S. H. J. Ind. Chem. Soc. 1969, 46, 148):