Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:5]([OH:7])=[O:6])[CH2:4][CH2:3][CH2:2]1.Br[CH2:9][CH:10]1[CH2:12][CH2:11]1>>[CH:10]1([CH2:9][C:1]2([C:5]([OH:7])=[O:6])[CH2:4][CH2:3][CH2:2]2)[CH2:12][CH2:11]1
Reactant: BrCC1CC1
Reactant: O=C(O)C1CCC1
Product: O=C(O)C1(CC2CC2)CCC1

Procedure:
The title compound was prepared according to the procedure described for Intermediate 15.1 from cyclobutanecarboxylic acid and (bromomethyl)cyclopropane.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:10]3[N:18]=[C:17]([N:19]4[CH2:24][CH2:23][CH:22]([C:25]([OH:27])=[O:26])[CH2:21][CH2:20]4)[N:16]=[CH:15][C:11]=3[N:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][CH:7]=1.S(Cl)(Cl)=O.[CH3:32]O>>[CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:10]3[N:18]=[C:17]([N:19]4[CH2:24][CH2:23][CH:22]([C:25]([O:27][CH3:32])=[O:26])[CH2:21][CH2:20]4)[N:16]=[CH:15][C:11]=3[N:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(Nc2ncnc3cnc(N4CCC(C(=O)O)CC4)nc23)c1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)C1CCN(c2ncc3ncnc(Nc4cccc(C)c4)c3n2)CC1

Procedure:
Prepared from compound 46 of Example 1 by reaction with thionyl chloride and methanol.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](OS(C(F)(F)F)(=O)=O)=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1.[CH3:19][C:20]1[CH:21]=[C:22]([SH:26])[CH:23]=[CH:24][CH:25]=1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:26][C:22]2[CH:21]=[C:20]([CH3:19])[CH:25]=[CH:24][CH:23]=2)=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1
Reactant: Cc1ccc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c1
Reactant: Cc1cccc(S)c1
Product: Cc1cccc(Sc2ccc(C)cc2[N+](=O)[O-])c1

Procedure:
The product from Example 4a (9.46 g, 33.17 mmol) was reacted with 3-methylthiophenol (4.12 g, 33.17 mmol) in place of thiophenol following the procedure from Example 1e for 18 h giving the crude title compound which was purified by silica gel column chromatography eluting with 5% EtOAc hexane providing a solid (7.50 g, 87%).
Reaction SMILES: [CH3:1][C:2]12[C:8]([CH3:10])([CH3:9])[C:5]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][C:21]#[N:22])=[CH:16][CH:15]=3)=[O:12])([CH2:6][CH2:7]1)[O:4][C:3]2=[O:23].[N-:24]=[N+:25]=[N-:26].[Na+].[Cl-].[NH4+].CN(C)C=O>[Cl-].[Na+].O.O>[CH3:1][C:2]12[C:8]([CH3:9])([CH3:10])[C:5]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][C:21]4[NH:26][N:25]=[N:24][N:22]=4)=[CH:16][CH:15]=3)=[O:12])([CH2:6][CH2:7]1)[O:4][C:3]2=[O:23]
Reactant: CC12CCC(C(=O)Nc3ccc(CC#N)cc3)(OC1=O)C2(C)C
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC12CCC(C(=O)Nc3ccc(Cc4nnn[nH]4)cc3)(OC1=O)C2(C)C
Temperature: 135 °C
Yield: 60 %

Procedure:
4,7,7-Trimethyl-3-oxo-N-[4-(cyanomethyl)phenyl]-2-oxabicyclo[2.2.1]-heptane-1-carboxamide (6 g, prepared in the preceding paragraph), sodium azide (6.24 g), ammonium chloride (5.1 g) and dimethylformamide (100 mL) were heated in a 135° C. oil bath for 20 hours under a nitrogen atmosphere. Water was added to the hot mixture until homogeneity was achieved. The mixture was then cooled to room temperature, poured onto saturated brine solution in a separatory funnel, and extracted with ethyl acetate. The extracts were washed with saturated brine solution, dried over MgSO4 and concentrated in a rotary evaporator. The crude product was dissolved in hot acetone, then cooled in a 0° C. freezer to yield 4.1 g. (60% yield) of the title compound as a dark yellow solid; m.p. 224°-225° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][S:15][CH3:16])=[CH:10][CH:9]=2)=O)=[CH:4][CH:3]=1.[C:19]([O:23][CH2:24][CH3:25])(=[O:22])[NH:20][NH2:21]>C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C(O)C>[CH2:24]([O:23][C:19]([NH:20][N:21]=[C:6]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][S:15][CH3:16])=[CH:10][CH:9]=1)[C:5]1[CH:17]=[CH:18][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:22])[CH3:25]
Reactant: CSCc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Reactant: CCOC(=O)NN
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: CCOC(=O)NN=C(c1ccc(Cl)cc1)c1ccc(CSC)cc1
Temperature: 25 °C
Yield: 86.4 %

Procedure:
An ethanol solution (100 ml) of 4-chloro-4'-methylmercaptomethylbenzophenone (8.3 g), ethyl carbazate (10 g) and pyridinium p-toluenesulfonate (0.1 g) was heated for 16 hours with refluxing. After cooling to a room temperature, the reaction mixture was poured into ice water, and then the precipitated crystals were collected by filtration, and washed with water. After air-drying, 4-chloro-4'-methylmercaptomethylbenzophenone ethoxycarbonylhydrazone (9.4 g) was obtained as an isomer mixture.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([CH3:8])([CH3:7])[C:4](O)=[O:5].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:30])[C:21]2[CH:26]=[C:25]([CH2:27][NH2:28])[CH:24]=[CH:23][C:22]=2[Cl:29])=[CH:15][C:14]=1[C:31]([NH:33][C:34]1[CH:39]=[CH:38][C:37]([Br:40])=[CH:36][CH:35]=1)=[O:32].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:30])[C:21]2[CH:26]=[C:25]([CH2:27][NH:28][C:4]([C:3]([CH3:8])([CH3:7])[C:2]([F:10])([F:9])[F:1])=[O:5])[CH:24]=[CH:23][C:22]=2[Cl:29])=[CH:15][C:14]=1[C:31]([NH:33][C:34]1[CH:35]=[CH:36][C:37]([Br:40])=[CH:38][CH:39]=1)=[O:32]
Reactant: COc1ccc(NC(=O)c2cc(CN)ccc2Cl)cc1C(=O)Nc1ccc(Br)cc1
Reactant: CC(C)(C(=O)O)C(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(NC(=O)c2cc(CNC(=O)C(C)(C)C(F)(F)F)ccc2Cl)cc1C(=O)Nc1ccc(Br)cc1
Reaction time: 8 h

Procedure:
To 1.0 mL of a 0.13 M solution of 3,3,3-trifluoro-2,2-dimethyl-propionic acid (0.13 mmol) in DMF was added 1.0 mL of a 0.1 M solution of N-[4-methoxy-3-(4-bromophenyl)aminocarbonyl-phenyl]-2-chloro-5-aminomethyl-benzamide (0.10 mmol) in DMF and triethylamine (70 μL, 0.50 mmol). Then 1.0 mL of a 0.115 M solution of TBTU (0.115 mmol) in DMF was added and the mixture was stirred overnight. The reaction mixture was directly purified via prep. HPLC to furnish the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:10][C@:11]2([CH3:14])[CH2:13][O:12]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]=[CH:23][CH2:24][O:25][CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:18][CH:17]=1>>[Cl:1][C:2]1[N:3]([CH2:10][C@@:11]([CH3:14])([OH:12])[CH2:13][N:29]2[CH2:28][CH2:27][CH:26]([O:25][CH2:24][CH:23]=[CH:22][C:19]3[CH:18]=[CH:17][C:16]([Cl:15])=[CH:21][CH:20]=3)[CH2:31][CH2:30]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: Clc1ccc(C=CCOC2CCNCC2)cc1
Reactant: C[C@@]1(Cn2cc([N+](=O)[O-])nc2Cl)CO1
Product: C[C@](O)(CN1CCC(OCC=Cc2ccc(Cl)cc2)CC1)Cn1cc([N+](=O)[O-])nc1Cl
Yield: 56.3 %

Procedure:
Using (R)-2-chloro-1-(2-methyloxiran-2-yl-methyl)-4-nitroimidazole prepared in Example 12 (0.217 g, 1.00 mmol) and 4-[3-(4-chloro-phenyl)-2-propenyloxy]piperidine (0.250 g, 0.995 mmol) gave (S)-1-(2-chloro-4-nitroimidazol-1-yl)-3-{4-[3-(4-chlorophenyl)-2-propenyloxy]piperidin-1-yl}-2-methylpropan-2-ol (0.263 g, yield 56%) as a brown liquid in the same manner as in Example 254.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH:12]([CH3:15])[CH2:11]2)=[CH:4][C:3]=1[N:16]1[C:20](=[O:21])[C:19]2[CH2:22][CH2:23][CH2:24][CH2:25][C:18]=2[C:17]1=[O:26].[CH2:27]([NH2:31])[CH:28]([CH3:30])[CH3:29].C(N(CC)CC)C>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH:12]([CH3:15])[CH2:11]2)=[CH:4][C:3]=1[NH:16][C:20](=[O:21])[C:19]1[CH2:22][CH2:23][CH2:24][CH2:25][C:18]=1[C:17]([NH:31][CH2:27][CH:28]([CH3:30])[CH3:29])=[O:26]
Reactant: CC1CCC(Oc2cc(N3C(=O)C4=C(CCCC4)C3=O)c(F)cc2Cl)C1
Reactant: CC(C)CN
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CC(C)CNC(=O)C1=C(C(=O)Nc2cc(OC3CCC(C)C3)c(Cl)cc2F)CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.8 %

Procedure:
N-{2-Fluoro-4-chloro-5-(3-methylcyclopentyl)oxyphenyl}-3,4,5,6-tetrahydrophthalimide (1.20 g, 3.18 mmol), isobutylamine (0. 360 g, 4.92 mmol), triethylamine (0.450 g, 4.44 mmol) and benzene (25 ml) as a solvent were placed into a round bottom flask (50 cc) and stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitated crystals were isolated by filtration. The crystals were washed with hexane and dried to obtain N-{2-fluoro-4-chloro-5-(3-methylcyclopentyl)oxyphenyl}-N'-isobutyl-3,4,5,6-tetrahydrophthalamide as white crystals (0.700 g, 48.7% yield).
Reaction SMILES: [BH4-].[Na+].[CH3:3][CH2:4][C@@:5]1([OH:28])[C:10](=[O:11])[O:9][CH2:8][C:7]2[C:12]([N:14]3[C:26](=[CH:27][C:6]1=2)[C:25]1[C:16](=[CH:17][C:18]2[C:23]([N:24]=1)=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:15]3)=[O:13]>CO>[CH2:4]([C:5]1([OH:28])[C:6]2[CH:27]=[C:26]3[N:14]([CH2:15][C:16]4[C:25]3=[N:24][C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH:17]=4)[C:12](=[O:13])[C:7]=2[CH2:8][O:9][CH:10]1[OH:11])[CH3:3]
Reactant: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3ccccc3nc2-1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCC1(O)c2cc3n(c(=O)c2COC1O)Cc1cc2ccccc2nc1-3
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Sodium borohydride (14 g, 370 mmol) is added by portions to a suspension of (S)-(+)-camptothecin (14 g, 40 mmol, which can be obtained from different commercial sources such as Aldrich Chemical Co. (Milwaukee, Wis.)), in methanol (750 ml) and the resultant mixture is heated gently to 55° C. in order to obtain a limpid solution which is then agitated for 16 hours at ambient temperature. The solvent is then evaporated off under reduced pressure, the residue is taken up in water (250 ml), neutralized by the addition of acetic acid (21 ml) and left at rest for 2 hours at 4° C. The resultant suspension is filtered and washed successively with cold water, acetone and diethyl ether, which allows the sought product to be obtained, after drying under reduced pressure, in the form of a white solid m.p. 280° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:18])[N:10]([CH:19]([CH3:21])[CH3:20])[C:9]=2[CH2:22]O)=[CH:4][CH:3]=1.P(Br)(Br)[Br:25]>C(OCC)C>[Br:25][CH2:22][C:9]1[N:10]([CH:19]([CH3:21])[CH3:20])[C:11](=[O:18])[C:12]2[C:17]([C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: CC(C)n1c(CO)c(-c2ccc(F)cc2)c2ccccc2c1=O
Reactant: BrP(Br)Br
Solvent: CCOCC
Product: CC(C)n1c(CBr)c(-c2ccc(F)cc2)c2ccccc2c1=O

Procedure:
A solution of 4-(4-fluorophenyl)-3-hydroxymethyl-2-isopropyl-1-oxo-1,2-dihydroisoquinoline [5.0 g; prepared as described in Reference Example 2(e)] in diethyl ether (200 ml) was treated with phosphorus tribromide (2.0 ml). The resulting mixture was stirred and heated at reflux for 90 minutes, and then cooled and diluted with diethyl ether (200 ml). The solution was washed with water (3×50 ml), dried over magnesium sulphate, and evaporated to dryness, to give 3-bromomethyl-4-(4-fluorophenyl)-2-isopropyl-1-oxo-1,2-dihydroisoquinoline in the form of a white solid (5.8 g), m.p. 116°-119° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8](=[O:31])[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])=[CH:22][CH:21]=1)=[C:10]([CH2:17][CH3:18])[NH:11]2.Cl[CH:34]([F:36])[F:35]>>[CH3:1][O:2][C:3](=[O:32])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8]([O:31][CH:34]([F:36])[F:35])=[C:9]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])=[CH:24][CH:25]=1)[C:10]([CH2:17][CH3:18])=[N:11]2
Reactant: FC(F)Cl
Reactant: CCc1[nH]c2c(Cl)ccc(OCC(=O)OC)c2c(=O)c1Cc1ccc(C(=O)C(C)C)cc1
Product: CCc1nc2c(Cl)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(C(=O)C(C)C)cc1

Procedure:
The title compound was prepared by the method of Preparation 10c using [8-chloro-2-ethyl-3-(4-isobutyrylbenzyl)-4-oxo-1,4-dihydroquinolin-5-yloxy]acetic acid methyl ester and chlorodifluoromethane.
Reaction SMILES: Cl.[N:2]1([C:8]2[CH:20]=[CH:19][C:11]([C:12]([O:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:13])=[CH:10][CH:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>N1C=CC=CC=1>[CH3:21][S:22]([N:5]1[CH2:4][CH2:3][N:2]([C:8]2[CH:9]=[CH:10][C:11]([C:12]([O:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:13])=[CH:19][CH:20]=2)[CH2:7][CH2:6]1)(=[O:24])=[O:23]
Reactant: CCCCOC(=O)c1ccc(N2CCNCC2)cc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CCCCOC(=O)c1ccc(N2CCN(S(C)(=O)=O)CC2)cc1
Reaction time: 8 h

Procedure:
To a mixture of 27 g. (0.1 mole) n-butyl 4-(piperazin-1-yl)-benzoate hydrochloride and 270 ml. anhydrous pyridine are added at 5°-10° C. 11.4 g. (0.1 mole) methanesulphonyl chloride. The reaction mixture is left to stand overnight at 20° C. and then poured into 250 ml. ice water and extracted twice with methylene chloride. The extracts are dried with anhydrous sodium sulphate and evaporated in a vacuum. After trituration of the residue with ligroin, 17.1 g. (55% of theory) of the desired product are obtained as yellow crystals; m.p. 145°-150° C.
Reaction SMILES: [C:1]1(=[O:30])[N:5]([CH2:6][CH2:7][C:8]2[C:9](=[O:24])[NH:10][C:11](=[O:23])[N:12]([C@@H:14]3[O:22][CH2:21][C@@H:19]([OH:20])[C@@H:17]([OH:18])[C@H:15]3[OH:16])[CH:13]=2)[C:4](=[O:25])[C:3]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:2]12.[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[Cl-].[NH4+]>N1C=CC=CC=1.ClCCl>[C:31]([O:16][C@@H:15]1[C@H:17]([OH:18])[C@H:19]([OH:20])[CH2:21][O:22][C@H:14]1[N:12]1[CH:13]=[C:8]([CH2:7][CH2:6][N:5]2[C:4](=[O:25])[C:3]3=[CH:26][CH:27]=[CH:28][CH:29]=[C:2]3[C:1]2=[O:30])[C:9](=[O:24])[NH:10][C:11]1=[O:23])(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C1c2ccccc2C(=O)N1CCc1cn([C@@H]2OC[C@@H](O)[C@@H](O)[C@H]2O)c(=O)[nH]c1=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(O[C@@H]1[C@H](O)[C@H](O)CO[C@H]1n1cc(CCN2C(=O)c3ccccc3C2=O)c(=O)[nH]c1=O)c1ccccc1
Temperature: -70 °C
Reaction time: 0.58 h
Yield: 60597.3 %

Procedure:
10.6 g (0.025 mmol) of 5-(2-phtalimidoethyl)-1-(β-D-ribopyranosyl)uracil were dissolved in 20 ml of pyridine in a heated and argon-flushed 1 l four-necked flask and mixed with 200 ml of dichloromethane. The mixture was cooled to −70° C., 3.82 ml (0.033 mmol) of benzoyl chloride in 5 ml of pyridine and 20 ml of dichloromethane were slowly added dropwise with cooling and the mixture was stirred at −70° C. for 35 min. The reaction mixture was poured onto 600 ml of cooled ammonium chloride solution and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water, dried and concentrated to dryness in vacuo. Chromatography on silica gel (ethyl acetate/heptane 1:1) yielded 7.9 g (60%) of 1-(2′-O-benzoyl-β-D-ribopyranosyl)-5-(2-phtalimidoethyl)uracil.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][NH:5][C:4](=O)[CH:3]=1.S(Cl)([Cl:14])=O>CN(C)C=O>[Cl:14][C:4]1[CH:3]=[C:2]([CH3:1])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=1
Reactant: Cc1cc(=O)[nH]cc1[N+](=O)[O-]
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1cc(Cl)ncc1[N+](=O)[O-]
Yield: 95 %

Procedure:
A mixture of 4-methyl-5-nitro-1H-pyridine-2-one (5.00 g, 32.44 mmol), thionyl chloride (20 ml), and two drops of dimethylformamide was heated atreflux under nitrogen for 52 hours. The resultant orange colored solution was evaporated under reduced pressure, and a small amount of anhydrous toluene was added and then removed via evaporation under reduced pressure to remove traces of thionyl chloride. The residual oil then passed througha silica gel filter (dried at 150° C. under vacuum overnight, approximately 100 g) followed by methylene chloride (1 1). This filtrate was evaporated under reduced pressure to afford 2-chloro-4-methyl-5-nitropyridine (5.30 g, 30.71 mmol, 95%) as an orange oil, which crystallized below 0° C.; IR (CHCl3) 1605, 1550, 1520, 1450, 1360, 1345 cm-1 ; 1H NMR (CDCl3) δ 9.03 (s, 1H), 7.83 (s, 1H), 2.60 (s, 3H); LRMS (m/z, relative intensity) 174 (25), 173 (19), 172 (M+, 68), 157 (74), 155 (100), 128 (27), 101 (47), 100(55], 99 (74), 90 (43), 75 (36).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:13](=[O:15])[CH3:14].[N:16]1([CH2:21][CH2:22][C:23]2[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=2)[NH2:26])[CH2:20][CH2:19][CH2:18][CH2:17]1>>[Cl:12][C:9]1[N:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][C:3]([C:13](=[O:15])[CH3:14])=[C:2]2[NH:26][C:25]1[CH:27]=[CH:28][CH:29]=[C:23]([CH2:22][CH2:21][N:16]2[CH2:17][CH2:18][CH2:19][CH2:20]2)[CH:24]=1
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1Cl
Reactant: Nc1cccc(CCN2CCCC2)c1
Product: CC(=O)c1cnc2ccc(Cl)nc2c1Nc1cccc(CCN2CCCC2)c1
Yield: 58.2 %

Procedure:
Following general procedure I, 1-(4,6-dichloro-1,5-naphthyridin-3-yl)ethanone (250 mg, 1.0 mmol) was reacted with 3-[2-(pyrrolidin-1-yl)ethyl]aniline (240 mg, 1.3 mmol) to afford the desired product (230 mg, 57%) as a yellow solid: 1H NMR (500 MHz, CDCl3) δ 10.79 (br s, 1H), 8.99 (s, 1H), 8.16 (d, J=8.7 Hz, 1H), 7.52 (d, J=8.8 Hz, 1H), 7.29-7.20 (m, 1H), 7.07 (d, J=7.7 Hz, 1H), 7.03-6.96 (m, 2H), 2.85-2.77 (m, 2H), 2.72-2.66 (m, 2H), 2.59-2.49 (m, 4H), 2.53 (s, 3H), 1.84-1.74 (m, 4H); ESI MS m/z 395 [M+H]+
Reaction SMILES: F[C:2]1[CH:32]=[CH:31][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[C:21]([C:22]4[CH:27]=[CH:26][N:25]=[C:24]([NH:28][CH3:29])[N:23]=4)=[CH:20][CH:19]=[CH:18][N:17]=3)=[C:11]([CH3:30])[CH:10]=2)=[O:7])=[CH:4][C:3]=1[C:33]([F:36])([F:35])[F:34].[CH3:37][N:38]([CH3:43])[CH2:39][CH2:40][NH:41][CH3:42]>CN(C=O)C.C(OCC)(=O)C>[CH3:37][N:38]([CH3:43])[CH2:39][CH2:40][N:41]([CH3:42])[C:2]1[CH:32]=[CH:31][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[C:21]([C:22]4[CH:27]=[CH:26][N:25]=[C:24]([NH:28][CH3:29])[N:23]=4)=[CH:20][CH:19]=[CH:18][N:17]=3)=[C:11]([CH3:30])[CH:10]=2)=[O:7])=[CH:4][C:3]=1[C:33]([F:34])([F:36])[F:35]
Reactant: CNc1nccc(-c2cccnc2Oc2ccc(NC(=O)c3ccc(F)c(C(F)(F)F)c3)cc2C)n1
Reactant: CNCCN(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CNc1nccc(-c2cccnc2Oc2ccc(NC(=O)c3ccc(N(C)CCN(C)C)c(C(F)(F)F)c3)cc2C)n1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 4-fluoro-N-(3-methyl-4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)-3-(trifluoromethyl)benzamide (0.10 g, 0.22 mmol) and N1,N1,N2-trimethylethane-1,2-diamine (0.045 g, 0.44 mmol) in DMF (2 mL) was heated to 100 deg. C. for 48 h. Additional N1,N1,N2-trimethylethane-1,2-diamine (0.045 g, 0.44 mmol) was added, and the reaction heated for 6 h. Additional N1,N1,N2-trimethylethane-1,2-diamine (0.045 g, 0.44 mmol) was added, and the reaction heated for 48 h. The reaction was cooled to ambient temperature, was diluted with ethyl acetate, and washed with saturated aqueous sodium bicarbonate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a solid. Purification by reverse-phase HPLC using acetonitrile/water/TFA as eluent gave 4-((2-(dimethylamino)ethyl)(methyl)amino)-N-(3-methyl-4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)-3-(trifluoromethyl)benzamide as a white solid. MS m/z=580 [M+1]+. Calc'd for C30H32F3N7O2: 579.62.
Reaction SMILES: [F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[O:4][C:5]1[C:21](=[O:22])[N:20]([CH2:23][CH3:24])[C:8]2[N:9]=[C:10]([NH:13][CH:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[CH:12][C:7]=2[CH:6]=1.N[C@@H]1CC[O:34]C[C@H]1O.C(OCC)(=O)C>CN1CCCC1=O>[F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[O:4][C:5]1[C:21](=[O:22])[N:20]([CH2:23][CH3:24])[C:8]2[N:9]=[C:10]([NH:13][CH:14]3[CH2:19][CH2:18][O:17][CH2:16][CH:15]3[OH:34])[N:11]=[CH:12][C:7]=2[CH:6]=1
Reactant: CCn1c(=O)c(Oc2ccc(F)cc2F)cc2cnc(NC3CCOCC3)nc21
Reactant: N[C@@H]1CCOC[C@H]1O
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CCn1c(=O)c(Oc2ccc(F)cc2F)cc2cnc(NC3CCOCC3O)nc21
Yield: 21.9 %

Procedure:
A mixture of the sulfone (see example 95 for preparation) (0.50 g, 1.31 mmol) and trans-4-amino-3-hydroxy-tetrahydropyran (0.23 g, 1.97 mmol) (see following ref for preparation: (a) Marquis, Robert W et al J. Med. Chem. (2001), 44(5), 725-736. (b) Gribble, Andrew D et al PCT Int. Appl. (1998), 74 pp. (c) Mochalin, V. B et al Zh. Org. Khim. (1971), 7(4), 825-8). in 2 mL of 1-methyl-2-pyrrolidinone was heated at 100° C. for 12 h. The reaction mixture was cooled, ethyl acetate (15 mL) was added and the organic solution was washed with water (3×, 15 mL), brine and then dried (MgSO4). Evaporation of the solvent under reduced pressure and column chromatography (CH2Cl2/methanol—97/3) afforded 120 mg of product (mpt. 174.9-176.3° C., MS (M+H)=419)
Reaction SMILES: [CH:1]12[N:7]([CH2:8][CH2:9][O:10][C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][C:12]=3[C:18]3[N:19]([CH3:24])[N:20]=[CH:21][C:22]=3[Br:23])[CH:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.C1C([N+]([O-])=O)=CC=C([Cl-][C:35]([O-])=[O:36])C=1.[F:38][C:39]1[CH:46]=[C:45]([F:47])[CH:44]=[CH:43][C:40]=1[CH2:41][NH2:42].C(N(CC)C(C)C)(C)C>ClCCCl>[CH:4]12[N:7]([CH2:8][CH2:9][O:10][C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:35]([NH:42][CH2:41][C:40]4[CH:43]=[CH:44][C:45]([F:47])=[CH:46][C:39]=4[F:38])=[O:36])=[CH:13][C:12]=3[C:18]3[N:19]([CH3:24])[N:20]=[CH:21][C:22]=3[Br:23])[CH:1]([CH2:2][CH2:3]1)[CH2:6][CH2:5]2
Reactant: Cn1ncc(Br)c1-c1cc(N)ccc1OCCN1C2CCC1CC2
Reactant: NCc1ccc(F)cc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: Cn1ncc(Br)c1-c1cc(NC(=O)NCc2ccc(F)cc2F)ccc1OCCN1C2CCC1CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.1 %

Procedure:
4-[2-(7-Aza-bicyclo[2.2.1]hept-7-yl)-ethoxy]-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenylamine (50.0 mg, 0.13 mmol) was added to a solution of 4-nitrophenylchloroformate (26.0 mg, 0.13 mmol) in 1,2-dichloroethane (4.0 mL) and the mixture stirred at room temperature for 1 hour. To the resulting precipitate mixture was added 2,4-difluorobenzylamine (0.030 mL, 0.25 mmol) and N,N-diisopropylethylamine (0.030 mL, 0.17 mmol), and the mixture stirred an additional 1 hour. The mixture was concentrated and purified by RP-HPLC. The collected fractions were concentrated and 12% sodium hydroxide (aq) (0.2 mL) was added to give pH 9. The solution was extracted into ethyl acetate and the organic layer was dried over sodium sulfate, filtered, and evaporated to dryness to give a white solid (62 mg, 87%). LCMS m/z (%)=560 (M+H79Br, 100), 562 (M+H81Br, 91). 1H NMR (400 MHz, DMSO-d6) δ: 8.59 (bs, 1H), 7.58 (bs, 1H), 7.48-7.38 (m, 2H), 7.29 (bs, 1H), 7.24-7.18 (m, 1H), 7.10-7.04 (m, 2H), 6.60-5.59 (m, 1H), 4.29 (d, J=4.0 Hz, 2H), 4.06-3.96 (m, 2H), 3.64 (s, 3H), 3.11 (bs, 2H), 2.58-2.54 (m, 2H), 1.54-1.52 (m, 4H), 1.15-1.13 (m, 4H).
Reaction SMILES: N#N.[CH2:3]([O:5][C:6]([C:8]1[N:9]=[C:10]([CH2:13][OH:14])[O:11][CH:12]=1)=[O:7])[CH3:4].CCN(CC)CC.[S:22](Cl)([CH3:25])(=[O:24])=[O:23]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:3]([O:5][C:6]([C:8]1[N:9]=[C:10]([CH2:13][O:14][S:22]([CH3:25])(=[O:24])=[O:23])[O:11][CH:12]=1)=[O:7])[CH3:4]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)c1coc(CO)n1
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1coc(COS(C)(=O)=O)n1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 2-hydroxymethyl-oxazole-4-carboxylic acid ethyl ester (345 mg, 2.02 mmol) in dry CH2Cl2 (10 mL) was treated at 0° C. with Et3N (0.40 mL, 2.87 mmol) followed by DMAP (25 mg, 0.20 mmol) and Ms-Cl (0.20 mL, 2.60 mmol). After stirring at 0° C. for 2 h, the reaction was quenched with water (5 mL). The org. layer was dried over Na2SO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (1:2→1:1 EA-Hept) gave the title compound as a yellow solid. TLC: rf (1:1 EA-Hept)=0.23. LC-MS-conditions 01: tR=0.73 min; [M+H]+=249.94.