Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:15]2[C:6](=[CH:7][C:8]3[C:13]([CH:14]=2)=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:5]([OH:16])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:24][CH2:25][O:26][P:27](Cl)([O:29][CH2:30][CH3:31])=[O:28].C(OCC)(=O)C>C1(C)C=CC=CC=1>[P:27]([O:16][C:5]1[C:6]2[C:15](=[CH:14][C:13]3[C:8]([CH:7]=2)=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:2]([CH3:1])=[CH:3][CH:4]=1)([O:29][CH2:30][CH3:31])([O:26][CH2:25][CH3:24])=[O:28]
Reactant: CCOP(=O)(Cl)OCC
Reactant: Cc1ccc(O)c2cc3ccccc3cc12
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOP(=O)(OCC)Oc1ccc(C)c2cc3ccccc3cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-Methyl-1-anthrol (0.01 mole), triethylamine (0.01 mole) tetrahydrofuran (25 ml) and toluene (25 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The mixture is cooled to a temperature of about 0° C. and O,O-diethyl chloridophosphate (0.01 mole) dissolved in toluene (25 ml) is added with stirring over a period of about 30 minutes. After the addition is completed the reaction mixture is allowed to warm to room temperature and stirring is continued for a period of about 16 hours. After this time the reaction mixture is filtered to remove triethylamine hydrochloride. The filtrate is then washed with water, dried over anhydrous magnesium sulfate and stripped of solvents leaving a residue. This residue is subjected to flash chromatography using ethyl acetate as the eluant to yield the desired product O,O-diethyl O-(4-methyl-1-anthryl) phosphate.
Reaction SMILES: [C:1]1(=[O:10])[CH:9]2[CH:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:3][NH:2]1.C(N(CC)CC)C.[O:18](C(OC(C)(C)C)=O)[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=O>O1CCCC1.CN(C)C1C=CN=CC=1>[C:22]([O:21][C:19]([N:2]1[CH2:3][CH:4]2[CH:9]([CH2:8][CH2:7][CH2:6][CH2:5]2)[C:1]1=[O:10])=[O:18])([CH3:25])([CH3:24])[CH3:23]
Reactant: O=C1NCC2CCCCC12
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC2CCCCC2C1=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To 3 (835 mg, 6 mmol) in suspension in tetrahydrofuran (7 mL) was successively added, under an argon atmosphere, 4-dimethylaminopyridine (18.3 mg; 0.15 mmol), triethylamine (0.84 mL; 6 mmol) and BOC2O (2.62 g; 12 mmol). The reaction mixture was stirred at room temperature for 3 days. The solvent was removed under vacuum. The residue was diluted with diethyl ether (20 mL) and washed with water (2×10 mL). The phases were separated, and the organic phase was dried over MgSO4 and concentrated. The crude oil was purified over silica gel chromatography (ether/heptane 1:1) to give 4 (986 mg; 4.1 mmol; 70%) as a white solid.
Reaction SMILES: [OH:1][CH:2]1[S:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]1=[O:13].C(N(CC)CC)C.[CH:21]([N:24]=[C:25]=[O:26])([CH3:23])[CH3:22]>C(Cl)(Cl)Cl>[CH:21]([NH:24][C:25]([O:1][CH:2]1[S:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]1=[O:13])=[O:26])([CH3:23])[CH3:22]
Reactant: CC(C)N=C=O
Reactant: O=C1C(O)SCN1c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)NC(=O)OC1SCN(c2ccccc2)C1=O
Reaction time: 4 h

Procedure:
A stirred solution of 5-hydroxy-3-phenyl-4-thiazolidinone (prepared as in Preparative Example 17 above) (0.24 g) and triethylamine (0.01 ml) in chloroform (5 ml) was treated with iso-propyl isocyanate (0.116 g). The mixture was stirred for 4 hours, then evaporated under reduced pressure. Recrystallisation of the solid residue from diethyl ether/hexane afforded the title compound as colourless needles, yield 0.14 g, mp 130°-132° C.
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1)=[O:5].C(N(CC)CC)C.[CH:27]1[CH:28]=[CH:29][N:30]2[CH2:36][C:35]3[CH:37]=[CH:38][CH:39]=[CH:40][C:34]=3[NH:33][CH2:32][C:31]=12>C(Cl)Cl>[CH3:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([N:33]2[C:34]3[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=3[CH2:36][N:30]3[CH:29]=[CH:28][CH:27]=[C:31]3[CH2:32]2)=[O:12])=[CH:9][CH:8]=1)=[O:5]
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Temperature: 0 °C
Reaction time: 0.05 h
Yield: 131.1 %

Procedure:
To a mixture of 1.93 g of 4-[(2-methylbenzoyl)amino]benzoyl chloride in 15 ml of methylene chloride, cooled to 0° C. is added 1.13 ml of triethylamine. After stirring for 3 minutes, a mixture of 1.0 g of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine in 5 ml of methylene chloride is added. The cooling bath is removed and after about 30 minutes a complete solution is obtained. The reaction mixture is allowed to stir at room temperature for 48 hours and the volatiles are concentrated in vacuo to a residue. The residue is dissolved in 100 ml of ethyl acetate and washed with water, 2N citric acid, aqueous NaHCO3 and brine. The solution is dried with Na2SO4 and the volatiles concentrated in vacuo to give 3.0 g of a residue. A 300 mg sample of the residue is purified by thick layer chromatography using 10% ethyl acetate-methylene chloride to give 160 mg of the desired product. The remainder of the crude material is purified by flash chromatography using 10% ethyl acetate in methylene chloride to give the desired product as a residue which is crystallized from ethyl acetate to give 800 mg of the desired product as white crystals, m.p. 212°-215° C.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([C:9]3[N:17]=[C:16]4[C:12]([N:13]=[C:14]([CH:19]=[O:20])[N:15]4[CH3:18])=[C:11]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:10]=3)[C:7]3[CH:27]=[CH:28][CH:29]=[CH:30][C:6]=3[N:5]=2)[CH2:3][CH2:2]1.[OH-:31].[Na+]>CCO.O.[N+]([O-])([O-])=O.[Ag+]>[CH:1]1([C:4]2[N:8]([C:9]3[N:17]=[C:16]4[C:12]([N:13]=[C:14]([C:19]([OH:31])=[O:20])[N:15]4[CH3:18])=[C:11]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:10]=3)[C:7]3[CH:27]=[CH:28][CH:29]=[CH:30][C:6]=3[N:5]=2)[CH2:3][CH2:2]1
Reactant: Cn1c(C=O)nc2c(N3CCOCC3)nc(-n3c(C4CC4)nc4ccccc43)nc21
Reactant: [OH-]
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cn1c(C(=O)O)nc2c(N3CCOCC3)nc(-n3c(C4CC4)nc4ccccc43)nc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.8 %

Procedure:
To a suspension of 2-(2-cyclopropylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (500 mg, 1.24 mmol) in EtOH (16 mL) was added AgNO3 (265 mg, 1.56 mmol) followed by a solution of NaOH (302 mg, 7.5 mmol) in H2O (5 mL). The resulting black suspension was allowed to stir at r.t. for 30 min then filtered through Celite® and the resulting filtrate concentrated in vacuo. The resulting residue was dissolved in H2O and basified by the addition of aq. NaOH. The aqueous phase was extracted with DCM then acidified to pH 2 with HCl. The aqueous phase was concentrated in vacuo to half volume then cooled on ice. The resulting precipitate was collected by filtration and dried in vacuo affording the title compound (280 mg, 55%).—1H NMR (DMSO, 400 MHz): δ 8.12-8.11 (1 H, m), 7.72-7.68 (1 H, m), 7.44-7.43 (2 H, m), 4.60 (4 H, brd s), 4.04 (3 H, s), 3.90-3.70 (4 H, m), 3.06-3.00 (1 H, m), 1.33-1.31 (4 H, m)
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][S:7][CH:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][N:4]([CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:3]1=[O:23].Br[CH:25]([CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:26]([O:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:27].C(OCC)(=O)C>C(Cl)Cl>[CH2:29]([O:28][C:26]([CH:25]([NH:1][CH:2]1[CH2:8][S:7][CH:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][N:4]([CH2:15][C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[C:3]1=[O:23])[CH2:33][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)=[O:27])[CH2:30][CH2:31][CH3:32]
Reactant: CCCCOC(=O)C(Br)CCc1ccccc1
Reactant: CC(C)(C)OC(=O)CN1CC(c2ccccc2)SCC(N)C1=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCCOC(=O)C(CCc1ccccc1)NC1CSC(c2ccccc2)CN(CC(=O)OC(C)(C)C)C1=O

Procedure:
0.34 g of t-butyl α-(6-amino-5-oxo-2-phenylperhydro-1,4-thiazepin-4-yl)acetate [prepared as described in Example 7(g) above] was N-alkylated with 0.45 g of butyl 2-bromo-4-phenylbutyrate in the manner described in Example 1(h). The resulting product was subjected to silica gel column chromatography using a 1:40 by volume mixture of ethyl acetate and methylene chloride as the eluent. As a result, the title compound was separated into isomers A and B (resulting from the asymmetric carbon atom to which the phenethyl group is attached).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([Cl:12])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([O:13][CH:14]([CH3:16])[CH3:15])[N:3]=1.[F-:17].[Cs+]>CS(C)=O>[Cl:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[CH:5]=[C:4]([O:13][CH:14]([CH3:16])[CH3:15])[N:3]=[C:2]2[F:17]
Reactant: [F-]
Reactant: CC(C)Oc1cc2c(Cl)cccc2c(Cl)n1
Agent: [Cs+]
Solvent: CS(C)=O
Product: CC(C)Oc1cc2c(Cl)cccc2c(F)n1
Temperature: 140 °C

Procedure:
To a solution of 1,5-dichloro-3-isopropoxyisoquinoline (598 mg, 2.335 mmol) in DMSO (5 mL) was added CsF (390 mg, 2.57 mmol) and heated to 140° C. for 2 hrs. LC/MS showed the desired product. The reaction was diluted with ethyl acteate and washed with water, and brine. The organic phase was collected, dried over MgSO4, and concentrated under vacuum to give the crude product as a reddish brown solid. Crude material purified via silica gel chromatography (90 g column; 0-40% EtOAc:Hex) to get the product 5-chloro-1-fluoro-3-isopropoxyisoquinoline (520 mg, 93% yield) as a yellow solid. MS: MS m/z 240.15(M++1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:16][CH3:17])=[CH:5][C:6]2[N:11]([CH3:12])[C:10](=[O:13])[O:9][C:8](=O)[C:7]=2[CH:15]=1.Cl.[NH2:19][CH2:20]C(OC)=O.CC(O)=O>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[C:4]([O:16][CH3:17])=[CH:5][C:6]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:20][NH:19][C:8](=[O:9])[C:7]=2[CH:15]=1
Reactant: COc1cc2c(=O)oc(=O)n(C)c2cc1OC
Reactant: COC(=O)CN
Agent: Cl
Solvent: c1ccncc1
Solvent: CC(=O)O
Product: COc1cc2c(cc1OC)N(C)C(=O)CNC2=O
Temperature: 130 °C
Yield: 71 %

Procedure:
Heat under reflux for 6 hours a mixture of 320 mg (1.35 mmol) of 6,7-dimethoxy-1-methyl-1,2-dihydro-4H-3,1-benzoxazine-2,4-dione (XVI), 452 mg (3.24 mmol) of methyl glycinate hydrochloride in 4 ml of pyridine. Add 3 ml of AcOH and heat at 130° C. for 12 hours. Evaporate to dryness. Add 10 ml of a water-ice mixture. Allow to crystallize at 0° C. for 30 minutes. Filter and wash twice with 2 ml of H2O, twice with 1 ml of EtOH and twice with 5 ml of Et2O. Recrystallize in EtOH. One obtains 240 mg of the abovenamed product in the form of colorless crystals. Yield: 71%. M: 260–263° C. 1H-NMR (CDCl3, 300 MHz): d 3.42 (s, 3H, NCH3), 3.75–3.92 (m, 2H, CH2), 3.98 (s, 6H, 2×OCH3), 6.39 (s, 1H exchangeable, NH), 6.69 (s, 1H Ar), 7.37 (s, 1H Ar).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([NH:12][C:13](=[O:15])[CH3:14])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.Cl.[CH3:17][CH:18]1[CH2:23][NH:22][CH2:21][CH:20]([CH3:24])[N:19]1[C:25]1[N:30]=[CH:29][CH:28]=[CH:27][N:26]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:24][CH:20]1[N:19]([C:25]2[N:26]=[CH:27][CH:28]=[CH:29][N:30]=2)[CH:18]([CH3:17])[CH2:23][N:22]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]3([NH:12][C:13](=[O:15])[CH3:14])[CH2:11][CH2:10]3)=[CH:5][CH:4]=2)[CH2:21]1
Reactant: CC1CNCC(C)N1c1ncccn1
Reactant: CC(=O)NC1(c2ccc(CCl)cc2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)NC1(c2ccc(CN3CC(C)N(c4ncccn4)C(C)C3)cc2)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 647.6 %

Procedure:
N-[1-(4-Chloromethylphenyl)cyclopropyl]acetamide (22.3 mg) and 2-(2,6-dimethylpiperazin-1-yl)pyrimidine hydrochloride (265 mg) were dissolved in N,N-dimethylformamide (10 ml), potassium carbonate (415 mg) was added and the mixture was stirred at 80° C. for 8 hr. Water (20 mL) was added and the mixture was stirred, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The solvent was evaporated and the obtained residue was purified by column chromatography (Yamazen HI-FLASH™ COLUMN size 2 L, elution solvent: hexane/ethyl acetate) to give the title compound (245 mg).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[C:4]([C:20]2[O:21][C:22]([CH2:25]Cl)=[N:23][N:24]=2)[CH:3]=1.[I-].[Na+].[NH2:29][CH2:30][CH:31]([OH:39])[CH2:32][N:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.CCN(C(C)C)C(C)C>C(#N)C.C(Cl)Cl>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[C:4]([C:20]2[O:21][C:22]([CH2:25][NH:29][CH2:30][CH:31]([OH:39])[CH2:32][N:33]3[CH2:34][CH2:35][O:36][CH2:37][CH2:38]3)=[N:23][N:24]=2)[CH:3]=1
Reactant: O=S(=O)(c1ccccc1)n1ncc2c(-c3nnc(CCl)o3)cc(Br)cc21
Reactant: NCC(O)CN1CCOCC1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1)n1ncc2c(-c3nnc(CNCC(O)CN4CCOCC4)o3)cc(Br)cc21
Temperature: 70 °C
Yield: 57.6 %

Procedure:
6-Bromo-4-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]-1-(phenylsulfonyl)-1H-indazole (300 mg, 0.661 mmol) and sodium iodide (138 mg, 0.921 mmol) were weighed into a round-bottomed flask and dissolved in acetonitrile (2 ml) before 1-amino-3-morpholin-4-ylpropan-2-ol (212 mg, 1.322 mmol, available from Enamine Ltd) and DIPEA (0.231 ml, 1.322 mmol) were added. The mixture was heated to 70° C. for 2 h, then cooled, diluted with DCM and washed with 2 M aqueous HCl (5 ml). The organic layer was separated with a hydrophobic frit and the aqueous layer was neutralised to pH 7 by addition of 2M NaOH resulting in the formation of a solid precipitate. This was filtered off under vacuum and dried in air for 2 h to give the title compound as a cream solid (220 mg).
Reaction SMILES: [OH:1][C@@H:2]([C:4]1[N:15]([C@H:16]2[CH2:21][CH2:20][C@H:19]([CH2:22][C:23]([O:25]CC)=[O:24])[CH2:18][CH2:17]2)[C:7]2=[C:8]3[S:14][CH:13]=[CH:12][C:9]3=[N:10][CH:11]=[C:6]2[N:5]=1)[CH3:3].O.[OH-].[Li+].CO.Cl>O.O1CCCC1>[OH:1][C@@H:2]([C:4]1[N:15]([C@H:16]2[CH2:21][CH2:20][C@H:19]([CH2:22][C:23]([OH:25])=[O:24])[CH2:18][CH2:17]2)[C:7]2=[C:8]3[S:14][CH:13]=[CH:12][C:9]3=[N:10][CH:11]=[C:6]2[N:5]=1)[CH3:3]
Reactant: CCOC(=O)C[C@H]1CC[C@H](n2c([C@@H](C)O)nc3cnc4ccsc4c32)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: C[C@@H](O)c1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](CC(=O)O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of ethyl (trans-4-{2-[(1R)-1-hydroxyethyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl}cyclohexyl)acetate (0.15 g, 0.39 mmol) and lithium hydroxide, monohydrate (0.079 g, 1.9 mmol) in water (0.7 mL)/methanol (1.7 mL)/tetrahydrofuran (1.7 mL) was stirred at room temperature overnight. The reaction was acidified with 1N aq. HCl solution to pH=4, extracted with methylene chloride. The combined organic layers were dried over MgSO4 and concentrated to give the desired product (0.11 g, 79%) to be used in the next step directly. LCMS calculated for C18H22N3O3S (M+H)+: m/z=360.1. Found: 360.1.
Reaction SMILES: [OH:1][CH2:2][C@:3]1([C:32]([O:34]C)=[O:33])[CH2:7][CH2:6][CH2:5][C@H:4]1[N:8]([CH3:31])[S:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]=[C:22]([CH3:30])[CH:21]=2)=[CH:14][CH:13]=1)(=[O:11])=[O:10].[OH-].[Na+].Cl.[CH2:39](N(CC)CC)C>>[CH3:39][C@@:4]1([N:8]([CH3:31])[S:9]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH2:19][C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]=[C:22]([CH3:30])[CH:21]=3)=[CH:16][CH:17]=2)(=[O:11])=[O:10])[CH2:5][CH2:6][CH2:7][C@:3]1([CH2:2][OH:1])[C:32]([OH:34])=[O:33]
Reactant: COC(=O)[C@@]1(CO)CCC[C@H]1N(C)S(=O)(=O)c1ccc(OCc2cc(C)nc3ccccc23)cc1
Reactant: CCN(CC)CC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(COc2ccc(S(=O)(=O)N(C)[C@]3(C)CCC[C@]3(CO)C(=O)O)cc2)c2ccccc2n1

Procedure:
According to the procedure of Example 56, Step 4, methyl (1S,2R)-1-(hydroxymethyl) -2-[methyl({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]cyclopentanecarboxylate (213 mg, 0.439 mmol), 5M sodium hydroxide solution (0.44 mL), and triethylamine hydrochloride (365 mg, 2.63 mmol) provided methyl (1S,2R)-1-(hydroxymethyl)-2-[methyl({4-[(2-methylquinolin -4-yl)methoxy]phenyl}sulfonyl)amino]cyclopentanecarboxylic acid. To the acid was added BOP (867 mg, 1.96 mmol), hydroxylamine hydrochloride (649 mg, 9.27 mmol), and triethylamine (2.1 mL) to give (1S,2R)-N-hydroxy-1-(hydroxymethyl) -2-[methyl({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]cyclopentanecarboxamide (86.7 mg, 41%) as a colorless solid after purification via HPLC, eluting with a gradient of 15-100% MeCN/H2O (10 min). LCMS (M−H): 1.57 min, 484.3; 1H NMR (400 MHz, MeOD) δ ppm 1.44-1.49 (m, 1H) 1.56-1.62 (m, 2H) 1.64-1.68 (m, 1H) 2.02-2.12 (m, 1H) 2.67 (s, 3H) 3.43-3.53 (m, 2H) 3.67 (d, J=11.37 Hz, 1H) 5.58 (s, 2H) 7.21 (d, J=9.09 Hz, 2H) 7.50 (s, 1H) 7.56 (t, J=7.71 Hz, 1H) 7.69-7.75 (m, 1H) 7.84 (d, J=8.84 Hz, 2H) 7.96 (d, J=8.59 Hz, 1H) 8.01 (d, J=8.34 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[CH:27]([O:29]CCCC)=[CH2:28].C1C=CC(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)C.CN(C=O)C>[C:27]([C:3]1[C:4]2[CH2:10][CH2:9][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:7][CH2:6][C:5]=2[CH:17]=[CH:18][C:2]=1[Cl:1])(=[O:29])[CH3:28]
Reactant: C=COCCCC
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(=O)c1c(Cl)ccc2c1CCN(C(=O)C(F)(F)F)CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.7 %

Procedure:
Combine 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.6 g, 1.41 mmol), butyl vinyl ether (0.9 mL, 7.06 mmol), palladium(II) acetate (32 mg, 0.14 mmol), DPPP (58 mg, 0.14 mmol), triethylamine (90.4 mL, 2.82 mmol), anhydrous DMF (10 mL) and stir at 90° C. for 2 h. Cool the reaction mixture to room temperature, add diethyl ether (25 mL) and wash with brine (15 mL). Separate the organic layer, dry over anhydrous Na2SO4, filter and concentrate in vacuo. Dissolve the residue in methanol (20 mL), add 1N aqueous HCl (18 mL) and stir at 70° C. for 2 h. Cool the reaction mixture to room temperature and remove methanol by evaporation. Dissolve the residue in diethyl ether (20 mL), wash with brine, collect the organic layer and dry over Na2SO4. Concentrate in vacuo and purify the crude mixture by chromatography on silica gel eluting with hexane/EtOAc (1:0 to 3:2 gradient) to obtain the desired intermediate as a colorless oil (0.4 g, 90%). MS (ES+) m/z: 320 (M+H)+.
Reaction SMILES: [CH2:1]([C:6]1[S:10][C:9]([NH:11][C:12]([C:14]2[N:15]([CH3:22])[CH:16]=[C:17]([N+:19]([O-:21])=[O:20])[CH:18]=2)=[O:13])=[N:8][C:7]=1[C:23](O)=[O:24])[CH2:2][CH:3]([CH3:5])[CH3:4].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:50][N:51]([CH2:53][CH2:54][CH2:55][NH2:56])[CH3:52]>CN(C=O)C.CN1CCOCC1>[CH3:50][N:51]([CH3:52])[CH2:53][CH2:54][CH2:55][NH:56][C:23]([C:7]1[N:8]=[C:9]([NH:11][C:12]([C:14]2[N:15]([CH3:22])[CH:16]=[C:17]([N+:19]([O-:21])=[O:20])[CH:18]=2)=[O:13])[S:10][C:6]=1[CH2:1][CH2:2][CH:3]([CH3:5])[CH3:4])=[O:24]
Reactant: CC(C)CCc1sc(NC(=O)c2cc([N+](=O)[O-])cn2C)nc1C(=O)O
Reactant: CN(C)CCCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)CCc1sc(NC(=O)c2cc([N+](=O)[O-])cn2C)nc1C(=O)NCCCN(C)C

Procedure:
5-Isopentyl-2-{[(1-methyl-4-nitro-1H-pyrrol-2-yl)carbonyl]amino}-1,3-thiazole-4-carboxylic acid (570 mg, 1.56 mmol; see step (iv) above) was dissolved in DMF (2.5 mL, dry) to which NMM (0.5 mL, dry), HBTU (1.18 g, 3.12 mmol) and dimethylaminopropylamine (318 mg, 3.12 mmol, Aldrich) were added at room temperature with stirring. After the standard work up and purification, the sub-title compound was obtained as a yellow solid (660 mg, 94%), m.p.>230° C.
Reaction SMILES: [F:1][CH:2]([F:34])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]([CH3:21])[CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[CH:11]=[C:10]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[N:9]=2)[C:6]2[CH:28]=[CH:29][CH:30]=[C:31]([O:32][CH3:33])[C:5]=2[N:4]=1.CCN(CC)CC.[CH3:42][S:43](Cl)(=[O:45])=[O:44]>C1COCC1.O>[F:34][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]([CH3:21])[CH:15]3[CH2:20][CH2:19][N:18]([S:43]([CH3:42])(=[O:45])=[O:44])[CH2:17][CH2:16]3)[CH:11]=[C:10]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[N:9]=2)[C:6]2[CH:28]=[CH:29][CH:30]=[C:31]([O:32][CH3:33])[C:5]=2[N:4]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)cc(N(C)C2CCNCC2)n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)cc(N(C)C2CCN(S(C)(=O)=O)CC2)n1
Temperature: 0 °C
Yield: 8.9 %

Procedure:
A mixture of 95 mg (2 mmol) of 2-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-methyl-6-(4-morpholinyl)-N-(4-piperidinyl)-4-pyrimidinamine and 61 mg (6 mmol) of Et3N in 15 mL THF was cooled to 0° C. and 46 mg (4 mmol) of methanesulphonyl chloride was added. The stirred mixture was allowed to warm to room temperature, and after 2 hrs it was diluted with water to give a precipitate of 98 mg (89% yield) of 2-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-methyl-N-[1-(methylsulfonyl)-4-piperidinyl]-6-(4-morpholinyl)-4-pyrimidinamine: mp (MeOH) 191-193° C.; 1H NMR (CDCl3) δ 7.77 (dd, J=8.4. 0.6 Hz, 1H), 7.37 (t, JHF=53.4 Hz, 1H), 7.31 (t, J=8.2 Hz, 1H), 6.79 (d, J=7.6 Hz, 1H), 5.40 (s, 1H), 4.96 (m, 1H), 4.05 (s, 3H), 3.99-3.93 (m, 2H), 3.83 (m, 4H), 3.64 (m, 4H), 2.90 (s, 3H), 2.82 (s, 3H), 2.81 (dt, J=12.0, 2.4 Hz, 2H), 1.91 (dq J=12.3, 4.3 Hz, 2H), 1.85-1.76 (m, 2H); Anal. Calcd. for C24H31F2N7O4S: C, 52.3; H, 5.7; N, 17.8. Found: C, 52.5; H, 5.7; N, 17.9%.
Reaction SMILES: [CH:1]1([CH2:4][C:5]2[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13](S(C)=O)[N:12]=3)=[CH:9][N:8]=[C:7]([NH2:20])[N:6]=2)[CH2:3][CH2:2]1.Cl.[O:22]1[CH2:27][CH2:26][CH2:25][CH:24]([NH2:28])[CH2:23]1.C(N(CC)CC)C>CS(C)=O>[CH:1]1([CH2:4][C:5]2[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH:28][CH:24]4[CH2:25][CH2:26][CH2:27][O:22][CH2:23]4)[N:12]=3)=[CH:9][N:8]=[C:7]([NH2:20])[N:6]=2)[CH2:3][CH2:2]1
Reactant: NC1CCCOC1
Reactant: CS(=O)c1nccc(-c2cnc(N)nc2CC2CC2)n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Nc1ncc(-c2ccnc(NC3CCCOC3)n2)c(CC2CC2)n1
Yield: 13 %

Procedure:
To a solution of 4′-(cyclopropylmethyl)-2-(methylsulfinyl)-4,5′-bipyrimidin-2′-amine (5-2) (50 mg, 0.173 mmol) in DMSO (1 ml), was added Tetrahydro-pyran-3-ylamine HCl (119 mg, 0.864 mmol) and triethylamine (0.120 ml, 0.864 mmol) and the reaction was microwaved for 45 min at 160° C. The reaction was purified directly by reverse phase HPLC with a gradient of 10-90% acetonitrile in water over 15 minutes and then further purified by flash chromatography with a gradient of 25-100% ethyl acetate in heptane to give the desired product as a white solid (7.36 mg).