Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:13]([OH:15])=[O:14])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][CH:10]1[CH2:12][CH2:11]1.[F:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][C:22]=1[F:23]>>[CH:10]1([CH2:9][O:8][C:7]2[C:2]([C:20]3[CH:19]=[CH:18][C:17]([F:16])=[C:22]([F:23])[CH:21]=3)=[CH:3][C:4]([C:13]([OH:15])=[O:14])=[CH:5][N:6]=2)[CH2:12][CH2:11]1
Reactant: O=C(O)c1cnc(OCC2CC2)c(Br)c1
Reactant: OB(O)c1ccc(F)c(F)c1
Product: O=C(O)c1cnc(OCC2CC2)c(-c2ccc(F)c(F)c2)c1

Procedure:
The title compound was synthesized in analogy to Example BQ using 5-bromo-6-(cyclopropylmethoxy)-3-pyridinecarboxylic acid (CAN 912454-38-7) and B-(3,4-difluorophenyl)-boronic acid, (CAN 168267-41-2) as starting materials; MS (ESI): 304.2 (M−H)−.
Reaction SMILES: C(O[C:4]([SH:6])=[S:5])C.[K].Br[C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:10]=1[NH2:19].Cl>CN(C)C=O>[SH:6][C:4]1[S:5][C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:16])([F:18])[F:17])=[CH:11][C:10]=2[N:19]=1
Reactant: Nc1cc(C(F)(F)F)ccc1Br
Reactant: CCOC(=S)S
Agent: Cl
Agent: [K]
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc2sc(S)nc2c1
Temperature: 25 °C
Yield: 92 %

Procedure:
In analogy to the procedure of Chaudhuri, N. Synth. Commun. 1996, 26, 20, 3783, O-ethylxanthic acid, potassium salt (Lancaster, 7.5 g, 46.9 mmol) was added to a solution of 2-bromo-5-trifluoromethylphenylamine (Aldrich, 5.0 g, 20.8 mmol) in N,N-dimethylformamide (DMF, 30 mL). The mixture was heated to reflux for 4 hours. After cooling to room temperature, the mixture was poured into ice water and acidified with 2N HCl. The solid product was collected by filtration. Recrystalization from CHCl3/Hexanes gave 239 (4.5 g, 92%) as a white solid.
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[C:9](=[O:10])[C:8]2[C:11]([CH3:19])=[C:12]([C:14](=[O:18])[N:15]([CH3:17])[CH3:16])[S:13][C:7]=2[N:6]=[CH:5]1.S(Cl)([Cl:22])=O>ClCCCl>[Cl:22][CH2:2][CH2:3][N:4]1[C:9](=[O:10])[C:8]2[C:11]([CH3:19])=[C:12]([C:14](=[O:18])[N:15]([CH3:17])[CH3:16])[S:13][C:7]=2[N:6]=[CH:5]1
Reactant: O=S(Cl)Cl
Reactant: Cc1c(C(=O)N(C)C)sc2ncn(CCO)c(=O)c12
Solvent: ClCCCl
Product: Cc1c(C(=O)N(C)C)sc2ncn(CCCl)c(=O)c12
Yield: 83 %

Procedure:
29.9 g (106 mM [sic]) of 3-(2-hydroxyethyl)-5-methyl-6-dimethylcarbamoylthieno [2,3-d]pyrimidin-4-one in 200 ml of 1,2-dichloroethane were heated to reflux (slow dissolution) and then 12.7 ml (175 mM [sic]) of thionyl chloride in 20 ml of 1,2-dichloroethane were added dropwise. After refluxing for 1 h, the reaction mixture was cooled and concentrated. The crude product was partitioned between methylene chloride and water at pH=9. Drying and concentration of the organic phase resulted in isolation of 44.1 g (83%) of product as a dark oil which was purified by column chromatography (silica gel, eluent ethyl acetate). 23.8 g (76%) of product were isolated with melting point 120-122° C.
Reaction SMILES: [CH2:1]([O:3][N:4]=[C:5]([C:28]1[N:29]=[C:30]([NH:33]C=O)[S:31][CH:32]=1)[C:6]([NH:8][CH:9]1[C:26](=[O:27])[N:11]2[C:12]([C:23]([O-:25])=[O:24])=[C:13]([CH2:16][N+:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:14][S:15][C@H:10]12)=[O:7])[CH3:2].Cl.O.C(OCC)(=O)C>CO>[CH2:1]([O:3][N:4]=[C:5]([C:28]1[N:29]=[C:30]([NH2:33])[S:31][CH:32]=1)[C:6]([NH:8][CH:9]1[C:26](=[O:27])[N:11]2[C:12]([C:23]([O-:25])=[O:24])=[C:13]([CH2:16][N+:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:14][S:15][C@H:10]12)=[O:7])[CH3:2]
Reactant: CCON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(C[n+]3ccccc3)CS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: CCON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(C[n+]3ccccc3)CS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 26.4 %

Procedure:
A mixture of 7-[2-ethoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer) (1.4 g) in methanol (20 ml) and conc. hydrochloric acid (0.85 g) were stirred for 2.5 hours at room temperature. The reaction mixture was added to a mixture of water and ethyl acetate. The aqueous layer was separated, washed with ethyl acetate and adjusted to pH 4.0 with 10% aqueous solution of sodium hydroxide. The resulting solution was subjected to column chromatography on macroporous non-ionic adsorption resin "Diaion HP-20" (Trademark: prepared by Mitsubishi Chemical Industries) and eluted with 5% aqueous solution of isopropyl alcohol. The fractions containing the object compound were concentrated and lyophilized to give 7-[2-ethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer) (0.35 g).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6]/[C:7]/2=[N:12]\O.CC(C[AlH]CC(C)C)C.CCCCCC.[F-].[Na+].Cl>C(Cl)Cl.O>[Br:1][C:2]1[C:3]2[CH2:4][CH2:5][CH2:6][CH2:7][NH:12][C:8]=2[CH:9]=[CH:10][CH:11]=1
Reactant: O/N=C1\CCCc2c(Br)cccc21
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Agent: [F-]
Solvent: O
Solvent: ClCCl
Solvent: CCCCCC
Product: Brc1cccc2c1CCCCN2
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.1 %

Procedure:
To a solution of (E)-5-bromo-3,4-dihydronaphthalen-1(2H)-one oxime (1.41 g, 5.87 mmol) in DCM (20 mL) at −10° C. under nitrogen was slowly added a solution of 1.0 M DIBAL-H in hexane (35.2 mL, 35.2 mmol). Upon completion of addition, the reaction mixture was stirred at room temperature for 2 h. After this time, the reaction mixture was cooled to 0° C. and then sodium fluoride (7.40 g, 176 mmol) and water (3.0 mL) were slowly added. The resulting mixture was stirred at 0° C. for 30 min and then CELITE® was added. The mixture was filtered and rinsed with DCM (100 mL). The filtrate was dried over anhydrous Na2SO4, filtered, and concentrated to provide the crude product. The crude product was converted to the HCl salt with aqueous 1.0 N HCl (3.0 mL) and then purified by preparative HPLC (PHENOMENEX® Axia Luna 5μ C18 30×100 mm; 10 min gradient from 80% A:20% B to 0% A:100% B and 5 min 100% B (A=90% H2O/10% MeOH+0.1% TFA); (B=90% MeOH/10% H2O+0.1% TFA); detection at 220 nm). The purified product was free based with a solution of saturated sodium bicarbonate (15 mL) and was then extracted with ethyl acetate (20 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to afford the title compound (612 mg, 45% yield). LCMS, [M+Na]+=236.0. 1H NMR (400 MHz, MeOD) δ 7.12 (dd, J=7.8, 1.4 Hz, 1H), 6.88 (t, J=7.8 Hz, 1H), 6.83 (dd, J=7.8, 1.4 Hz, 1H), 3.08-3.02 (m, 4H), 1.86-1.79 (m, 2H), 1.69-1.62 (m, 2H).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Si:13]([N:20]1[C@H:23]([CH2:24][C:25]([S:30][CH3:31])([S:28][CH3:29])[S:26][CH3:27])[CH2:22][C:21]1=[O:32])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].[CH:33](=[O:35])[CH3:34]>O1CCCC1>[Si:13]([N:20]1[C@H:23]([CH2:24][C:25]([S:28][CH3:29])([S:26][CH3:27])[S:30][CH3:31])[C@@H:22]([C@H:33]([OH:35])[CH3:34])[C:21]1=[O:32])([C:16]([CH3:17])([CH3:19])[CH3:18])([CH3:15])[CH3:14]
Reactant: CSC(C[C@@H]1CC(=O)N1[Si](C)(C)C(C)(C)C)(SC)SC
Reactant: CC=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CSC(C[C@@H]1[C@@H]([C@@H](C)O)C(=O)N1[Si](C)(C)C(C)(C)C)(SC)SC
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 50.3 %

Procedure:
n-Butyllithium (14.8 ml of 2.5 N hexane solution, 37.0 mmol) is added by syringe to a solution of diisopropylamine (3.74 g, 37.0 mmol) in 180 ml of freshly distilled tetrahydrofuran at -78° C. The resulting solution is stirred at -78° C. for 15 min prior to the addition of a solution of (4S)-1-(t-butyldimethylsilyl)-4-[2,2,2-tri(methylthio)ethyl]azetidin-2-one (12.34 g, 35.16 mmol) in 35 ml of tetrahydrofuran. This solution is stirred at -78° C. for 10 min prior to the addition of acetaldehyde (4.62 g, 105 mmol). The solution is stirred for an additional 5 min. at -78° C. and then quenched by addition of saturated aqueous ammonium chloride solution, and allowed to warm to room temperature. The mixture is poured into 250 ml of ether and washed with water (2×100 ml) and brine and dried over magnesium sulfate. Removal of solutions in vacuo gives an oil which is chromatographed on a silica gel column (1:1 ether:petroleum ether) to give (3S,4R)-1-(t-butyldimethylsilyl)-3-[(R)-1-hydroxyethyl]-4-[2,2,2-tri(methylthio)ethyl]-azetidin-2-one (7.0 g, 50.4%) at Rf =0.2. The product can be recrystallized from petroleum ether. Alternatively, the trans R product can be isolated from the crude reaction mixture by direct crystallization from a petroleum ether solution.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]([Cl:14])=[C:12]2[C:8]([C:9]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[C:10](Br)[NH:11]2)=[CH:7][CH:6]=1)=[O:4].[Li+].[Cl-].C([O-])([O-])=O.[Na+].[Na+].[CH3:30][O:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1>C1(C)C=CC=CC=1.C(O)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:13]([Cl:14])=[C:12]2[C:8]([C:9]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[C:10]([C:35]3[CH:36]=[CH:37][C:32]([O:31][CH3:30])=[CH:33][CH:34]=3)[NH:11]2)=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(Br)[nH]c2c1Cl
Reactant: COc1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccc(OC)cc3)[nH]c2c1Cl
Temperature: 70 °C
Reaction time: 18 h
Yield: 81.9 %

Procedure:
To 572.0 mgs (1.54 mmol) of Methyl-2-bromo-7-chloro-3-cyclohexyl-1H-indole-6-carboxylate in 8 mL of toluene and 8 mL of ethanol was added 2 equivalents of LiCl (3.08 mmol, 130.6 mgs), 2.5 equivalents of Na2CO3 (3.85 mmol, 408.1 mgs) in 4 mL of water, and 1.5 equivalents of para-methoxyphenyl boronic acid (2.31 mmol, 351.0 mgs). To this mixture was then added 0.1 equivalents of PdCl2(PPh3)2 (150.0 μmol, 105.3 mgs), and the mixture was degassed then flushed with N2 (×3). The reaction mixture was heated to 70° C. overnight. After 18 hours, the mixture was cooled to room temperature, concentrated to near dryness then extracted with ethyl acetate. The crude product was purified using automated flash chromatography (Biotage Horizon™, gradient elution, 0 to 40% Ethyl Acetate/Hexane) to give 502.0 mgs (82%) of Methyl-7-chloro-3-cyclohexyl-2-(4-methoxyphenyl)-1H-indole-6-carboxylate as an ivory colored solid. The LC/MS data was obtained on a Shimadzu analytical LC/Micromass Platform LC (ESI+) at 220 nm using the following set of conditions: Phenomenex 10 μm C18, 4.6×30 mm column, with a gradient of 0-100% B (B=90% HPLC grade methanol/0.1% trifluoroacetic acid/10% HPLC grade water), (A=90% HPLC grade water/0.1% trifluoroacetic acid/10% HPLC grade methanol), in 2 minutes with a 1 minute hold at a rate of 5 mL/minute.
Reaction SMILES: [C:1](Cl)(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:12]([C:16]1[CH:42]=[CH:41][C:19]([CH2:20][O:21][C:22]2[CH:23]=[C:24]([CH:38]=[CH:39][CH:40]=2)[C:25]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[S:34](=[O:37])(=[O:36])[NH2:35])=[O:26])=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13]>CN(C)C1C=CN=CC=1.O1CCCC1>[C:12]([C:16]1[CH:42]=[CH:41][C:19]([CH2:20][O:21][C:22]2[CH:23]=[C:24]([CH:38]=[CH:39][CH:40]=2)[C:25]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[S:34]([NH:35][C:1](=[O:10])[CH:2]=[CH:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)(=[O:36])=[O:37])=[O:26])=[CH:18][CH:17]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: CC(C)(C)c1ccc(COc2cccc(C(=O)Nc3ccccc3S(N)(=O)=O)c2)cc1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(COc2cccc(C(=O)Nc3ccccc3S(=O)(=O)NC(=O)C=Cc3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.7 %

Procedure:
In a stream of nitrogen and at 0° C., 126 mg (0.75 mmol) of cinnamoyl chloride was added to an anhydrous tetrahydrofuran (10 ml) solution containing 300 mg (0.68 mmol) of 3-(4-t-butylbenzyloxy)-N-(2-sulfamoylphenyl)benzamide produced in Reference Example 2 and 167 mg (1.36 mmol) of 4-dimethylaminopyridine, the mixture was stirred at room temperature for 1 hour and then the solvent was evaporated under a reduced pressure. The resulting residue was dissolved in ethyl acetate, washed with water, a potassium hydrgensulfate aqueous solution and saturated brine in that order and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. The resulting crude crystals were washed with methanol to obtain 370 mg (yield: 95.0%) of the title compound.
Reaction SMILES: [C:1](=[O:36])([O:14][CH2:15]/[C:16](/[C:26]1[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][CH:27]=1)=[C:17](/[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)\[CH2:18][OH:19])[O:2][CH2:3][CH:4]([O:10][N+:11]([O-:13])=[O:12])[CH2:5][O:6][N+:7]([O-:9])=[O:8].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=[O:39].CC(=CC)C.P(=O)(O)(O)O.[O-]Cl=O.[Na+]>ClCCl.C1COCC1.CC(O)(C)C.O>[N+:11]([O:10][CH:4]([CH2:5][O:6][N+:7]([O-:9])=[O:8])[CH2:3][O:2][C:1]([O:14][CH2:15][C:16]([C:26]1[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:33])=[O:34])=[CH:28][CH:27]=1)=[C:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:18]([OH:39])=[O:19])=[O:36])([O-:13])=[O:12]
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Reactant: CS(=O)(=O)c1ccc(/C(COC(=O)OCC(CO[N+](=O)[O-])O[N+](=O)[O-])=C(/CO)c2ccccc2)cc1
Agent: CC=C(C)C
Agent: O=P(O)(O)O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(COC(=O)OCC(CO[N+](=O)[O-])O[N+](=O)[O-])=C(C(=O)O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 38.7 %

Procedure:
To a solution of 3.1 g of 2,3-bis(nitrooxy)propyl (2Z)-4-hydroxy-2-[4-(methylsulfonyl)phenyl]-3-phenylbut-2-en-1-yl carbonate in 30 mL of dichloromethane was added 3.1 g of Dess-Martin reagent and the resultant mixture was stirred at rt for 2 h. Then 3 mL of water was added and the resultant mixture was stirred at rt for 0.5 h. The cloudy mixture was then filtered and filtrate extracted 3× with EtOAc. The organic layers were combined, dried (Na2SO4), filtered and concentrated in vacuo to give a pale yellow residue. The crude material was then dissolved in a solvent mixture of 5 mL of THF with 5 mL of t-BuOH and to this was added 2 mL of 2-methyl-2-butene followed by the addition of 2 mL of 1 M of phosphoric acid and 1.16 g of NaClO2. The reaction mixture was stirred at rt for 3.5 h. The organic phase was separated and the aqueous phase was extracted with EtOAc. The combined organic layer was dried (Na2SO4), filtered, and then concentrated in vacuo. The crude was purified by recrystallization from warm ether to afford 1.23 g of the title compound as a white solid. 1H NMR (500 MHz, acetone-d6): δ 7.79 (d, 2H), 7.47 (d, 2H), 7.22-7.14 (m, 5H), 5.75-5.72 (m, 1H), 5.43 (s, 2H), 5.03 (dd, 1H), 4.83 (dd, 1H), 4.63 (dd, 1H), 4.47 (dd, 1H), 3.08 (s, 3H).
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[F:27][C:28]1[N:36]=[C:35]([F:37])[CH:34]=[CH:33][C:29]=1[C:30](O)=[O:31].C(N(C(C)C)CC)(C)C>CN(C=O)C.C(OCC)(=O)C.O>[F:27][C:28]1[N:36]=[C:35]([F:37])[CH:34]=[CH:33][C:29]=1[C:30]([N:3]([O:4][CH3:5])[CH3:2])=[O:31]
Reactant: O=C(O)c1ccc(F)nc1F
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CON(C)C(=O)c1ccc(F)nc1F
Temperature: 25 °C
Reaction time: 48 h
Yield: 91.9 %

Procedure:
N,O-dimethylhydroxylamine hydrochloride (14.7 g), WSC (28.9 g), and HOBt (20.4 g) were added to a solution of 2,6-difluoronicotinic acid (6 g) and diisopropylethylamine (10 mL) in DMF (100 mL), and the reaction solution was stirred at room temperature for two days. Water and ethyl acetate were added to the reaction solution, and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: ethyl acetate) to obtain 7.01 g of the title compound.
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:58][N:59]([CH3:63])[CH2:60][CH2:61][NH2:62]>>[CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:62][CH2:61][CH2:60][N:59]([CH3:63])[CH3:58])=[O:29])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN(C)CCN
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)NCCN(C)C)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and N,N-dimethylethylenediamine. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.13-1.27 (m, 2 H) 1.27-1.51 (m, 2 H) 1.51-1.86 (m, 6 H) 2.17 (s, 6 H) 2.39 (t, J=7.8 Hz, 2 H) 3.31 (s, 3 H) 3.38 (m, 2 H) 3.93 (s, 3 H) 4.06 (t, J=13.39 Hz, 2 H) 4.46 (m, 1 H) 7.48 (d, J=8.0 Hz, 1 H) 7.52 (s, 1 H) 7.91 (s, 1 H) 8.21 (s, 1 H) 8.28 (d, J=8.34 Hz, 1 H) 8.35 (br. s., 1 H). [M+H] calculated for C26H35F2N7O3, 532; found 532.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[C:10](O)[N:9]=[C:8]([S:13][CH2:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)[N:7]=1)=[O:5])[CH3:2].N1C=CC=CC=1C.O=P(Cl)(Cl)[Cl:34]>>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[C:10]([Cl:34])[N:9]=[C:8]([S:13][CH2:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(O)nc(SCc2ccc3ccccc3c2)n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccn1
Product: CCOC(=O)c1cc(Cl)nc(SCc2ccc3ccccc3c2)n1
Yield: 70 %

Procedure:
A solution of 6-hydroxy-2-(2-naphthylmethylthio)-pyrimidine-4-carboxylic acid ethyl ester (2.32 g, 6.81 mmol) and 2-picoline (0.7 ml) in POCl3 (7 ml) were stirred at rt for 3 hrs, then poured onto ice. The solid was collected by filtration then heated briefly with NH4OH for 15 min. The solid was collected and recrystallized from methanol to yield 1.72 g (70%) of 6-chloro-2-(2-naphthylmethylthio)-pyrimidine-4-carboxylic acid ethyl ester, mp 95-96° C.
Reaction SMILES: ClN1C(=O)CCC1=O.[CH:9](=[N:11][OH:12])[CH3:10].[C:13]([O:17][CH3:18])(=[O:16])[C:14]#[CH:15].C(N(CC)CC)C>C(Cl)(Cl)Cl.O.N1C=CC=CC=1>[CH3:10][C:9]1[CH:15]=[C:14]([C:13]([O:17][CH3:18])=[O:16])[O:12][N:11]=1
Reactant: CC=NO
Reactant: C#CC(=O)OC
Agent: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(C)no1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 62 %

Procedure:
To a solution of N-chlorosuccinimide (2.67 g, 20 mmol) and pyridine (0.1 mL) in chloroform (18 mL), was added, portionwise, acetaldehyde oxime (1.18 g, 20 mmol), at about 5° C. After complete addition the mixture was stirred at rt for about 10 min and then methyl propiolate (2.22 mL, 25 mmol) was added. Subsequently, a solution of triethylamine (2.92 mL, 21 mmol) in chloroform (3 mL) was added dropwise, at such a rate that the temperature was maintained between 15 and 18° C. After complete addition the mixture was stirred at about 18° C. for about 20 min, then water (15 mL) was added. The layers were separated and the organic layer was washed with water (15 mL), dried (MgSO4), filtered, and concentrated in vacuo. The residue was treated with diethyl ether (20 mL) and the formed precipitate was collected by filtration and dried to give methyl 3-methylisoxazole-5-carboxylate (1.75 g, 12.4 mmol, 62%) as a brown solid which was used as such: 1H-NMR (CDCl3, Bruker 400 MHz) 2.38 (3 H, s); 3.96 (3 H, s); 6.80 (1 H, s).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][OH:20])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.OCCN1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[NH:33]1[C:32]2[C:31](=[C:4]([C:2]3[N:3]=[C:4]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[C:5]4[S:10][C:9]([CH2:11][N:12]5[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][OH:20])[CH2:14][CH2:13]5)=[CH:8][C:6]=4[N:7]=3)[CH:5]=[CH:6][CH:8]=2)[CH:35]=[CH:34]1
Reactant: OCCN1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: OCCN1CCNCC1
Product: OCCN1CCN(Cc2cc3nc(-c4cccc5[nH]ccc45)nc(N4CCOCC4)c3s2)CC1

Procedure:
Via 2-[4-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperazin-1-yl]-ethanol, prepared from N-(2-hydroxyethyl)piperazine (commercially available).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:19]=[CH:18][C:17]4[N:16]([CH2:20][C:21]([O:23]C(C)(C)C)=[O:22])[CH2:15][C@@H:14]5[CH2:28][O:29][CH2:30][CH2:31][N:13]5[C:12]=4[N:11]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[ClH:32]>>[ClH:32].[NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:19]=[CH:18][C:17]4[N:16]([CH2:20][C:21]([OH:23])=[O:22])[CH2:15][C@@H:14]5[CH2:28][O:29][CH2:30][CH2:31][N:13]5[C:12]=4[N:11]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: CC(C)(C)OC(=O)CN1C[C@@H]2COCCN2c2nc(-c3cccc4[nH]ccc34)ncc21
Agent: Cl
Product: O=C(O)CN1C[C@@H]2COCCN2c2nc(-c3cccc4[nH]ccc34)ncc21
Temperature: 70 °C
Reaction time: 1 h
Yield: 113.1 %

Procedure:
A mixture of (R)-tert-butyl 2-(2-(1H-indol-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)acetate (250 mg, 0.593 mmol), HCl (4M in 1,4-dioxane) (10 mL, 40.0 mmol) and 1 N hydrochloric acid (2 mL, 2 mmol) was stirred at 70° C. for 1 hour. The mixture was subsequently concentrated in vacuo to give an HCl salt of the title compound as a brown solid (245 mg, 103%). 1H NMR (400 MHz, DMSO-d6) δ 3.17-3.74 (m, 5 H), 3.90-4.03 (m, 2 H), 4.06-4.17 (m, 2 H), 4.46 (d, J=18.19 Hz, 1 H), 4.73 (d, J=12.13 Hz, 1 H), 7.00 (br s, 1 H), 7.29 (t, J=7.83 Hz, 1 H), 7.52-7.62 (m, 2 H), 7.69 (d, J=7.83 Hz, 2 H), 11.61 (br s, 1 H), 13.14 (br s, 1 H) 14.22 (br s, 1 H). ESI-MS m/z [M+H]+ calc'd for C19H19N5O3, 366.15; found 366.2.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8]([CH:11]=[O:12])=[CH:7][C:6]=2[CH:13]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:20](Br)[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>CN(C=O)C.O>[CH2:20]([O:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8]([CH:11]=[O:12])=[CH:7][C:6]=2[CH:13]=1)[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: O=CC1=Cc2cc(O)ccc2OC1
Reactant: CCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCOc1ccc2c(c1)C=C(C=O)CO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The starting material is prepared as follows: A mixture of 6-hydroxy-2H-1-benzopyran-3-carboxaldehyde (4.0 g, 22.7 mmol) and potassium carbonate (6.26 g, 45.3 mmol) in 80 ml of DMF is treated with n-hexyl bromide (4.5 g, 27.2 mmol). The mixture is stirred overnight at room temperature. Additional potassium carbonate (3.1 g, 22.4 mmol) and n-hexyl bromide (1.0 g, 6.1 mmol) are added and, after another overnight reaction, no more starting material is detected in the reaction mixture. The reaction mixture is diluted with water and extracted three times with dichloromethane. The combined organic phases are dried (MgSO4) and evaporated. Purification by silica gel chromatography (10% ethyl acetate/hexane) yields 6-(n-hexyloxy)-2H-1-benzopyran-3-carboxaldehyde, m.p. 36°-38° C., which is converted as described above to 3-(N-hydroxyaminomethyl)-6-(n-hexyloxy)-2H-1-benzopyran.