Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[NH:12][C:11]2[CH2:21][O:22][C:23](=[O:24])[C:10]1=2.[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:25]([NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[NH:12][C:11]2[CH2:21][O:22][C:23](=[O:24])[C:10]1=2)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)C1=C(C)NC2=C(C(=O)OC2)C1c1ccccc1N
Reactant: BrCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C1=C(C)NC2=C(C(=O)OC2)C1c1ccccc1NCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3.5 g (10 mmol) of ethyl 4-(2-aminophenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate hydrochloride and 1.4 ml (11 mmol) of benzyl bromide are dissolved in 50 ml of absolute acetone, 1.4 g of potassium carbonate are added, and the mixture is stirred overnight at room temperature. The mixture is concentrated, water is added, and the product is filtered off under suction and recrystallized from methanol.
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:29][CH:5]2[CH:6]([C:19]3[CH:24]=[CH:23][C:22]([O:25]COC)=[CH:21][CH:20]=3)[O:7][C:8]3[C:9]([CH3:18])=[CH:10][C:11]([O:14]COC)=[CH:12][C:13]=3[CH:4]2[CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)(O)[C:52]#[N:53].CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[F:30][C:2]1([F:1])[CH2:29][CH:5]2[CH:6]([C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)[O:7][C:8]3[C:9]([CH2:18][C:52]#[N:53])=[CH:10][C:11]([OH:14])=[CH:12][C:13]=3[CH:4]2[CH2:3]1
Reactant: COCOc1ccc(C2Oc3c(C)cc(OCOC)cc3C3CC(F)(F)CC32)cc1
Reactant: CC(C)(O)C#N
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#CCc1cc(O)cc2c1OC(c1ccc(O)cc1)C1CC(F)(F)CC21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of preparation 20 (58 mg, 0.132 mmol) and triphenyl phosphine (175 mg, 0.67 mmol) and acetone cyanohydrin (0.125 mL, 1.37 mmol) in 1 mL of THF at 0° C. add dropwise via syringe diisopropylazodicarboxylate (0.13 mL, 0.66 mmol). Let the solution warm slowly to room temperature overnight. Concentrate the solution, adsorb the material to silica gel, and purify by silica gel flash chromatography (10 g, 0-30% A/B, A=EtOAc, B=10% CH2Cl2 in hexanes). Dissolve the material in 2 mL of THF and add 1 mL of 5 M aqueous HCl. Stir the solution overnight. Dilute the solution with EtOAc and a little methanol for solubility, wash with saturated aqueous sodium bicarbonate, brine, dry over Na2SO4, filter and concentrate. Adsorb the material to silica gel and purify by silica gel flash chromatography (4 g, 10-60% A/B, A=10% methanol in EtOAc, B=hexanes) to afford example 10. HRMS calc. for C20H17F2NNaO3: 380.1074; found: 380.1060 (M+Na).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH:13]([CH2:16][NH2:17])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:19]1[N:24]=[CH:23][CH:22]=[CH:21][N:20]=1.C(N(CC)C(C)C)(C)C>CC(O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH:13]([CH2:16][NH:17][C:19]2[N:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCC1CCN(C(=O)OCc2ccccc2)C1
Reactant: Brc1ncccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: O=C(OCc1ccccc1)N1CCC(CNc2ncccn2)C1

Procedure:
A mixture of 3-aminomethyl-pyrrolidine-1-carboxylic acid benzyl ester (0.15 g), 2-bromopyrimidine (0.25 g), 2-propanol (10 mL), and of N,N-diisopropylethylamine (0.1 mL) was heated to reflux overnight. Purification of the residue obtained after concentration under reduced pressure by preparative chromatography, and eluting with ethyl acetate, gave 3-(pyrimidin-2-ylaminomethyl)-pyrrolidine-1-carboxylic acid benzyl ester as a solid:
Reaction SMILES: C(O)C.[C:4]([C:7]1[C:15]2[S:14][C:13](=[O:16])[NH:12][C:11]=2[C:10]([OH:17])=[CH:9][CH:8]=1)(=[O:6])[CH3:5].I([Cl:21])(=O)=O.I(Cl)(=O)=O.C([N+](C)(C)C)C1C=CC=CC=1>O>[Cl:21][CH2:5][C:4]([C:7]1[C:15]2[S:14][C:13](=[O:16])[NH:12][C:11]=2[C:10]([OH:17])=[CH:9][CH:8]=1)=[O:6]
Reactant: CC(=O)c1ccc(O)c2[nH]c(=O)sc12
Reactant: O=I(=O)Cl
Agent: C[N+](C)(C)Cc1ccccc1
Solvent: CCO
Solvent: O
Product: O=C(CCl)c1ccc(O)c2[nH]c(=O)sc12
Temperature: 78 °C

Procedure:
Ethanol (1500 mL) was added to a mixture of 7-acetyl-4-hydroxy-3H-benzothiazol-2-one (150 g) (WO2004/016578) and benzyltrimethylammonium dichloroiodate (374 g) in a flask fitted with an overhead stirrer. The mixture was heated to 78° C. for 1 h and left to cool to room temperature overnight. The mixture was poured into water (2 L), and the precipitate collected by filtration, washed with water, filtered to near dryness, and suspended in ethyl acetate. The mixture was heated to reflux and allowed to cool to room temperature with stirring. The solid was collected by filtration, washed with cold ethyl acetate (200 mL) then re-suspended in diethyl ether (1 L). The solid was collected, filtered again and washed with ether (200 mL) and dried in vacuo to give the subtitled compound.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:20])[NH:5][C:6](=[O:19])[NH:7][C:8]=1[C:9](=[O:18])[C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].Cl[CH2:22][C:23](=[O:25])[CH3:24]>>[CH2:22]([N:7]1[C:8]([C:9](=[O:18])[C:10]2[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=2)=[C:3]([CH2:1][CH3:2])[C:4](=[O:20])[NH:5][C:6]1=[O:19])[C:23]([CH3:24])=[O:25]
Reactant: CC(=O)CCl
Reactant: CCc1c(C(=O)c2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Product: CCc1c(C(=O)c2cc(C)cc(C)c2)n(CC(C)=O)c(=O)[nH]c1=O
Yield: 44 %

Procedure:
5-Ethyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and chloroacetone were reacted by the same way with the example 1 to obtain the titled compound (145 mg, yield: 44%).
Reaction SMILES: [CH:1]1([O:6][N:7]=[C:8]([C:31]2[N:32]=[C:33]([NH:36]C=O)[S:34][CH:35]=2)[C:9]([NH:11][CH:12]2[C:29](=[O:30])[N:14]3[C:15]([C:26]([OH:28])=[O:27])=[C:16]([CH2:19][S:20][C:21]4[S:22][CH:23]=[N:24][N:25]=4)[CH2:17][S:18][C@H:13]23)=[O:10])[CH2:5][CH2:4][CH:3]=[CH:2]1.CO.Cl.C(=O)(O)[O-].[Na+]>O.O1CCCC1>[CH:1]1([O:6][N:7]=[C:8]([C:31]2[N:32]=[C:33]([NH2:36])[S:34][CH:35]=2)[C:9]([NH:11][CH:12]2[C:29](=[O:30])[N:14]3[C:15]([C:26]([OH:28])=[O:27])=[C:16]([CH2:19][S:20][C:21]4[S:22][CH:23]=[N:24][N:25]=4)[CH2:17][S:18][C@H:13]23)=[O:10])[CH2:5][CH2:4][CH:3]=[CH:2]1
Reactant: O=CNc1nc(C(=NOC2C=CCC2)C(=O)NC2C(=O)N3C(C(=O)O)=C(CSc4nncs4)CS[C@H]23)cs1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Nc1nc(C(=NOC2C=CCC2)C(=O)NC2C(=O)N3C(C(=O)O)=C(CSc4nncs4)CS[C@H]23)cs1
Yield: 84 %

Procedure:
A mixture of 7-[2-(2-cyclopenten-1-yl)oxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer)(2.5 g), methanol (17.5 ml),conc.hydrochloric acid (0.88 g) and tetrahydrofuran (5.0 ml) was stirred for 1.5 hours at room temperature. To the reaction mixture were added water and a saturated aqueous solution of sodium bicarbonate so that the pH was adjusted to pH 5.0. The resulting mixture was evaporated and to the residue was added ethyl acetate. The mixture was adjusted to pH 7.5 with a saturated aqueous solution of sodium bicarbonate. The aqueous layer was separated, washed with ethyl acetate and evaporated and then the residue was adjusted to pH 3.0 with 10% hydrochloric acid. The precipitates were collected by filtration, washed with water, dried over phosphorus pentoxide under reduced pressure to give 7-[2-(2-cyclopenten-1-yl)oxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer)(2.00 g). mp. 152° to 157° C. (dec.).
Reaction SMILES: [CH2:1]([NH:8][C@H:9]([C:12]([OH:14])=[O:13])[CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:22][C:23](Cl)=[O:24].[OH-].[Na+]>O.CCCCCCC.C1COCC1>[CH2:1]([N:8]1[C:23](=[O:24])[CH2:22][O:11][CH2:10][CH:9]1[C:12]([OH:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)[C@H](CO)NCc1ccccc1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: O=C(O)C1COCC(=O)N1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84.9 %

Procedure:
To a reactor was charged N-benzyl-L-serine (1.0 eq) and THF (6.1 volumes). The resulting solution was cooled to 0±5° C. and a pre-cooled solution (0–5° C.) of potassium carbonate (3.0 eq) in water (6.1 volumes) was added. Chloroacetyl chloride (1.4 eq) then was added via addition funnel while maintaining the internal temperature below 5° C. The biphasic reaction mixture was aged for approximately 30 min at 0±5° C. After aging, the mixture was sampled for HPLC analysis. If >6 area percent remaining N-benzyl-L-serine was present, additional chloroacetyl chloride was added. Once the reaction completeness specification has been met, 50 wt % sodium hydroxide is charged while keeping the internal temperature between 5 and 10° C. until the pH remains constant >13.5. The reaction was deemed complete when HPLC analysis showed <1 area percent (combined) intermediates. The mixture was warmed to 25° C., and heptane (2.03 volumes) was added. The mixture was stirred rapidly for 10 min, and then the phases were allowed to separate. The organic upper phase was discarded, and the rich aqueous phase was treated again with heptane (3.04 volumes). After stirring rapidly for 10 min, the phases were allowed to settle, and the organic upper phase was discarded. The rich aqueous portion was cooled to −5–0° C. and 37 wt % hydrochloric acid was added while maintaining a batch temperature <10° C. until pH <2. The resulting slurry was kept at −10–0° C. for a minimum of 4 h. The slurry was filtered over Whatman 1 filter paper, or equivalent, and washed with pre-cooled (3–7° C.) water (2×4.57 volumes). The wet cake was dried in vacuo at 40–45° C. After drying, 1.475 kg (84.9%, uncorrected) of 4-benzyl-5-oxo-morpholine-3-carboxylic acid was obtained. HPLC Ret Time: 1.82 min (YMC S5 ODS column 4.6×50 mm, 10–90% aqueous methanol over 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm); Chiral HPLC Ret Time: 7.94 min, e.e. 100%, (Chiralcel OJ-R, 150×4.6 mm, 5 μM, eluent: MeOH:0.2% aq. H3PO4 [50:50], flow rate 1 mL/min, 210 nm).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([O:19][CH:20]1[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]1)[C:11]1[CH:12]=[C:13]([CH2:17]O)[CH:14]=[CH:15][CH:16]=1.C(N(CC)CC)C.[CH3:34][S:35](Cl)(=O)=O.C[S-].[Na+]>ClCCl.O.CO>[CH3:26][N:23]1[CH2:24][CH2:25][CH:20]([O:19][CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][S:35][CH3:34])[CH:12]=2)[C:2]2[NH:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:1]=2)[CH2:21][CH2:22]1
Reactant: CS(=O)(=O)Cl
Reactant: CN1CCC(OC(c2cccc(CO)c2)c2nc3ccccc3[nH]2)CC1
Agent: C[S-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CO
Product: CSCc1cccc(C(OC2CCN(C)CC2)c2nc3ccccc3[nH]2)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of {3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}methanol (example 528B, 320 mg) in dichloromethane (3 mL) is added triethylamine (0.16 mL). The reaction mixture is cooled to 0° C., and methanesulfonyl chloride (84 μL) is added dropwise. The reaction mixture is stirred at room temperature for 3 h, then cooled to 0° C. and sodium thiomethoxide (191 mg) is added. After one night at room temperature, methanol (2 mL) is added to help solubilizing the suspension. The reaction mixture is stirred at room temperature overnight. Water is added and the aqueous phase is extracted by dichloromethane. The organic phase is washed by water, then dried over magnesium sulfate and concentrated. The residue is purified by chromatography on silica gel (gradient dichloromethane/methanol/ammonia from 90/10/0 to 90/10/0.1 then 80/20/0.1), followed by a purification by preparative thin-layer chromatography (dichloromethane/methanol/ammonia from 90/10/0.1) to give 2-[(1-methylpiperidin-4-yloxy)(3-methylsulfanylmethylphenyl)methyl]-1H-benzimidazole. MS, [M+H]+=382.1;
Reaction SMILES: [OH:1][C:2]1[CH:17]=[C:16]([O:18][CH2:19][C:20]([C:22]2[CH:31]=[CH:30][C:29]3[C:28]([CH3:33])([CH3:32])[CH2:27][CH2:26][C:25]([CH3:35])([CH3:34])[C:24]=3[CH:23]=2)=[O:21])[CH:15]=[CH:14][C:3]=1[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[C:36](Cl)(=[O:38])[CH3:37]>>[C:36]([O:1][C:2]1[CH:17]=[C:16]([O:18][CH2:19][C:20]([C:22]2[CH:31]=[CH:30][C:29]3[C:28]([CH3:33])([CH3:32])[CH2:27][CH2:26][C:25]([CH3:35])([CH3:34])[C:24]=3[CH:23]=2)=[O:21])[CH:15]=[CH:14][C:3]=1[C:4]([O:6][CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:5])(=[O:38])[CH3:37]
Reactant: CC(=O)Cl
Reactant: CC1(C)CCC(C)(C)c2cc(C(=O)COc3ccc(C(=O)OCc4ccccc4)c(O)c3)ccc21
Product: CC(=O)Oc1cc(OCC(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)ccc1C(=O)OCc1ccccc1
Yield: 77.7 %

Procedure:
By reaction of 2.36 g (5 mmol) of benzyl 2-hydroxy-4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthoylmethoxy)benzoate and 360 μl (5 mmol) of acetyl chloride in a manner analogous to Example 4(b), 2 g (80%) of the expected product which melts at 137°-138° C. are collected.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([N:7]([CH2:48][CH:49]([CH3:51])[CH3:50])[C:8]([C:10]1[CH:47]=[CH:46][C:13]2[N:14]([CH2:33][CH2:34][CH2:35][N:36]([CH3:45])[CH2:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=3)[C:15]([S:17][CH2:18][C:19](=[O:32])[C:20]3[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[C:22]([O:30][CH3:31])[CH:21]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9])[CH:4]([CH3:6])[CH3:5]>CO>[OH:32][CH:19]([C:20]1[CH:21]=[C:22]([O:30][CH3:31])[C:23]([O:28][CH3:29])=[C:24]([O:26][CH3:27])[CH:25]=1)[CH2:18][S:17][C:15]1[N:14]([CH2:33][CH2:34][CH2:35][N:36]([CH3:45])[CH2:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=2)[C:13]2[CH:46]=[CH:47][C:10]([C:8]([N:7]([CH2:48][CH:49]([CH3:51])[CH3:50])[CH2:3][CH:4]([CH3:5])[CH3:6])=[O:9])=[CH:11][C:12]=2[N:16]=1
Reactant: COc1cc(C(=O)CSc2nc3cc(C(=O)N(CC(C)C)CC(C)C)ccc3n2CCCN(C)CCc2ccccn2)cc(OC)c1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(C(O)CSc2nc3cc(C(=O)N(CC(C)C)CC(C)C)ccc3n2CCCN(C)CCc2ccccn2)cc(OC)c1OC
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Sodium borohydride (8 mg, 2 eq) is added at 0° C. to a solution of N,N-diisobutyl-1-{3-[methyl(2-pyridin-2-ylethyl)amino]propyl}-2-{[2-oxo-2-(3,4,5-trimethoxyphenyl)ethyl]thio}-1H-benzimidazole-5-carboxamide (69 mg, 1 eq) in methanol (2 ml). After stirring for 10 minutes at 0° C., the mixture is taken to a temperature of approximately 20° C. and stirred at this temperature for 30 minutes. The mixture is then concentrated under reduced pressure at 40° C. then water saturated with ammonium chloride and dichloromethane is added. After decanting and extracting, the organic phases are combined and washed with salt water, dried over sodium sulphate and evaporated under reduced pressure at 40° C. Purification of the oil obtained by flash chromatography on silica gel (100% dichloromethane to dichloromethane/methanol 80:20) produces the expected compound in the form of an oil (61 mg, 88% yield).
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]([F:19])([F:18])[C:7]1[CH:17]=[CH:16][C:10](/[CH:11]=[CH:12]/[C:13](O)=[O:14])=[CH:9][CH:8]=1.N1C=CC=CC=1>C(Cl)Cl>[F:5][C:6]([F:19])([F:18])[C:7]1[CH:17]=[CH:16][C:10](/[CH:11]=[CH:12]/[C:13]([Cl:3])=[O:14])=[CH:9][CH:8]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)/C=C/c1ccc(C(F)(F)F)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Cl)/C=C/c1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Thionyl chloride (335 ml, 4.6 mmol) was added at 0° C. to 4-trifluoromethyl-E-cinnamic acid (1 g, 4.6 mmol) and pyridine (375 ml, 4.6 mmol) in dry CH2Cl2. The mixture was then stirred for 1 h without cooling, again cooled to 0° C. and filtered with the exclusion of moisture. The filtrate (10 ml) contained the title compound and was used in aliquots for the next reaction step.
Reaction SMILES: Br.[N:2]12[CH2:8][C:5]([C:9]([O:11]CC)=O)([CH2:6][CH2:7]1)[CH2:4][CH2:3]2.Cl.[O:15]([NH2:17])[CH3:16]>C(N(CC)CC)C>[N:2]12[CH2:8][C:5]([C:9]([NH:17][O:15][CH3:16])=[O:11])([CH2:4][CH2:3]1)[CH2:6][CH2:7]2
Reactant: CCOC(=O)C12CCN(CC1)C2
Reactant: CON
Agent: Br
Agent: Cl
Solvent: CCN(CC)CC
Product: CONC(=O)C12CCN(CC1)C2

Procedure:
Ethyl 1 -azabicyclo[2.2.1]hept-4-ylcarboxylate hydrobromide salt (D17, 16.85 g, 0.067 mole) was converted to the acid chloride hydrochloride salt and treated with methoxylamine hydrochloride (6.19 g, 0.074 mole) and triethylamine as in the method of Description 8 to give the title compound (D18) as a pale brown crystalline solid (4.60 g, 40%) m.p. 129°-134° C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12](=[O:13])[CH2:11][NH:10][C:9]2=[O:14])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Br[CH2:18][C:19]([NH2:21])=[O:20].Cl>CN(C=O)C>[I:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12](=[O:13])[CH2:11][N:10]([CH2:18][C:19]([NH2:21])=[O:20])[C:9]2=[O:14])[CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)CBr
Reactant: O=C1CNC(=O)N1c1cccc(I)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NC(=O)CN1CC(=O)N(c2cccc(I)c2)C1=O
Yield: 53.7 %

Procedure:
A solution of 3-(3-iodophenyl)imidazolidine-2,4-dione (1 g) in DMF (20 ml) was treated with sodium hydride (60% oil dispersion, 158 mg) and 2-bromoacetamide (1.36 g) at 20° C. After 2 h the reaction mixture was treated with aqueous 2M HCl, extracted with EtOAc and dried (MgSO4). The solvent was removed under reduced pressure and the residue was purified by chromatography on Biotage (40 g) eluting with EtOAc to give the title compound (638 mg). LCMS RT=2.32 min.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([O:9][CH2:10][C:11]([CH3:14])([OH:13])[CH3:12])=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:3]=1.[H-].[Na+]>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[O:9][CH2:10][C:11]([CH3:14])([CH3:12])[O:13][C:6]=2[N:7]=1
Reactant: CC(C)(O)COc1c(Cl)nc(Cl)nc1N1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C)COc2c(nc(Cl)nc2N2CCOCC2)O1
Temperature: 25 °C
Reaction time: 5 h
Yield: 69.8 %

Procedure:
To a solution of 1-(2,4-dichloro-6-morpholin-4-yl-pyrimidin-5-yloxy)-2-methyl-propan-2-ol (2.18 g, 6.77 mmol) in THF (150 mL) was added sodium hydride (812 mg, 20.31 mmol, 60% dispersion in mineral oil) and the resulting mixture stirred at RT for 5 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The combined organic extracts were dried (Na2SO4) and concentrated in vacuo. The resultant residue was triturated with cyclohexane affording 2-Chloro-7,7-dimethyl-4-morpholin-4-yl-6,7-dihydro-[1,4]dioxino[2,3-d]pyrimidine as a white solid (1.35 g, 70%). LCMS: RT=3.03 min, [M+H]+=286/288.
Reaction SMILES: [CH2:1]1[O:38][C:37]2[CH:36]=[CH:35][C:5]([CH2:6][N:7]([S:22]([C:25]3[C:30]([CH3:31])=[CH:29][C:28]([O:32][CH3:33])=[CH:27][C:26]=3[CH3:34])(=[O:24])=[O:23])[C@H:8]([CH2:16][NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[C:9]([O:11]C(C)(C)C)=[O:10])=[CH:4][C:3]=2[O:2]1.FC(F)(F)C(O)=O>FC(F)(F)C(O)=O.C(Cl)Cl>[CH2:1]1[O:38][C:37]2[CH:36]=[CH:35][C:5]([CH2:6][N:7]([S:22]([C:25]3[C:26]([CH3:34])=[CH:27][C:28]([O:32][CH3:33])=[CH:29][C:30]=3[CH3:31])(=[O:23])=[O:24])[C@H:8]([CH2:16][NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[C:9]([OH:11])=[O:10])=[CH:4][C:3]=2[O:2]1
Reactant: COc1cc(C)c(S(=O)(=O)N(Cc2ccc3c(c2)OCO3)[C@H](CNS(C)(=O)=O)C(=O)OC(C)(C)C)c(C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C)c(S(=O)(=O)N(Cc2ccc3c(c2)OCO3)[C@H](CNS(C)(=O)=O)C(=O)O)c(C)c1
Reaction time: 2 h
Yield: 99.1 %

Procedure:
A solution of tert-butyl 2(R)-[(3,4-methylendioxybenzyl)-(2,6-dimethyl-4-methoxybenzenesulfonyl)amino]-3-methanesulfonylamino-propionate (1.37 g, 2 mmol) in 20% trifluoracetic acid-methylene chloride (15 ml) was stirred for 1 hour. Extra trifluoroacetic acid (0.5 ml) was added and stirring continued for two hours. The material was then condensed on the rotary evaporator and the residue was taken up in toluene (40 ml) and again condensed. This procedure was repeated twice (2×40 ml toluene, to remove traces of trifluoracetic acid) to provide 2(R)-[(3,4-methylendioxybenzyl)-(2,6-dimethyl-4-methoxybenzenesulfonyl)amino]-3-methanesulfonylamino-propionic acid as a tan green foamy solid (1.02 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:30])=[C:4]([C:8]2[C:20]3[C:19]4[C:14](=[CH:15][C:16]([O:21][CH2:22][CH2:23][O:24][CH3:25])=[CH:17][CH:18]=4)[NH:13][C:12]=3[C:11]([C:26]([NH2:28])=[O:27])=[N:10][C:9]=2[CH3:29])[CH:5]=[CH:6][CH:7]=1.[NH:31]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[C:34](=O)[O:33][C:32]1=O.COC(OC)OC.O.O.O.O.O.O.[N+]([O-])([O-])=O.[La+3].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O>O1CCCC1.CCOC(C)=O.O.CO.CS(C)=O>[CH3:25][O:24][CH2:23][CH2:22][O:21][C:16]1[CH:15]=[C:14]2[C:19]([C:20]3[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([N:1]5[C:34](=[O:33])[C:35]6[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=6)[N:31]=[CH:32]5)[C:3]=4[CH3:30])=[C:9]([CH3:29])[N:10]=[C:11]([C:26]([NH2:28])=[O:27])[C:12]=3[NH:13]2)=[CH:18][CH:17]=1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: COCCOc1ccc2c(c1)[nH]c1c(C(N)=O)nc(C)c(-c3cccc(N)c3C)c12
Agent: O=[N+]([O-])[O-]
Agent: [La+3]
Solvent: CS(C)=O
Solvent: COC(OC)OC
Solvent: CCOC(C)=O
Product: COCCOc1ccc2c(c1)[nH]c1c(C(N)=O)nc(C)c(-c3cccc(-n4cnc5ccccc5c4=O)c3C)c12
Temperature: 95 °C
Yield: 7.8 %

Procedure:
A sealed pressure tube containing 4-(3-amino-2-methylphenyl)-7-(2-methoxyethoxy)-3-methyl-9H-pyrido[3,4-b]indole-1-carboxamide (0.364 g, 0.9 mmol), 1H-benzo[d][1,3]oxazine-2,4-dione (0.367 g, 2.250 mmol), trimethoxymethane (0.887 ml, 8.10 mmol) and lanthanum nitrate hexahydrate (0.117 g, 0.270 mmol) in tetrahydrofuran (Volume: 4.50 ml) was heated at 95° C. overnight. The reaction was cooled to room temperature, diluted with EtOAc (100 mL) and water (30 mL); the insolubles were filtered, and the layers were separated. The organic layer was washed with water (30 mL) and brine (30 mL), dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography using an ISCO 40 g column eluting with 30-100% EtOAc/hexane (solid loading). Appropriate fractions were collected and concentrated in vacuo to give impure product It was diluted with MeOH (3 mL) and DMSO (0.1 mL) and subjected to autoprep HPLC. The appropriate fractions were collected; NaHCO3 (solid) was added, and the fractions were concentrated in vacuo not to dryness. It was extracted with CH2Cl2 (3×); the organic layers were combined, dried over Na2SO4, filtered and concentrated in vacuo to give 7-(2-methoxyethoxy)-3-methyl-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-9H-pyrido[3,4-b]indole-1-carboxamide (0.0372 g, 0.070 mmol, 7.75% yield) as a light tan solid, LC/MS (M+H)=534.18; 1H NMR (500 MHz, DMSO-d6) (recognizable peaks for the major atropoisomer) δ ppm 11.44 (d, J=5.8 Hz, 1H), 8.46 (s, 1H), 8.24 (ddd, J=7.9, 3.3, 1.2 Hz, 1H), 8.12-8.17 (m, 1H), 7.85-7.93 (m 1H), 7.79 (dd, J=7.9, 2.6 Hz, 1H), 7.71 (br d, J=2.5 Hz, 1H), 7.51-7.68 (m, 2H), 7.46 (br ddd, J=7.1, 5.3, 1.4 Hz, 1H), 7.28 (d, J=2.2 Hz, 1H), 6.83 (d, J=8.9 Hz, 1 H), 6.59-6.70 (m, 2H), 4.10-4.16 (m, 2H), 3.69 (br q, J=4.7 Hz, 2H), 3.33 (s, 3H), 2.42 (s, 3H), 1.70 (s, 3H).