Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:14]=[O:15])=[CH:4][NH:5][C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1.[H-].[Na+].C1OCCOCCOCCOCCOC1.[CH3:33][N:34]1[CH:38]=[C:37]([S:39](Cl)(=[O:41])=[O:40])[CH:36]=[N:35]1>O1CCCC1.O>[Cl:1][C:2]1[C:3]([CH:14]=[O:15])=[CH:4][N:5]([S:39]([C:37]2[CH:36]=[N:35][N:34]([CH3:33])[CH:38]=2)(=[O:41])=[O:40])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=Cc1c[nH]c(-c2cccnc2F)c1Cl
Reactant: Cn1cc(S(=O)(=O)Cl)cn1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cn1cc(S(=O)(=O)n2cc(C=O)c(Cl)c2-c2cccnc2F)cn1
Reaction time: 0.25 h
Yield: 65 %

Procedure:
To a solution of 4-chloro-5-(2-fluoropyridin-3-yl)-1H-pyrrole-3-carbaldehyde (150 mg) in tetrahydrofuran (20 mL) was added sodium hydride (60% in oil, 81 mg) at room temperature and the mixture was stirred for 15 min. 15-Crown-5 (442 mg) was added dropwise and the mixture was stirred for 5 min. 1-methyl-1H-pyrazole-4-sulfonyl chloride (242 mg) was added and the mixture was further stirred for 30 min. The reaction mixture was diluted with water, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=1:1→1:4) to give the title compound as a colorless oil (yield 160 mg, 65%).
Reaction SMILES: [F:1][CH:2]([C:7]([O:9][CH3:10])=[O:8])[C:3]([O:5][CH3:6])=[O:4].C=O.[C:13](=O)(O)[O-:14].[K+].[Cl-].[NH4+]>>[OH:14][CH2:13][C:2]([F:1])([C:7]([O:9][CH3:10])=[O:8])[C:3]([O:5][CH3:6])=[O:4]
Reactant: O=C([O-])O
Reactant: COC(=O)C(F)C(=O)OC
Agent: C=O
Agent: [Cl-]
Agent: [K+]
Product: COC(=O)C(F)(CO)C(=O)OC

Procedure:
150 g (1 mol) of dimethyl α-fluoromalonate (see Journal of Fluorine Chemistry 25 (1984), 203-212) are added dropwise to a mixture of 96 g of a 35 percent strength by weight aqueous solution of formaldehyde (1.1 mol) and 10 g (0.1 mol) of potassium bicarbonate at a temperature of 25° C. in the course of one hour. The reaction solution is then mixed with four times the volume of a saturated aqueous ammonium chloride solution and the mixture is extracted three times with 150 ml of methylene chloride each time. The combined extraction solutions are dried over sodium sulfate. After evaporation of the methylene chloride, dimethyl α-hydroxymethyl-α-fluoromalonate is obtained as a colorless solid.
Reaction SMILES: [CH3:1][S:2]([CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]([C:19]2[N:20]=[C:21]3[C:27]([C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:26][N:25](COCC[Si](C)(C)C)[C:22]3=[N:23][CH:24]=2)[CH:11]=[C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:13]=1)(=[O:4])=[O:3].CO.Cl.C([O-])(O)=O.[Na+]>CCOC(C)=O>[CH3:1][S:2]([CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]([C:19]2[N:20]=[C:21]3[C:27]([C:28](=[O:33])[C:29]([CH3:31])([CH3:30])[CH3:32])=[CH:26][NH:25][C:22]3=[N:23][CH:24]=2)[CH:11]=[C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:13]=1)(=[O:4])=[O:3]
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3cc(OCCS(C)(=O)=O)cc(N4CCCC4)c3)nc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)C(=O)c1c[nH]c2ncc(-c3cc(OCCS(C)(=O)=O)cc(N4CCCC4)c3)nc12
Reaction time: 0.83 h
Yield: 62.1 %

Procedure:
To a flask containing 1-[2-[3-(2-methanesulfonyl-ethoxy)-5-pyrrolidin-1-yl-phenyl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one (75 mg, 0.13 mmol) was added methanol (1 ml) and aqueous 6N HCl (1.5 ml). The flask was capped and placed in a heated oil bath (90° C.). After stirring for 50 minutes the mixture was cooled to ambient and the volatiles were stripped (rotovap/pump). The remainder was taken up in EtOAc (15 ml) and 5% aqueous NaHCO3 (15 ml) and stirred for 5 minutes. The material was partitioned and the organic phase collected and washed with brine (15 ml). The aqueous phases were back extracted with EtOAc (2×15 ml). The organics were combined, dried (MgSO4), filtered and stripped to provide a crude semi-solid. The material was purified by crystallization from hot CH2Cl2/hexanes (containing 4 drops of methanol) to afford 38 mg of 1-{2-[3-(2-methanesulfonyl-ethoxy)-5-pyrrolidin-1-yl-phenyl]-5H-pyrrolo[2,3-b]pyrazin-7-yl}-2,2-dimethyl-propan-1-one as a yellow solid. MP 230-232° C., M+H=471.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[CH:12]=[CH:13][C:14]([CH2:16][OH:17])=[CH:15][C:4]=2[N:3]=1>C(Cl)Cl.O=[Mn]=O>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[CH:12]=[CH:13][C:14]([CH:16]=[O:17])=[CH:15][C:4]=2[N:3]=1
Reactant: Nc1nc2cc(CO)ccc2c2cccnc12
Agent: O=[Mn]=O
Solvent: ClCCl
Product: Nc1nc2cc(C=O)ccc2c2cccnc12

Procedure:
A solution of (5-aminobenzo[f][1,7]naphthyridin-8-yl)methanol (from Example 85) (1.0 eq.) and activated MnO2 (20 eq.) in DCM (0.1 M) was stirred at ambient temperature over night. The reaction mixture was diluted with DCM. The MnO2 was filtered off, and the filtrate was concentrated en vacuo to obtain a crude residue. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-10% MeOH/DCM to give 5-aminobenzo[f][1,7]naphthyridine-8-carbaldehyde as a yellow solid: 1H NMR (acetone-d6): δ 10.19 (s, 1H), 9.14 (dd, 1H), 9.01 (dd, 1H), 8.63 (d, 1H), 8.14 (d, 1H), 7.93 (dd, 1H), 7.81 (dd, 1H), 6.96 (br s, 2H). LRMS [M+H]=224.1
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([Cl:10])=[C:6]([CH:9]=1)C=O.[CH3:11][O:12][CH:13](OC)[O:14][CH3:15].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.C(Cl)Cl>[Br:1][C:2]1[CH:9]=[C:6]([CH:13]([O:14][CH3:15])[O:12][CH3:11])[C:5]([Cl:10])=[N:4][CH:3]=1
Reactant: O=Cc1cc(Br)cnc1Cl
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: COC(OC)c1cc(Br)cnc1Cl

Procedure:
A mixture of 5-bromo-2-chloronicotinaldehyde (981 mg, 2.43 mmol), trimethylorthoformate (1.46 mL, 13.4 mmol) and p-toluenesulfonic acid monohydrate (42.3 mg, 0.222 mmol) in MeOH (18 mL) was refluxed for 16 hours. The mixture was diluted in CH2Cl2 and washed with 10% aqueous potassium carbonate and brine, dried over sodium sulfate, filtered and concentrated. The crude product was used in the next step without further purification.
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].O[CH:19](O)[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:21].[BH3-]C#N.[Na+]>CO>[C:22]1([CH:20]([OH:21])[CH2:19][NH:15][C:14]2[CH:16]=[CH:17][C:11]([CH2:10][CH2:9][NH:8][C:1]([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2])=[CH:12][CH:13]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(c1ccccc1)C(O)O
Reactant: CC(C)(C)OC(=O)NCCc1ccc(N)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)NCCc1ccc(NCC(O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
4-(N-Boc-2-aminoethyl)aniline 28 (1.25 g, 5.29 mmole) was dissolved in methanol (30 mL), followed by addition of phenyl glyoxal 24 (0.708 g, 5.28 mmole). The reaction mixture was stirred for 1 h at rt, prior to addition of NaCNBH3 (0.665 g, 10.6 mmole). The final mixture was stirred for 12 h at rt, concentrated, and purified by flash silica column chromatography (2 to 5% MeOH/CH2Cl2) to give N-(2-phenyl-2-hydroxyethyl)-4-(N-Boc-2-aminoethyl)aniline as a pale yellow oil (1.71 g, 91%): Rf=0.18 in 5% MeOH/CH2Cl2. 1H-NMR (CD3OD, 299.96 MHz): δ (ppm) 7.4-7.25 (m, 5H), 7.0-6.95 (d, 2H), 6.63-6.60 (d, 2H), 4.85-4.79 (dd, 1H), 3.3-3.21 (t, 2H), 3.2-3.15 (m, 2H), 2.64-2.5 (t, 2H), 1.42 (s, 9H).
Reaction SMILES: [C:1]([C:5]1[CH:11]=[CH:10][C:8](N)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[FH:18].N([O-])=O.[Na+]>>[C:1]([C:5]1[CH:11]=[CH:10][C:8]([F:18])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: F
Reactant: CC(C)(C)c1ccc(N)cc1
Agent: O=N[O-]
Agent: [Na+]
Solvent: c1ccncc1
Product: CC(C)(C)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a steel bomb were combined 4-tert-butyl aniline (1 eq) and 70% hydrogen fluoride-pyridine (25 g/gm aniline). Sodium nitrite (1.5 eq) was then added portion wise over 5 minutes. The resulting solution was allowed to stir for 1 h at room temperature and then the bomb was sealed and heated at 85° C. for 1 h. Solution was then quenched with water/ice and extracted with ethyl ether. Organics washed with brine and dried with sodium sulfate and concentrated to afford 1-tert-butyl-4-fluorobenzene.
Reaction SMILES: [CH3:1][Si:2]([CH3:19])([CH3:18])[CH2:3][CH2:4][O:5][C:6]([NH:8][C:9]1([C:15]([OH:17])=O)[CH2:14][O:13][CH2:12][O:11][CH2:10]1)=[O:7].[CH2:20]([O:22][C:23](=[O:33])[CH:24]=[CH:25][C:26]1[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=1)[CH3:21].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=NC2N(O)N=NC=2C=1.N1C(C)=CC(C)=CC=1C>CS(C)=O>[CH2:20]([O:22][C:23](=[O:33])/[CH:24]=[CH:25]/[C:26]1[CH:27]=[CH:28][C:29]([NH:32][C:15]([C:9]2([NH:8][C:6]([O:5][CH2:4][CH2:3][Si:2]([CH3:1])([CH3:19])[CH3:18])=[O:7])[CH2:10][O:11][CH2:12][O:13][CH2:14]2)=[O:17])=[CH:30][CH:31]=1)[CH3:21]
Reactant: CCOC(=O)C=Cc1ccc(N)cc1
Reactant: C[Si](C)(C)CCOC(=O)NC1(C(=O)O)COCOC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: Cc1cc(C)nc(C)c1
Solvent: CS(C)=O
Product: CCOC(=O)/C=C/c1ccc(NC(=O)C2(NC(=O)OCC[Si](C)(C)C)COCOC2)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 54 %

Procedure:
5-(2-trimethylsilanyl-ethoxycarbonylamino)-1,3-dioxane-5-carboxylic acid from above (0.050 g, 0.17 mmol), ethyl-4-aminocinnamate (0.036 g, 0.19 mmol), HATU (0.098 g, 0.26 mmol), HOAt (0.035 g, 0.26 mmol) and 2,4,6-collidine (0.062 mL, 0.51 mmol) were combined in anhydrous DMSO (1 mL). The solution was warmed to 60° C. and stirred for 6 h before another 1.5 equivalents of HATU was added and stirring was continued for another 2 hours to ensure complete consumption of the acid. The reaction mixture was diluted with dichloromethane and washed with 1N HCl (×2). The organic phase was dried with MgSO4, filtered and concentrated. The residue was subjected to flash chromatography to afford 0.043 g (54%) of the protected amide derivative as a yellow oil.
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3]/[CH:4]=[CH:5]/[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH3:12][O:13][CH:14]([O:17][CH3:18])[CH2:15][NH2:16].[BH3-]C#N.[Na+].C(O)(C(F)(F)F)=O>CO>[CH3:12][O:13][CH:14]([O:17][CH3:18])[CH2:15][NH:16][CH2:1][CH2:2][CH2:3]/[CH:4]=[CH:5]/[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: COC(CN)OC
Reactant: CCCCC/C=C/CCC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CCCCC/C=C/CCCNCC(OC)OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
trans-4-Decenal (7.2 g, 46.6 mmol) was mixed with 40 mL (0.37 moL) of aminoacetaldehyde dimethylacetal in 400 mL of methanol and stirred at room temperature for 30 minutes. NaCNBH3 (2.9 g, 46.6 mmol) was added, the reaction was cooled in an ice bath, and 27 mL (0.35 moL) of TFA was added dropwise over 5 minutes. The ice bath was then removed and the reaction was stirred for 70 minutes at room temperature, concentrated to a third of its volume, and partitioned between ethyl acetate (250 mL) and 1N NaOH (200 mL). The organic layer was washed with water (3×75 mL), dried over MgSO4, filtered and concentrated under reduced pressure to yield 11.1 g (45.6 mmol) of 2-(trans-dec4-en-1-ylamino)acetaldehyde dimethyl acetal as a yellow oil that was used directly in the next step.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6](Cl)=[O:7])=[CH:2]1.[Cl:9][C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=1[O:17][CH3:18].[Al+3].[Cl-].[Cl-].[Cl-].CCCCCC>C(=S)=S>[O:1]1[CH:5]=[CH:4][C:3]([C:6]([C:14]2[CH:13]=[CH:12][C:11]([O:17][CH3:18])=[C:10]([Cl:9])[C:15]=2[Cl:16])=[O:7])=[CH:2]1
Reactant: COc1cccc(Cl)c1Cl
Reactant: O=C(Cl)c1ccoc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCCCCC
Solvent: S=C=S
Product: COc1ccc(C(=O)c2ccoc2)c(Cl)c1Cl

Procedure:
3-Furoyl chloride (18.0 g) and 2,3-dichloro anisole (24.7 g) are dissolved in 125 ml of CS2 and treated with AlCl3 (18.7 g), first at 5° C. and then at room temperature. After five hours the reaction is quenched with ice/HCl an extracted with CH2Cl2. Drying and evaporation gives a crystalline product that is titurated with hexane to yield 4-(3-furoyl)-2,3-dichloroanisole, mp 118°-122° C.
Reaction SMILES: [C:1]([N:16]([CH3:22])[CH2:17][CH2:18][C:19]([OH:21])=[O:20])(=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[OH-].[Na+].[CH3:25]O>C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:25][O:20][C:19](=[O:21])[CH2:18][CH2:17][N:16]([C:1](=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH3:22]
Reactant: CCCCCCCCCCCCCC(=O)N(C)CCC(=O)O
Reactant: CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCCCCCCCC(=O)N(C)CCC(=O)OC

Procedure:
313 g of N-myristoyl-N-methyl-β-alanine (manufactured by Kawaken Fine Chemical Co.) and 256 g of methanol were put into a 1000 ml flask, to which was added 2.85 g of p-toluenesulfonic acid as catalyst, and the mixture was heated for reaction under reflux for 5 hours. After its acid value was confirmed to be not larger than 10, the reaction mixture was neutralized with 1.2 g of an aqueous solution of sodium hydroxide (50%), and then the methanol was evaporated away under reduced pressure. The resulting residue was washed with water and dried to obtain N-myristoyl-N-methyl-β-alanine methyl ester. A 163 g portion of this N-myristoyl-N-methyl-β-alanine methyl ester and 379 g of decaglycerin (manufactured by Sakamoto Pharmaceutical Industry Co.), and then 1.1 g of sodium hydroxide were put into a 1000 ml flask, the atmosphere of which was then replaced with nitrogen. Then, the mixture was subjected to transesterification reaction by keeping it at 150° C. and not more than 60 mmHg for 6 hours to obtain 460 g of a pasty or oily product.
Reaction SMILES: [F:1][CH:2]([F:18])[O:3][C:4]1[C:9]2[O:10][CH:11]([CH3:15])[C:12](=[O:14])[NH:13][C:8]=2[CH:7]=[C:6]([CH:16]=O)[CH:5]=1.[CH3:19][NH:20][C:21](=[O:35])[C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[C:24]([CH3:34])[CH:23]=1>>[F:1][CH:2]([F:18])[O:3][C:4]1[C:9]2[O:10][CH:11]([CH3:15])[C:12](=[O:14])[NH:13][C:8]=2[CH:7]=[C:6]([CH2:16][N:31]2[CH2:30][CH2:29][N:28]([C:25]3[CH:26]=[CH:27][C:22]([C:21]([NH:20][CH3:19])=[O:35])=[CH:23][C:24]=3[CH3:34])[CH2:33][CH2:32]2)[CH:5]=1
Reactant: CC1Oc2c(cc(C=O)cc2OC(F)F)NC1=O
Reactant: CNC(=O)c1ccc(N2CCNCC2)c(C)c1
Product: CNC(=O)c1ccc(N2CCN(Cc3cc4c(c(OC(F)F)c3)OC(C)C(=O)N4)CC2)c(C)c1

Procedure:
Using 403A and N,3-dimethyl-4-(piperazin-1-yl)benzamide 298 in the general procedure for reductive aminations, the title compound was obtained as a white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.36-1.49 (m, 3H) 2.26 (s, 3H) 2.52-2.62 (m, 4H) 2.74 (d, J=4.55 Hz, 3H) 2.89 (br. s., 4H) 3.41-3.50 (m, 2H) 4.74 (q, J=6.65 Hz, 1H) 6.81 (s, 2H) 6.92-7.37 (m, 2H) 7.56-7.66 (m, 2H) 8.23 (d, J=4.55 Hz, 1H) 10.81 (s, 1H). ESI-MS: m/z 475.4 (M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[O:16][CH3:17])O.[I-:18].[Na+]>CC(=O)CC>[CH3:17][O:16][C:10]1[CH:11]=[C:12]([Cl:15])[CH:13]=[CH:14][C:9]=1[CH:7]=[CH:6][CH2:5][CH2:4][CH2:3][CH2:2][I:18]
Reactant: COc1cc(Cl)ccc1C(O)CCCCCBr
Reactant: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: COc1cc(Cl)ccc1C=CCCCCI

Procedure:
A mixture of 74 g. of 5-bromopentyl 2-methoxy-4-chlorophenyl carbinol, 50 g. of sodium iodide and 500 ml. of 2-butanone was heated under reflux for 2.5 days. The reaction mixture was concentrated, water added and the mixture extracted with ether. The ether extracts were dried over anhydrous magnesium sulfate and concentrated to give 84 g. of oil used directly in the next reaction without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:19][C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[N:9][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:11][CH:12]=1)=[O:5].[CH3:29][O:30][C:31]([C:33]1[CH:34]=[C:35]([CH:39]=[CH:40][CH:41]=1)[C:36](O)=[O:37])=[O:32].CCN=C=NCCCN(C)C.Cl>ClCCl.CN(C)C1C=CN=CC=1>[C:13]1([C:10]2[N:11]=[CH:12][C:7]([NH:6][C:4]([C:3]3[CH:19]=[C:20]([N:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)[CH:21]=[CH:22][C:2]=3[NH:1][C:36]([C:35]3[CH:34]=[C:33]([CH:41]=[CH:40][CH:39]=3)[C:31]([O:30][CH3:29])=[O:32])=[O:37])=[O:5])=[CH:8][N:9]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Nc1ccc(N2CCCCC2)cc1C(=O)Nc1cnc(-c2ccccc2)nc1
Reactant: COC(=O)c1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COC(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2C(=O)Nc2cnc(-c3ccccc3)nc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.7 %

Procedure:
To a solution of 2-amino-N-(2-phenylpyrimidin-5-yl)-5-(piperidin-1-yl)benzamide (2 g, 3.75 mmol, 1.00 equiv, 70%) in dichloromethane (30 mL) was added 3-(methoxycarbonyl)benzoic acid (1160 mg, 6.12 mmol, 1.20 equiv, 95%), EDC.HCl (2040 mg, 10.20 mmol, 2.00 equiv, 95%), and 4-dimethylaminopyridine (660 mg, 5.14 mmol, 1.00 equiv, 95%) and the resulting solution was stirred for 3 h at 25° C. in an oil bath. The mixture was concentrated under vacuum, diluted with 100 mL of ethyl acetate, washed with 1×100 mL of brine and then the organic layer was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with petroleum ether/ethyl acetate (2:1) to afford 1200 mg (60%) of product as a green to yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:25][C@H:26]1[CH2:31][CH2:30][CH2:29][NH:28][C@H:27]1[CH2:32][OH:33]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([N:28]2[CH2:29][CH2:30][CH2:31][C@H:26]([CH3:25])[C@@H:27]2[CH2:32][OH:33])=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Reactant: C[C@H]1CCCN[C@H]1CO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: C[C@H]1CCCN(C(=O)Cc2ccc(Cl)c(Cl)c2)[C@H]1CO
Reaction time: 16 h
Yield: 60.2 %

Procedure:
A solution of 3,4-dichlorophenylacetic acid (1.82 g) and 1,1'-carbonyldiimidazole (1.70 g) in dry tetrahydrofuran (30 ml) was stirred at room temperature under nitrogen for 20 min. A solution of cis-3-methyl-2-piperidinemethanol (1.15 g) in dry tetrahydrofuran (10 ml) was then added and stirring was continued for 16 h. before concentrating the reaction mixture in vacuo. The residue was dissolved in dichloromethane (50 ml), and this solution was washed with 2M hydrochloric acid (50 ml) and saturated aqueous sodium hydrogen carbonate (20 ml), dried and concentrated in vacuo to give a solid. This crude product was crystallised from ethyl acetate:methanol to give the isomerically pure title compound as needles (1.69 g) m.p. 161°-162°.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5](=[O:24])[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[S:13]([NH:16][C:17](NCCCC)=[O:18])(=[O:15])=[O:14])[CH3:3]>C1(C)C(C)=CC=CC=1>[CH3:3][CH:2]([O:4][C:5](=[O:24])[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[S:13]([N:16]=[C:17]=[O:18])(=[O:15])=[O:14])[CH3:1]
Reactant: CCCCNC(=O)NS(=O)(=O)c1cc(Cl)ccc1C(=O)OC(C)C
Solvent: Cc1ccccc1C
Product: CC(C)OC(=O)c1ccc(Cl)cc1S(=O)(=O)N=C=O
Temperature: 133 °C
Reaction time: 1 h
Yield: 127.9 %

Procedure:
A mixture of 388.2 g (1-methylethyl)-2-[(butylaminocarbonyl)aminosulfonyl]-4-chlorobenzoate and 3 L of xylene was azeotropically dried, then cooled to ~100° C. and 1.0 g of 1,8-diazabicyclo[2.2.2.]octane was added. The mixture was heated to ~141° C. and the addition of liquefied phosgene was begun. After 90 ml of phosgene had been added, the reaction temperature was 128° C. The temperature had risen to 132° C. after 1 hr., and an additional 10 ml phosgene was added. Heating was continued the remainder of the day, then the reaction mixture was allowed to cool overnight under a nitrogen atmosphere. The following morning, the reaction mixture was heated to reflux (133° C.) and 24 ml of phosgene was added over 1 hr. The mixture was heated an additional 2 hrs. (temperature--124° C.) and then cooled to ambient temperature. The reaction mixture was filtered under nitrogen, and the filtrate was concentrated in vacuo. The title compound (400.1 g) was isolated as an oil of sufficient purity for the subsequent coupling reaction.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][NH2:9])[CH:3]=1.[Cl:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13](Cl)=O>CO>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:13]([C:12]3[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=3[Cl:10])=[N:9][N:8]=[C:4]2[CH:3]=1
Reactant: NNc1cc(Br)ccn1
Reactant: O=C(Cl)c1ccccc1Cl
Solvent: CO
Product: Clc1ccccc1-c1nnc2cc(Br)ccn12
Temperature: 115 °C

Procedure:
A mixture of 1-(4-bromopyridin-2-yl)hydrazine (1.00 g, 5.3 mmol) and 2-chlorobenzoyl chloride (8.00 ml, 63 mmol, Aldrich) was heated to 115° C. for 3 h. The mixture was diluted with MeOH and concentrated over SiO2. The residue was purified using column chromatography (MeOH/CH2Cl2=0-10%) yielding the title compound as a tan solid. MS (ESI, pos. ion) m/z: 264.0 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:12])[CH:3]=1.[Br:13]N1C(=O)CCC1=O>[W].ClCCl>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH2:12][Br:13])[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(Br)cc1C
Agent: [W]
Solvent: ClCCl
Product: COC(=O)c1ccc(Br)cc1CBr
Temperature: -15 °C
Yield: 66 %

Procedure:
A mixture of methyl 4-bromo-2-methylbenzoate (45 g), N-bromosuccinimide (38.4 g) and dichloromethane was heated at reflux under irradiation from two 120 Watt tungsten lamps for five hours. The mixture was then cooled to -15° C. and filtered and the filtrate was evaporated. The residue was recrystallised from cyclohexane to give methyl 4-bromo-2-(bromomethyl)benzoate as pale yellow crystals (39.9 g), m.p. 79.2° C.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH:12]3[CH2:14][CH2:13]3)[C:7](=[O:15])[CH:6]3[CH2:16][O:17][CH2:18][CH2:19][N:5]3[C:4]=2[N:3]=1.[CH3:20]S(C)=O.IC.CC([O-])(C)C.[Na+]>O>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH:12]3[CH2:13][CH2:14]3)[C:7](=[O:15])[C:6]3([CH3:20])[CH2:16][O:17][CH2:18][CH2:19][N:5]3[C:4]=2[N:3]=1
Reactant: O=C1C2COCCN2c2nc(Cl)ncc2N1C1CC1
Reactant: CS(C)=O
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: CC12COCCN1c1nc(Cl)ncc1N(C1CC1)C2=O
Temperature: 0 °C
Reaction time: 16 h
Yield: 79 %

Procedure:
A round-bottomed flask equipped with a magnetic stirrer was added 2-chloro-5-cyclopropyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (121 mg, 0.431 mmol), DMSO (2 ml), and iodomethane (0.032 ml, 0.517 mmol). The mixture was cooled to 0° C. and added sodium 2-methylpropan-2-olate (49.7 mg, 0.517 mmol) and allowed to stir at 20° C. for 16 hours. The reaction solution was suspended in water, and the precipitate filtered. The collected solid was washed successively with small amount of ethanol and diethyl ether. The solid was collected and dried in-vacuo to afford 2-chloro-5-cyclopropyl-6a-methyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (100 mg, 0.339 mmol, 79% yield) as a tan solid. MS [M+H] found 295.