Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([NH2:10])(=[O:9])=[O:8])=[CH:4][C:3]=1[C:11]([OH:13])=[O:12].[C:14]1(C)C=CC=C[CH:15]=1>OS(O)(=O)=O.C(O)C>[Cl:1][C:2]1[S:6][C:5]([S:7]([NH2:10])(=[O:9])=[O:8])=[CH:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: Cc1ccccc1
Reactant: NS(=O)(=O)c1cc(C(=O)O)c(Cl)s1
Agent: O=S(=O)(O)O
Solvent: CCO
Product: CCOC(=O)c1cc(S(N)(=O)=O)sc1Cl

Procedure:
To a round bottom flask were added 5-chloro-4-carboxythiophene-2-sulfonamide (5.0 g, 20.7 mmole) along with toluene (25 mL), ethanol (20 ml), and conc. H2SO4 (25 drops). The reaction mixture was refluxed for 96 hours. The reaction mixture was cooled and the solvent was removed under vacuum. The residue was then poured onto ice and the pH adjusted to ~8.0 using 10% sodium carbonate. The basic aqueous layer was extracted with ethyl acetate and the organic layer was washed with water, brine, and dried (MgSO4). Solvent removal yielded 3.92 g (70%) of an off white solid which was used as is: mp =98°-99° C.
Reaction SMILES: [C:1]1([C:7](=[O:22])[CH2:8][C:9](=[O:21])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO[CH:25](OC)[N:26]([CH3:28])[CH3:27]>>[C:7]([C:8]1[C:9](=[O:21])[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)=[CH:27][N:26]([CH3:28])[CH:25]=1)(=[O:22])[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(CC(=O)c1ccccc1)Cc1cccc(C(F)(F)F)c1
Reactant: COC(OC)N(C)C
Product: Cn1cc(C(=O)c2ccccc2)c(=O)c(-c2cccc(C(F)(F)F)c2)c1
Reaction time: 18 h

Procedure:
To a 9 g. portion of 1-phenyl-4-(3-trifluoromethylphenyl)-1,3-butanedione was added 60 ml. of N,N-dimethylformamide dimethyl acetal. The reaction mixture was stirred under reflux for 16 hours, and was then evaporated to a dark brown oil under vacuum. The oil was dissolved in 150 ml. of tetrahydrofuran, and to it was added 10 ml. of 40% aqueous methylamine. The mixture was allowed to stand at ambient temperature for 18 hours, and was then evaporated under vacuum to an oil, which was taken up in diethyl ether, washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated under vacuum to an oil again. The oil was triturated under 1.2 liters of diisopropyl ether to obtain 2.4 g. of the desired product, which was identified by nmr analysis in CDCl3, showing characteristic peaks at δ7.2-8.0 (m, 11H, aromatic); 3.63 (s, 3H, N--CH3).
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.[NH:13]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C@H:14]([C:25]([OH:27])=O)[CH2:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[NH:18][CH:17]=1.[NH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C1COCC1>[NH:13]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C@H:14]([C:25]([NH:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:27])[CH2:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[NH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: Nc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.8 %

Procedure:
4.72 g (24.6 mmol) of EDCl was added to 100 ml of THF solution of 5.00 g (16.4 mmol) of Boc-Trp-OH (manufactured by Tokyo Chemical Industry Co., Ltd), 1.50 ml (16.4 mmol) of aniline and 1.89 g (1.64 mmol) of HO-Su, followed by stirring for 16 hours at room temperature. After a reaction mixture was concentrated under reduced pressure, the concentrate was extracted by adding water and ethyl acetate. After an organic layer was washed sequentially with a diluted hydrochloric acid, an aqueous solution of sodium hydrogen carbonate and water (one time for each), the organic layer was dried over sodium sulfate. After the drying agent was separated by filtration, the filtrate was concentrated under reduced pressure, thereby obtaining crude amide. The obtained amide compound was purified by a silica gel column chromatography (hexane/ethyl acetate=5/1 to 1/1 (volume ratio)), thereby obtaining 3.10 g of the product with a yield of 49.8%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[N:20]=[C:19]3[N:21]=[C:22]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([NH2:30])[CH:25]=4)[O:23][C:18]3=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:32][N:33]([CH3:43])[C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=1)[C:37](Cl)=[O:38]>N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[N:20]=[C:19]3[N:21]=[C:22]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][C:37](=[O:38])[C:36]5[CH:40]=[CH:41][CH:42]=[C:34]([N:33]([CH3:32])[CH3:43])[CH:35]=5)[CH:25]=4)[O:23][C:18]3=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc3oc(-c4cccc(N)c4)nc3n2)CC1
Reactant: CN(C)c1cccc(C(=O)Cl)c1
Agent: Cl
Solvent: c1ccncc1
Product: CN(C)c1cccc(C(=O)Nc2cccc(-c3nc4nc(CN5CCN(C(=O)OC(C)(C)C)CC5)ccc4o3)c2)c1
Temperature: 160 °C
Yield: 22.5 %

Procedure:
4-[2-(3-Amino-phenyl)-oxazolo[4,5-b]pyridin-5-ylmethyl]-piperazine-1-carboxylic acid tert-butyl ester (83 mg, 0.2 mmol) was dissolved in 1 mL of pyridine along with 1 eq of 3-dimethylamino benzoyl chloride hydrochloride (44 mg, 0.2 mmol). The reaction mixture was heated in a Biotage microwave reactor (160° C.) for 10 min. It was then cooled to room temperature and concentrated. The resulting residue was purified by chromatography (Isco, gradient elution, CH2Cl2 to 95% CH2Cl2, 4% MeOH and 1% Et3N) to afford 25 mg of 4-{2-[3-(3-dimethylamino-benzoylamino)-phenyl]-oxazolo[4,5-b]pyridin-5-ylmethyl}-piperazine-1-carboxylic acid tert-butyl ester (23% yield).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:21]=[CH:20][C:6]2[NH:7][C:8]([S:10][CH2:11][C:12]3[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][N:13]=3)=[N:9][C:5]=2[CH:4]=1.ClC1C=C(C=CC=1)C(OO)=[O:29]>>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:21]=[CH:20][C:6]2[NH:7][C:8]([S:10]([CH2:11][C:12]3[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][N:13]=3)=[O:29])=[N:9][C:5]=2[CH:4]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccnc(CSc2nc3cc(C(F)(F)F)ccc3[nH]2)c1
Product: COc1ccnc(CS(=O)c2nc3cc(C(F)(F)F)ccc3[nH]2)c1

Procedure:
0.1 g of the title compound of m.p. 166° C. (with decomposition, recrystallized twice from isopropanol) is obtained, by a method analogous to that in Example 1, starting from 0.3 g (0.92 mole) of 5-trifluoromethyl-2-[(4-methoxy-2-pyridylmethyl)thio]-(1H)-benzimidazole and 0.3 g of 85% strength m-chloroperoxybenzoic acid.
Reaction SMILES: O.[C:2]([OH:7])(=[O:6])[C:3]([OH:5])=[O:4].[C:8]([OH:13])(=[O:12])[C:9]([OH:11])=[O:10].[N:14]1([CH2:19][CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[S:32][C:31]4[CH:33]=[CH:34][CH:35]=[CH:36][C:30]=4[C:29]=3[C:37]([C:39]3[CH:44]=[CH:43][C:42](OCCCCN4CCCC4)=[CH:41][CH:40]=3)=[O:38])=[CH:24][CH:23]=2)[CH2:18][CH2:17][CH2:16][CH2:15]1.[NH2:55][CH2:56][CH2:57][N:58]1[CH2:62][CH2:61][CH2:60][CH2:59]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[OH2:4].[C:8]([OH:13])(=[O:12])[C:9]([OH:11])=[O:10].[C:2]([OH:7])(=[O:6])[C:3]([OH:5])=[O:4].[C:2]([OH:7])(=[O:6])[C:3]([OH:5])=[O:4].[N:58]1([CH2:57][CH2:56][NH:55][C:42]2[CH:41]=[CH:40][C:39]([C:37]([C:29]3[C:30]4[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=4[S:32][C:28]=3[C:25]3[CH:26]=[CH:27][C:22]([O:21][CH2:20][CH2:19][N:14]4[CH2:15][CH2:16][CH2:17][CH2:18]4)=[CH:23][CH:24]=3)=[O:38])=[CH:44][CH:43]=2)[CH2:62][CH2:61][CH2:60][CH2:59]1
Reactant: NCCN1CCCC1
Reactant: O=C(c1ccc(OCCCCN2CCCC2)cc1)c1c(-c2ccc(OCCN3CCCC3)cc2)sc2ccccc12
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1ccc(NCCN2CCCC2)cc1)c1c(-c2ccc(OCCN3CCCC3)cc2)sc2ccccc12
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 130.5 %

Procedure:
4-Fluorophenyl 2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl)benzo[b]thiophen-3-yl ketone (Example 145, Part A) (1.1 g; 2.5 mmol) was combined with 1.6 mL (12.3 mmol) of 1-(2-aminoethyl)pyrrolidine and 1.0 g (7.4 mmol) of potassium carbonate in 2 mL of dry DMF. The mixture was heated in an oil bath maintained at 130° C. for 18 h. After cooling to room temperature, the mixture was poured into 150 mL of water and stirred for 0.5 h. The product was isolated by filtration and washed with fresh water. The title compound (0.9 g; 68% yield) was purified by flash chromatography on silica gel, eluting with a gradient of hexanes(75-15%)/Et3N(5%)/THF(20-80%). Conversion to the trioxalate was effected as in Example 137, Part E.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([OH:18])([C:14]([O:16][CH3:17])=[O:15])[CH2:10][CH2:9]1)C1C=CC=CC=1.Cl[C:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][N:21]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:26][C:25]1[C:20]([N:8]2[CH2:9][CH2:10][C:11]([OH:18])([C:14]([O:16][CH3:17])=[O:15])[CH2:12][CH2:13]2)=[N:21][CH:22]=[CH:23][CH:24]=1
Reactant: COC(=O)C1(O)CCN(Cc2ccccc2)CC1
Reactant: Clc1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C1(O)CCN(c2ncccc2Cl)CC1
Temperature: 90 °C

Procedure:
Methyl 1-benzyl-4-hydroxy-4-piperidinecarboxylate (15.0 g, 77 mmol), 2,3-dichloropyridine (12.0 g, 81 mmol), and potassium carbonate (15.0 g, 108.7 mmol) were combined in DMF (200 mL) and heated at 90° C. for 2 days. The mixture was allowed to cool to room temperature, concentrated, and standard work-up provided a residue that was purified via chromatography (SiO2, ethyl acetate:hexanes, 1:6) to provide the title compound MS (EI, M+H)+271.
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][C:11]=2[N+:13]([O-:15])=[O:14])[NH:6][CH:5]=1.[CH3:16]I>CN(C=O)C>[I:3][C:4]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][C:11]=2[N+:13]([O-:15])=[O:14])[N:6]([CH3:16])[CH:5]=1
Reactant: O=[N+]([O-])c1ccnc2[nH]cc(I)c12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cc(I)c2c([N+](=O)[O-])ccnc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 145.3 %

Procedure:
To a stirred suspension of sodium hydride (0.872 g, 21.80 mmol) in DMF (80 mL) was added 3-iodo-4-nitro-1H-pyrrolo[2,3-b]pyridine (D16) (4.2 g, 14.53 mmol) predissolved in DMF (20 mL) dropwise over 30 mins at 0° C. The reaction mixture was then left stirring at 0° C. for 15 mins. After which, methyl iodide (1.090 mL, 17.44 mmol) was added and the resulting reaction mixture was stirred at 0° C. for ca. 1 hour. The reaction mixture was quenched with ammonium chloride solution (ca. 150 mL). The aqueous phase was extracted with ethyl acetate (3×80 mL). The combined organic phases were dried and concentrated. Another batch of 3-iodo-4-nitro-1H-pyrrolo[2,3-b]pyridine (D16) (4.2 g, 14.53 mmol) was treated in the same way. The residue from both reactions were combined and purified by chromatography on silica, eluting with a gradient of 0-50% ethyl acetate in cyclohexane to give the title compound (6.4 g). The impure fractions were re-purified by chromatography on silica, eluting with a gradient of 0-30% ethyl acetate in cyclohexane to give another batch of the title compound (1.32 g). LCMS (A): m/z (M+H)+ 304, C8H6IN3O2 requires 303 (acidic).
Reaction SMILES: C[C:2]1([CH3:9])[O:6][C@H:5]([CH2:7][OH:8])[CH2:4][O:3]1.[OH-].[K+].[CH2:12](Br)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]CC.O>C1(C)C=CC=CC=1>[CH2:2]([O:3][CH2:4][CH:5]([CH2:7][OH:8])[OH:6])[CH2:9][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH3:12]
Reactant: CC1(C)OC[C@@H](CO)O1
Reactant: CCCCCCCCCCCCCCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCOCC(O)CO
Temperature: 25 °C
Yield: 82.3 %

Procedure:
(R)-(−)-2,2-dimethyl-1,3-dioxolane-4-methanol (11 grams), powdered potassium hydroxide (20 grams) and hexadecyl bromide (27.96 grams) in toluene (150 ml) were stirred and refluxed for 6 hours, while removing the water formed by azeotropic distillation. The volume of the solvent was gradually reduced to about 40 ml. The reaction mixture was cooled to room temperature; water was added (100 ml) and the resulting mixture was extracted with dichloromethane (3×75 ml). The combined organic phase was washed with water (50 ml) and the solvent removed under reduced pressure. The residue was dissolved in 200 ml mixture of 90:10:5 methanol:water:concentrated hydrochloric acid (v/v) and the resulting solution was refluxed for 2 hours, followed by cooling to room temperature and addition of water (100 ml). The product was extracted with dichloromethane (3×100 ml), and the organic phase was washed consecutively with water (100 ml), saturated aqueous solution of sodium carbonate (100 ml) and again with water (100 ml). The solvent was removed under reduced pressure and the product was crystallized from hexane (200 ml) to give 21.69 grams (yield 82%) of pure 1-hexadecyl-glycerol, upon drying in a desiccator under reduced pressure.
Reaction SMILES: [OH:1][N:2]=[C:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.C([Li])CCC.I[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][CH:17]=1.Cl>O1CCCC1.CCCCCC>[OH:1][N:2]=[C:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[CH2:15][C:16]1[CH:17]=[CH:18][C:19]([CH:22]([CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:20][CH:21]=1
Reactant: ON=C1CCCCC1
Reactant: CCOC(=O)C(C)c1ccc(CI)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)C(C)c1ccc(CC2CCCCC2=NO)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 11.2 %

Procedure:
To a solution of 3.95 g of hydroxyiminocyclohexane in 40 ml of tetrahydrofuran was added 45 ml of 15% n-hexane solution of n-butyllithium at room temperature. After the mixture was stirred for 30 minutes at the same temperature, a solution of 9.4 g of ethyl 2-(4-iodomethylphenyl)propionate in 30 ml of tetrahydrofuran was added and stirring was continued for further 1 hour at room temperature. The reaction mixture was poured into a mixture of 100 ml of ice-water and 20 ml of concentrated hydrochloric acid, and extracted with ether. The product thus obtained was purified through a chromatography on a column of silica gel [eluent: ethyl acetate -- methylene chloride (1:3)] to afford 1.0 g of the starting compound recovered and 4.5 g of the desired compound, which by recrystallization from a mixture of ether and n-hexane yielded colorless crystals, m.p. 102°-104° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][C:12]#[N:13].Br[CH2:15][CH2:16][CH2:17]Br.[OH-].[K+]>CCOCC.CS(C)=O.C1OCCOCCOCCOCCOCCOC1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1([C:12]#[N:13])[CH2:17][CH2:16][CH2:15]1
Reactant: N#CCc1ccc2ccccc2c1
Reactant: BrCCCBr
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCOCC
Product: N#CC1(c2ccc3ccccc3c2)CCC1
Temperature: 15 °C
Yield: 392.9 %

Procedure:
A solution of 2-naphthylacetonitrile (10 g) and 1,3-dibromopropane (144 g) in a mixture of ether (350 ml) and dimethylsulphoxide (150 ml) was added dropwise at 20-25° C. under nitrogen over 2 hours to a stirred mixture of finely-powdered potassium hydroxide (150 g), 18-Crown-6 (1.3 g) and dimethylsulphoxide (570 ml). After the addition was complete, the mixture was cooled to 15° C. and quenched by the slow addition of water (330 ml). Ether (330 ml) was added, and the mixture was filtered through Hyflo Supercel filtration aid. The filter pad was washed well with ether, then the aqueous layer of the filtrate was separated, diluted with water (500 ml), and washed well with ether. All of the ethereal solutions were combined, washed with water (3×100 ml), and the solvents were removed in vacua. The residue was triturated with ethanol (100 ml) and the resulting solid was collected by filtration and dried in vacua to give 1-(2-naphthyl)cyclobutanecarbonitrile as a white solid (48.7 g), which was used without further purification.
Reaction SMILES: [OH:1]O.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][N:13]=[N:12][C:11]=2[C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[CH:6][CH:5]=1>C(O)(=O)C>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][N+:13]([O-:1])=[N:12][C:11]=2[C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:23])=[O:24])=[CH:18][CH:17]=2)=[CH:8][CH:9]=1
Reactant: CS(=O)(=O)c1ccc(-c2nnccc2-c2ccc(Cl)cc2)cc1
Reactant: OO
Solvent: CC(=O)O
Product: CS(=O)(=O)c1ccc(-c2n[n+]([O-])ccc2-c2ccc(Cl)cc2)cc1
Temperature: 50 °C
Reaction time: 6 h
Yield: 44.1 %

Procedure:
Hydrogen peroxide solution (31%, 5.2 ml) was added to a solution of 4-(4-chlorophenyl)-3-[4-(methylsulfonyl)phenyl]pyridazine (2.6 g, 7.55 mmol) in acetic acid (30 ml), followed by stirring at 50° C. for 6 hours. The reaction mixture was concentrated under reduced pressure, and to the residue, an aqueous solution of potassium carbonate was added. The thus-obtained mixture was extracted with chloroform, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was separated and purified by chromatography on a silica gel column [silica gel 100 g, benzene/ethyl acetate (1/1)], whereby the title compound was obtained as a pale yellow amorphous solid (1.2 g, 44.1%).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:13][OH:14]>>[OH:14][NH:13][C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Nc1nc(Cl)nc2ccccc12
Reactant: NO
Product: Nc1nc(NO)nc2ccccc12

Procedure:
Prepared as in Example 42 from 2-chloroquinazolin-4-amine (Example 38) and hydroxylamine. 1H NMR (400 MHz, DMSO-d6) δ 7.44-7.35 (m, 2H), 7.78-7.74 (m, 2H), 8.24-8.22 (m, 1H), 8.95-8.76 (m, 2H). MS 177 (MH+).
Reaction SMILES: C([O:4][C:5]1[CH:15]=[CH:14][C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][CH:6]=1)C=C.CN(C)[C:18]1[CH:23]=CC=C[CH:19]=1>C(OCC)(=O)C>[CH2:23]([C:15]1[CH:14]=[C:8]([CH:7]=[CH:6][C:5]=1[OH:4])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:18]=[CH2:19]
Reactant: CN(C)c1ccccc1
Reactant: C=CCOc1ccc(C(=O)OCC)cc1
Solvent: CCOC(C)=O
Product: C=CCc1cc(C(=O)OCC)ccc1O
Temperature: 200 °C
Reaction time: 48 h
Yield: 69 %

Procedure:
A mixture of ethyl 4-allyloxybenzoate (10.0 g, 48.5 mmol) and N,N-dimethylaniline (20 ml) was left under stirring at 200° C. for 48 h, then diluted with ethyl acetate (150 ml) and washed with 1M HCl. After drying and evaporating off the solvent, a crude was obtained which was purified by chromatography through a silica gel column, eluting with n-hexane:ethyl acetate, 95:5, thereby recovering 6.85 g of the title compound (69% yield).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][C:14]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)([C:17]#[N:18])[CH2:13][CH2:12]1)(C)(C)C.[OH:27]S(O)(=O)=O>>[NH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][C:14]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)([C:17]([NH2:18])=[O:27])[CH2:13][CH2:12]1
Reactant: O=S(=O)(O)O
Reactant: CC(C)(C)OC(=O)NCCCN1CCC(C#N)(c2ccc(Cl)cc2)CC1
Product: NCCCN1CCC(C(N)=O)(c2ccc(Cl)cc2)CC1
Yield: 79 %

Procedure:
3-(4-(4-chlorophenyl)-4-cyanopiperidin-1-yl)propylcarbamic acid tert-butyl ester (0.150 g, 5.39 mmol) in conc. H2SO4 (1 mL) was stirred at room temperature for 30 hours. The solution was concentrated, neutralized with 10% KOH solution and extracted into 25 mL of dichloromethane. The organic layer was dried over sodium sulfate, filtered and concentrated to give 0.185 g (79%) of 1-(3-aminopropyl)-4-(4-chlorophenyl)piperidine-4-carboxamide which was used as such for the subsequent step.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C@@:5]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[O:10][C:9](=[O:11])[N:8]([C@H:12]([C:14]2[CH:23]=[CH:22][C:17]([C:18](OC)=[O:19])=[CH:16][CH:15]=2)[CH3:13])[CH2:7][CH2:6]1.[BH4-].[Na+].CO>C1COCC1>[OH:19][CH2:18][C:17]1[CH:22]=[CH:23][C:14]([C@@H:12]([N:8]2[CH2:7][CH2:6][C@:5]([CH2:4][CH2:3][CH2:2][OH:1])([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[O:10][C:9]2=[O:11])[CH3:13])=[CH:15][CH:16]=1
Reactant: COC(=O)c1ccc([C@H](C)N2CC[C@](CCCO)(c3ccccc3)OC2=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@@H](c1ccc(CO)cc1)N1CC[C@](CCCO)(c2ccccc2)OC1=O
Yield: 5.4 %

Procedure:
To a solution of methyl 4-((S)-1-((R)-6-(3-hydroxypropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)benzoate (60 mg, 0.25 mmol) in THF (5 mL) was added NaBH4 (48 mg, 1.25 mmol). The mixture was heated to reflux for 15 minutes. Then methanol (3 mL) was added. The mixture was heated to reflux overnight. The reaction was quenched with water, and the solvent was removed. The aqueous layer was extracted with EtOAc for 3 times. The combined organic layer was washed with brine, dried over Na2SO4, and concentrated to give the crude product, which was purified by preparative TLC to give (R)-3-((S)-1-(4-(hydroxymethyl)phenyl)ethyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-one (5 mg, 5%). LC-MS Method 2 tR=1.29, min, m/z=370, 392; 1H NMR (CDCl3): 1.33 (m, 1H), 1.45 (m, 3H), 1.64 (m, 1H), 1.90 (m, 2H), 2.11-2.24 (m, 2H), 2.81 (m, 1H), 3.50 (m, 2H), 4.52 (s, 2H), 5.58 (m, 1H), 6.82 (m, 2H), 7.03 (m, 2H), 7.25 (m, 5H).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[C:23]([O:27][C:28]([N:30]([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[C:31]1[C:32]2[C:39]([I:40])=[CH:38][N:37]([C@@H:41]3[CH2:45][N:44]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[C@H:43]([CH2:53][OH:54])[CH2:42]3)[C:33]=2[N:34]=[CH:35][N:36]=1)=[O:29])([CH3:26])([CH3:25])[CH3:24].O>C(Cl)Cl>[C:23]([O:27][C:28]([N:30]([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[C:31]1[C:32]2[C:39]([I:40])=[CH:38][N:37]([C@@H:41]3[CH2:45][N:44]([C:46]([O:48][C:49]([CH3:50])([CH3:51])[CH3:52])=[O:47])[C@H:43]([CH:53]=[O:54])[CH2:42]3)[C:33]=2[N:34]=[CH:35][N:36]=1)=[O:29])([CH3:24])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncnc2c1c(I)cn2[C@H]1C[C@@H](CO)N(C(=O)OC(C)(C)C)C1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncnc2c1c(I)cn2[C@H]1C[C@@H](C=O)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dess-Martin periodinane (51 mg) was added to a solution of (2S,4S)-tert-butyl 4-(4-(bis(tert-butoxycarbonyl)amino)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (66 mg) obtained in Step 4 in methylene chloride (2 ml), and the resulting mixture was stirred at room temperature for 1 hour. Dess-Martin periodinane (100 mg) was further added to the mixture, and stirred at room temperature for 1 hour. Dess-Martin periodinane (70 mg) was additionally added thereto, and the resulting mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture to separate the organic layer. The organic layer was washed with a sodium hydrogen carbonate aqueous solution and a 10% sodium thiosulfate aqueous solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound as a light-yellow, amorphous substance (68 mg). Physical properties: m/z [M+H]+ 658.1
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[O:19](C(OC(C)(C)C)=O)[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=O>C1COCC1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:20](=[O:19])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[N:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: Nc1ccc(Br)cn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(Br)cn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-amino-5-bromopyridine (8.65 g, 50 mmol) in THF (100 mL) was added lithium hexamethyldisilazide (105 mL, 105 mmol) under nitrogen at 0° C. After the addition, the mixture was stirred for 30 mins at 0° C. At this point, (BOC)2O (12 g, 55 mmol) was added to the reaction mixture and the mixture was stirred for another 30 mins at 0° C. TLC (petroleum ether/ethyl acetate=5:1) indicated the reaction was complete. The reaction mixture was washed with 1 N HCl (20 mL), and the residue was extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, and evaporated in vacuo. The residue was purified by chromatography on silica to afford (I-29a) (8 g, 58.6%) as a white solid.