Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(OCCC(C)C)=O.CS[S:11][CH3:12].[Br:13][C:14]1[CH:20]=[CH:19][C:17](N)=[C:16]([N+:21]([O-:23])=[O:22])[CH:15]=1>>[Br:13][C:14]1[CH:20]=[CH:19][C:17]([S:11][CH3:12])=[C:16]([N+:21]([O-:23])=[O:22])[CH:15]=1
Reactant: CSSC
Reactant: Nc1ccc(Br)cc1[N+](=O)[O-]
Agent: CC(C)CCON=O
Product: CSc1ccc(Br)cc1[N+](=O)[O-]
Temperature: 85 °C
Yield: 97.1 %

Procedure:
A solution of isoamyl nitrite (10.05 mL, 75 mmol) in dimethyl disulfide (49.5 mL, 550 mmol) at 25° C. was slowly treated with 4-bromo-2-nitroaniline (10.85 g, 50 mmol). The reaction was exothermic with gas evolution. The resulting brown reaction mixture was heated to 80-90° C. for 2 h, at which time, thin layer chromatography analysis of the reaction mixture indicated the absence of starting material. The reaction mixture was cooled to 25° C. and then concentrated in vacuo. The resulting residue was dissolved in ethyl acetate (300 mL). The organic layer was washed successively with a 1N aqueous hydrochloric acid solution (1×300 mL) and a saturated aqueous sodium chloride solution (1×300 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 6/1 to 5/1 hexanes/ethyl acetate) afforded 4-bromo-1-methylsulfanyl-2-nitro-benzene (12.05 g, 97%) as a brown solid: EI-HRMS m/e calcd for C7H6BrNO2S (M+) 246.9372, found 246.9368.
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][C:18](OCC)=[O:19])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O>CCOCC>[CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][OH:19])[CH2:11][CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCCN1CCC(OCc2ccccc2)CC1
Solvent: O
Solvent: CCOCC
Product: OCCCCN1CCC(OCc2ccccc2)CC1
Yield: 83.1 %

Procedure:
The compound obtained from step 1 (4.8 g) was dissolved in ether, and cooled in an ice bath. LialH4 (0.1 g) was added slowly to the solution. The resulting mixture was reacted at room temperature for 1 hr. before adding water to end the reaction. The resulting solution was then extracted by using water and ester. An organic solution layer was dehydrated over magnesium sulfate, filtered, and concentrated under reduced pressure. The column chromatography was performed thereon, thereby obtaining crude yellowish liquid product (3.44 g, 83% yield) of the title.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:6]=1[C:12](=O)[CH3:13].[CH3:15]C(C)([O-])C.[K+]>>[I:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][OH:1])=[C:6]([C:12]([CH3:13])=[CH2:15])[CH:7]=1
Reactant: CC(C)(C)[O-]
Reactant: CC(=O)c1cc(I)ccc1OCCO
Agent: [K+]
Product: C=C(C)c1cc(I)ccc1OCCO

Procedure:
The product was prepared analogously to Example 11.1b starting from 1-[2-(2-hydroxyethoxy)-5-iodophenyl]ethanone and using potassium tert-butoxide as base. Yield: 2.50 g (43% of theoretical); C11H13IO2 (M=304.124); calc.: molpeak (M+H)+: 305; found: molpeak (M+H)+: 305; HPLC-MS: 5.65 minutes (method B).
Reaction SMILES: [C:1]1(O)[CH:8]=[C:6]([CH3:7])[CH:5]=[C:3]([OH:4])[CH:2]=1.[CH2:10]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]>>[CH2:17]([N:16]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:1]1[CH:2]=[C:3]([OH:4])[CH:5]=[C:6]([CH3:7])[CH:8]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCNCCCCCC
Reactant: Cc1cc(O)cc(O)c1
Product: CCCCCCN(CCCCCC)c1cc(C)cc(O)c1

Procedure:
Orcinol (5-resorcinol) was aminized by di-n-hexylamine, so as to obtain 1-di-n-hexylamino-3-methyl-5-hydroxybenzene. The hydroxy group thereof was etherized with methyl iodide, and then nitrosoized so as to obtain 1-di-n-hexylamino-3-methyl-4-nitroso-5-methoxybenzene.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH:11]=O)=[CH:5][CH:4]=1.[CH3:18][CH:19]([CH3:35])[C:20]([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:24]=1)=[O:21]>>[CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH2:11][N:32]2[CH2:33][CH2:34][CH:29]([C:25]3[CH:24]=[C:23]([NH:22][C:20](=[O:21])[CH:19]([CH3:18])[CH3:35])[CH:28]=[CH:27][CH:26]=3)[CH2:30][CH2:31]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Oc2cccc(C=O)c2)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: COc1ccc(Oc2cccc(CN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c2)cc1

Procedure:
Prepared by Procedure F and Scheme R using 3-(4-methoxyphenoxy)benzaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 459.2 (M+H)+.
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]([OH:8])[CH:2]=1.[CH3:9][S:10](Cl)(=[O:12])=[O:11].O.Cl>N1C=CC=CC=1>[CH3:9][S:10]([NH:7][C:6]1[CH:5]=[CH:4][C:3]([OH:8])=[CH:2][CH:1]=1)(=[O:12])=[O:11]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(O)cc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc(O)cc1
Temperature: 20 °C
Reaction time: 72 h
Yield: 23.1 %

Procedure:
5.4 g (49.5 mmol) of p-aminophenol are dissolved in 40 ml of anhydrous pyridine, and 5.7 g (1 equivalent) of methanesulfonyl chloride diluted in 12 ml of pyridine are added over 15 minutes at 20° C. under a stream of nitrogen. The reaction medium is stirred for 3 days at 20° C. and is then poured into 1.5 liters of water containing a sufficient amount of hydrochloric acid (67 g of 36% HCl) to neutralize the pyridine and to establish a pH≦1.5. The aqueous phase is separated out by settling and extracted twice with 250 ml of ethyl acetate. The organic phases are combined and washed with twice 250 ml of water and then concentrated under vacuum. The residue is recrystallized from 40 ml of ethyl acetate. The crystals are filtered off at 0° C. and washed with 15 ml of ethyl acetate. 2.14 g of crude p-methanesulfonamidophenol are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]2[C:3]=1[C:4]([CH2:12][CH:13]([OH:15])[CH3:14])=[CH:5][NH:6]2.[C:16]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])(=O)[CH2:17][CH2:18][CH3:19].B(F)(F)F.CCOCC>C(Cl)Cl>[CH2:25]([O:24][C:22](=[O:23])[CH2:21][C:16]1([CH2:17][CH2:18][CH3:19])[C:5]2[NH:6][C:7]3[C:3]([C:4]=2[CH2:12][CH:13]([CH3:14])[O:15]1)=[C:2]([Br:1])[CH:10]=[CH:9][C:8]=3[F:11])[CH3:26]
Reactant: CCCC(=O)CC(=O)OCC
Reactant: CC(O)Cc1c[nH]c2c(F)ccc(Br)c12
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CCCC1(CC(=O)OCC)OC(C)Cc2c1[nH]c1c(F)ccc(Br)c21
Reaction time: 3 h

Procedure:
To a solution of 1-(4-bromo-7-fluoro-1H-indol-3-yl)-propan-2-ol (155 mg, 0.570 mmol) and ethyl butyrylacetate (0.137 mL, 0.854 mmol) in CH2Cl2 (3 mL) was added BF3.OEt2 (0.11 mL, 0.854 mmol) dropwise at room temperature. After stirring for 3 hours, the mixture was diluted with CH2Cl2 (15 mL) and then washed with saturated aqueous NaHCO3 (15 mL) and brine (15 mL). The organic phase was dried (Na2SO4) and concentrated. The residue was purified by flash chromatography (silica, 10% EtOAc in hexanes) to give (5-bromo-8-fluoro-3-methyl-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid ethyl ester as a pale yellow solid (this sample contains ethyl butyrylacetate).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][C:13](=[O:15])[CH3:14])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].[Cl:22][C:23]1[CH:28]=[N:27][CH:26]=[C:25](Cl)[N:24]=1>CN(C=O)C>[Cl:22][C:23]1[N:24]=[C:25]([O:1][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([NH:12][C:13](=[O:15])[CH3:14])=[CH:4][CH:3]=2)[CH:26]=[N:27][CH:28]=1
Reactant: Clc1cncc(Cl)n1
Reactant: CC(=O)Nc1ccc(O)c2ccccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(Oc2cncc(Cl)n2)c2ccccc12
Temperature: 90 °C
Reaction time: 1 h
Yield: 68.2 %

Procedure:
Method KK. A mixture of N-(4-hydroxynaphthalen-1-yl)acetamide (1.22 g, 6.08 mmol) and potassium tert-butoxide (0.68 g, 6.08 mmol) in dry DMF (19 mL) was stirred for 1 hour under argon. To this mixture, 2,6-dichloropyrazine (1.09 g, 7.30 mmol) was added and the temperature was raised to 90° C. and maintained for 20 hours. The DMF was evaporated in vacuo. The resulting crude was dissolved in a (hot) mixture of AcOEt (25 mL) and acetone (175 mL) and filtered. The volume of the filtrate was reduced to 100 mL and this filtrate crystallised upon storage at low temperature to yield the title compound (1.30 g). Yield: 68%. 1H NMR (500 MHz, DMSO-d6) δ 2.21 (s, 3H), 7.42 (d, 1H, J=8.2 Hz), 7.57 (t, 1H, J=7.5 Hz), 7.64 (t, 1H, J=7.6 Hz), 7.72 (d, 1H, J=8.1 Hz), 7.90 (d, 1H, J=8.3 Hz), 8.16 (d, 1H, J=8.5 Hz), 8.52 (s, 1H), 8.72 (s, 1H), 10.02 (s, 1H). 13C NMR (125.8 MHz, DMSO-d6) δ 23.42, 117.59, 121.40, 121.65, 123.42, 126.53, 126.71, 126.85, 128.90, 131.85, 133.59, 137.50, 144.40, 145.04, 158.92, 169.04. m/z 314.0 [(M+H)+ calcd for C16H12ClN3O2 313.1].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1I.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[C:16]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[O:24][CH3:23])=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:22]
Reactant: COc1ccccc1B(O)O
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccccc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1ccccc1-c1ccccc1C(=O)NCCc1c[nH]c2ccc(Cl)cc12
Yield: 91.2 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-methoxybiphenyl-2-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2-iodobenzamide (0.075 g; 0.176 mmol), 2-methoxyphenylboronic acid (0.028 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 1 to 20% ethyl acetate in dichloromethane) furnished 0.065 g (90%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-methoxybiphenyl-2-carboxamide.
Reaction SMILES: [ClH:1].Cl.[C:3]([C:6]1[CH:7]=[CH:8][C:9]2[O:13][C:12]([CH2:14][CH:15]([C:19]3[CH:24]=[CH:23][C:22]([O:25][C@H:26]4[CH2:30][CH2:29][NH:28][CH2:27]4)=[CH:21][CH:20]=3)[C:16]([OH:18])=[O:17])=[CH:11][C:10]=2[CH:31]=1)(=[NH:5])[NH2:4].Cl.[C:33](=[NH:38])(OCC)[CH3:34].[OH-].[Na+].Cl>O.O.C(#N)C>[ClH:1].[ClH:1].[C:33]([N:28]1[CH2:29][CH2:30][C@H:26]([O:25][C:22]2[CH:21]=[CH:20][C:19]([CH:15]([CH2:14][C:12]3[O:13][C:9]4[CH:8]=[CH:7][C:6]([C:3](=[NH:4])[NH2:5])=[CH:31][C:10]=4[CH:11]=3)[C:16]([OH:18])=[O:17])=[CH:24][CH:23]=2)[CH2:27]1)(=[NH:38])[CH3:34]
Reactant: CCOC(C)=N
Reactant: N=C(N)c1ccc2oc(CC(C(=O)O)c3ccc(O[C@H]4CCNC4)cc3)cc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: CC(=N)N1CC[C@H](Oc2ccc(C(Cc3cc4cc(C(=N)N)ccc4o3)C(=O)O)cc2)C1
Yield: 130.3 %

Procedure:
1.1 g of 3-(5-amidino-2-benzofuranyl)-2-[4-[((3S)-3-pyrrolidinyl)oxy]phenyl]propionic acid dihydrochloride was dissolved in 20 ml of water. During ice cooling and stirring, 1.4 g of ethyl acetimidate hydrochloride was added gradually to the thus prepared solution while adjusting the pH of the solution to 8.5 with 1N sodium hydroxide aqueous solution. The resulting mixture was stirred for 15 minutes with ice cooling, and then adjusted to pH 2.0 with dilute hydrochloric acid. After concentrating the resulting reaction solution to dryness, the thus obtained residue was subjected to reversed phase high performance liquid chromatography using a column packed with octadecyl-bonded silica gel and using a water/acetonitrile mixture as an elution solvent. Thereafter, the thus eluted fractions of interest were pooled, mixed with dilute hydrochloric acid, and then concentrated to dryness. In this way, 780 mg of the title compound was obtained in a solid form.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:20]3[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:27])[NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][NH:16][C:15](=[O:19])[CH:14]=2)=[CH:4][CH:3]=1>ClCCCl.C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2=[C:8]3[N:9]=[C:10]([C:20]4[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=4[Cl:27])[NH:11][C:12]3=[C:13]3[C:14]([C:15](=[O:19])[NH:16][CH:17]=[CH:18]3)=[C:4]2[CH:3]=1
Reactant: O=c1cc(-c2[nH]c(-c3c(F)cccc3Cl)nc2-c2ccc(Br)cc2)cc[nH]1
Solvent: ClCCCl
Solvent: CCO
Product: O=c1[nH]ccc2c3[nH]c(-c4c(F)cccc4Cl)nc3c3ccc(Br)cc3c12

Procedure:
The intermediate from Example 1 Step D (2.9 g, 6.55 mmol) was dissolved in 200 mL of a 60:40 mixture of 1,2-dichloroethane-ethanol. The mixture was irradiated under a high intensity light for 3 days. The volatiles were removed in vacuo and the crude material was triturated with DCM and filtered. The product was triturated twice more with EtOAc and filtered. 1 NMR 400 MHz, DMSO-d6: δ14.12 (br, 1H), 11.82 (m, 1H), 10.55(m, 1H), 7.40˜7.90(m, 7H): [M+1]+ 442.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:7]=[CH:8][C:9]2[O:13][CH:12]([OH:14])[C:11]([CH3:16])([CH3:15])[C:10]=2[CH:17]=1)(=[O:4])=[O:3].[CH3:18][CH:19]([CH3:23])[CH2:20][CH2:21]O.O>S(=O)(=O)(O)O.C1C=CC=CC=1>[CH3:1][S:2]([O:5][C:6]1[CH:7]=[CH:8][C:9]2[O:13][CH:12]([O:14][CH2:21][CH2:20][CH:19]([CH3:23])[CH3:18])[C:11]([CH3:15])([CH3:16])[C:10]=2[CH:17]=1)(=[O:3])=[O:4]
Reactant: CC1(C)c2cc(OS(C)(=O)=O)ccc2OC1O
Reactant: CC(C)CCO
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Solvent: O
Product: CC(C)CCOC1Oc2ccc(OS(C)(=O)=O)cc2C1(C)C
Yield: 85.3 %

Procedure:
A mixture of 2,3-dihydro-3,3-dimethyl-2-hydroxybenzofuran-5-yl methanesulphonate (13g, 0.05 mole), 3-methyl-1-butanol (4.4g, 0.05 mole) and concentrated sulphuric acid (4 drops) in benzene (50 ml) was heated at reflux under a Dean and Stark trap until 0.9 ml water (0.05 mole) had been eliminated. The reaction mixture was cooled, washed with dilute aqueous sodium hydroxide solution and with water (twice) and dried over sodium sulphate. The benzene was then distilled off under reduced pressure to give 2,3-dihydro-3,3-dimethyl-2-(3-methylbutoxy)-5-benzofuranyl methanesulphonate as a yellow oil (14 g, 86% yield) which slowly solidified (melting point 35°-38° C.).
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]2[CH:13]=[N:14][C:15]([C:16](O)=[O:17])=[C:5]2[C@@H:4]2[CH2:19][CH2:20][CH2:21][N:3]12.[CH:22]1([C:25](=[N:27]O)[NH2:26])[CH2:24][CH2:23]1>CN(C)C=O>[CH:22]1([C:25]2[N:27]=[C:16]([C:15]3[N:14]=[CH:13][N:6]4[C:7]5[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=5[C:2](=[O:1])[N:3]5[CH2:21][CH2:20][CH2:19][C@H:4]5[C:5]=34)[O:17][N:26]=2)[CH2:24][CH2:23]1
Reactant: O=C(O)c1ncn2c1[C@@H]1CCCN1C(=O)c1ccccc1-2
Reactant: NC(=NO)C1CC1
Solvent: CN(C)C=O
Product: O=C1c2ccccc2-n2cnc(-c3nc(C4CC4)no3)c2[C@@H]2CCCN12

Procedure:
7.70 g (2.72 mmol) of (S)-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylic acid in 40 ml of N,N-dimethylformamide are stirred at room temperature for 10 minutes and at 85° for 20 minutes with 4.41 g (27.2 mmol) of N,N'-carbonyldiimidazole. 2.72 g (27.2 mmol) of cyclopropanecarboxamidoxime are subsequently added thereto and the mixture is stirred at 110° for a further hour. After removing the N,N-dimethylformamide the residue is stirred in 30 ml of acetic acid at 120° for 4 hours. The solution is evaporated and the residue is partitioned between methylene chloride and saturated sodium bicarbonate solution. The organic phase is separated, dried over magnesium sulphate and evaporated. By recrystallization from ethyl acetate there is obtained (S)-1-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one of melting point 211°-212°.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[C:7]([O:14][CH3:15])[CH:6]=2.[CH:16]1(O)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH:16]1([O:1][C:2]2[CH:3]=[N:4][C:5]3[C:10]([CH:11]=2)=[CH:9][C:8]([O:12][CH3:13])=[C:7]([O:14][CH3:15])[CH:6]=3)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: COc1cc2cc(O)cnc2cc1OC
Reactant: OC1CCCCC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cc2cc(OC3CCCCC3)cnc2cc1OC

Procedure:
To a THF solution (30 mL) at 0° C. is added 3-hydroxy-6,7-dimethoxyquinoline (0.237 g, 1.15 mmole), cyclohexanol (0.347 g, 3.46 mmole), Ph3P (0.908 g, 3.46 mmole). Diethylazodicarboxylate is added portionwise until the solution retained a deep red color (0.663 g, 3.81 mmole). After 4 hours the solution is concentrated and the residue chromatographed (50% EtOAc in hexanes). The product is recrystallized from isopropanol/hexanes as the HCl salt as a white solid (m.p. 229-232° C., dec.).
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[O:4][C:5]1[N:6]=[CH:7][C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[C:18]([CH3:20])[C:17]([O:21]C)=[C:16]([CH3:23])[CH:15]=3)[O:11][C:9]=2[N:10]=1.B(Br)(Br)Br.C(=O)([O-])O.[Na+]>ClCCl>[F:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[O:4][C:5]1[N:6]=[CH:7][C:8]2[N:13]=[C:12]([C:14]3[CH:15]=[C:16]([CH3:23])[C:17]([OH:21])=[C:18]([CH3:20])[CH:19]=3)[O:11][C:9]=2[N:10]=1
Reactant: COc1c(C)cc(-c2nc3cnc(Oc4ccccc4F)nc3o2)cc1C
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(-c2nc3cnc(Oc4ccccc4F)nc3o2)cc(C)c1O
Temperature: 0 °C
Reaction time: 1 h
Yield: 90.7 %

Procedure:
A solution of 510 mg of 5-(2-fluoro-phenoxy)-2-(4-methoxy-3,5-dimethyl-phenyl)-oxazolo[5,4-d]pyrimidine in 20 ml dichloromethane was cooled to 0° C., and over a period of 10 min 4.2 ml of a 1 M solution of boron tribromide in dichloromethane was added. The mixture was stirred at 0° C. for 1 h, and then another 2 ml of a 1 M solution of boron tribromide in dichloromethane were added. After stirring for another 1 h, 10 ml of a saturated aqueous solution of sodium hydrogencarbonate were added slowly. The aqueous layer was extracted twice with 15 ml of dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and the solvents were removed in vacuo to give 445 mg of the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[N:4][CH:3]=1.[C:14](OC(=O)C)(=[O:16])[CH3:15]>>[Br:1][C:2]1[S:6][C:5]([N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:14](=[O:16])[CH3:15])=[N:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: Brc1cnc(Nc2ccccn2)s1
Product: CC(=O)N(c1ccccn1)c1ncc(Br)s1
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
To a flask containing (5-Bromo-thiazol-2-yl)-pyridin-2-yl-amine (5-4, 4.58 g, 17.9 mmol was added 30 mL acetic anhydride. The suspension was then heated to 100° C. After about 1.5 hours, the acetic anhydride and acetic acid was removed under reduced pressure, heating the bath to 70° C. Two 70 mL portions of toluene were also added for azeotropic distillation. The product was obtained as a tan colored precipitate. 1H NMR (DMSO-d6): δ8.65 (d, 1H, J=3.9 Hz), 8.09 (t, 1H, J=8.6 Hz), 7.67 (d, 1H, J=8 Hz), 7.59 (t, 1H, J=6.6 Hz), 7.47 (s, 1H). mp 132-138° C.
Reaction SMILES: [O:1]([CH2:9][CH2:10][CH:11]1[C:16](=[O:17])[NH:15][C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[O:12]1)[Si](C(C)(C)C)(C)C.[F:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26]Cl.[K+].[Br-]>>[F:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26][N:15]1[C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[O:12][CH:11]([CH2:10][CH2:9][OH:1])[C:16]1=[O:17]
Reactant: CC(C)(C)[Si](C)(C)OCCC1Oc2ccccc2NC1=O
Reactant: Fc1cccc(CCl)c1
Agent: [Br-]
Agent: [K+]
Product: O=C1C(CCO)Oc2ccccc2N1Cc1cccc(F)c1

Procedure:
Prepared from 2-(2-tert-butyldimethylsiloxyethyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazine by Methods F and G, alkylating with 3-flourobenzyl chloride, in 49% overall yield and isolated as a gummy solid; IR (KBr) 3425, 1683, 1501, 1401, 1252, 1061, 751 cm-1 ; 1H NMR (CDCl3) δ 2.16-2.38 (m, 3H), 3.92 (t, J=5.8 Hz, 2H), 4.85 (dd, J=7.6, 5.5 Hz, 1H), 5.14 (s, 2H), 6.82-6.85 (m, 1H), 6.90-7.08 (m, 6H), 7.26-7.33 (m, 1H); MH+ at m/z=302; Anal. Calc'd for C17H16FNO3 : C, 67.76; H, 5.35; N, 4.65. Found: C, 67.48; H, 5.34; N, 4.57.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[C:12]([OH:14])[CH:11]=[C:10]([C:15]([F:18])([F:17])[F:16])[N:9]=2)=[N:6][CH:7]=1.C(N(CC)CC)C.[Cl:26][CH:27]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:28](Cl)=[O:29]>C1COCC1>[Cl:26][CH:27]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:28]([NH:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[N:13]=[C:12]([OH:14])[CH:11]=[C:10]([C:15]([F:18])([F:17])[F:16])[N:9]=2)=[CH:4][CH:3]=1)=[O:29]
Reactant: Nc1ccc(-c2nc(O)cc(C(F)(F)F)n2)nc1
Reactant: O=C(Cl)C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccc(-c2nc(O)cc(C(F)(F)F)n2)nc1)C(Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a cold (0° C.) solution of compound of example 15 (0.10 g, 0.39 mmol) in THF (10 mL), was added triethylamine (0.059 g, 0.58 mmol) and 2-chloro-2-phenylacetyl chloride (0.110 g, 0.58 mmol), and the reaction mixture was stirred at room temperature for 30 minutes. THF was removed under reduced pressure, and reaction mixture was quenched with water and extracted with ethyl acetate (3×10 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by column chromatography (silica gel, 5 methanol in chloroform as an eluent) to obtain the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][NH:21][C:22]([C:24]2([NH2:29])[CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:23])=[CH:16][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[OH:31]>[Pd]>[C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:15]=[CH:16][C:17]([CH2:20][NH:21][C:22]([C:24]2([NH2:29])[CH2:28][CH2:27][O:31][CH2:26][CH2:25]2)=[O:23])=[CH:18][CH:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CNC(=O)C2(N)CCCC2)cc1
Reactant: CO
Agent: [Pd]
Product: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CNC(=O)C2(N)CCOCC2)cc1
Reaction time: 1 h

Procedure:
The product obtained in step C is dissolved in 30 ml of methanol. 400 mg of 10% palladium-on-charcoal are added and the mixture is hydrogenated at atmospheric pressure. After 1 hour, the catalyst is filtered off and the filtrate is then concentrated under vacuum. The residue is chromatographed on silica using an ethyl acetate/methanol/33% aqueous ammonia mixture (99/1/0.5; v/v/v) as the eluent to give 0.93 g of the expected product in the form of a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[N+:12]([C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[S:25](Cl)(=[O:27])=[O:26])([O-:14])=[O:13]>>[N+:12]([C:15]1[CH:20]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:18]=[CH:17][C:16]=1[S:25]([NH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2)(=[O:27])=[O:26])([O-:14])=[O:13]
Reactant: Nc1cccc2cccnc12
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1S(=O)(=O)Cl
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1S(=O)(=O)Nc1cccc2cccnc12
Yield: 102.4 %

Procedure:
In a similar fashion using route 14 general procedure 26, 8-aminoquinoline (500 mg, 3 mmol) and 2-nitro-4-(trifluoromethyl)benzene-1-sulfonyl chloride (990 mg, 3 mmol) gave the title compound (1.22 g, 99%).