Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][O:9][C:10]1[CH:42]=[CH:41][C:13]([C:14]([NH:16][C@H:17]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:18][NH:19][C:20]([CH:22]2[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]2)=[O:21])=[O:15])=[CH:12][CH:11]=1.C1(OC)C=CC=CC=1>C(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]([NH:16][C@H:17]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:18][NH:19][C:20]([CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[O:21])=[O:15])=[CH:41][CH:42]=1
Reactant: COc1ccc(C(=O)N[C@@H](CNC(=O)C2CCN(C(=O)OC(C)(C)C)CC2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C(=O)N[C@@H](CNC(=O)C2CCNCC2)c2ccccc2)cc1
Reaction time: 1 h
Yield: 92 %

Procedure:
(Deprotection Method A) Trifluoroacetic acid was added to a stirring suspension of (R)-N-[2-(4-methoxybenzoylamino)-2-phenylethyl]-1-tert-butoxycarbonylpiperidine-4-carboxamide (2.0 g, 4.2 mmol), methylene chloride (20 mL), and anisole (0.5 g, 4.6 mmol) at room temperature. A solution was obtained and bubbling was observed. After 1 h, the reaction mixture was evaporated at 40° C. The residue was taken up in warm methanol, and to this stirring solution was added ether to precipitate the product. The precipitate was collected by vacuum filtration, washed with ethyl acetate, then dried under vacuum at 60° C. overnight to afford 1.9 g (92%) of a white solid
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:12]CC2C=CC=CC=2)=[C:9]([CH:11]=1)[NH2:10]>CO.[C].[Pd]>[ClH:1].[NH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([OH:12])=[C:9]([CH:11]=1)[NH2:10]
Reactant: NCCc1ccc(OCc2ccccc2)c(N)c1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: NCCc1ccc(O)c(N)c1

Procedure:
In the presence of 100 mg of palladiumcarbon, 2.6 g of 5-(2-aminoethyl)-2-benzyloxyaniline, hydrochloride, is hydrogenated in 20 ml of methanol; after recrystallization from ethanol, 0.52 g of 5-(2-aminoethyl)-2-hydroxyaniline, hydrochloride, is obtained, mp 159°-164° C.
Reaction SMILES: [Cl-].[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([C:13]#[N:14])=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[O:15][CH2:16][CH2:17][NH3+:18].[CH3:19][C:20]1[O:24][C:23]([CH:25]=O)=[CH:22][CH:21]=1>>[Cl:2][C:3]1[C:4]([O:15][CH2:16][CH2:17][NH:18][CH2:25][C:23]2[O:24][C:20]([CH3:19])=[CH:21][CH:22]=2)=[CH:5][CH:6]=[C:7]2[C:12]=1[CH:11]=[CH:10][C:9]([C:13]#[N:14])=[CH:8]2
Reactant: N#Cc1ccc2c(Cl)c(OCC[NH3+])ccc2c1
Reactant: Cc1ccc(C=O)o1
Agent: [Cl-]
Product: Cc1ccc(CNCCOc2ccc3cc(C#N)ccc3c2Cl)o1
Yield: 77 %

Procedure:
Prepared from 2-[(1-chloro-6-cyanonaphthalen-2-yl)oxy]ethanaminium chloride and 5-methylfuran-2-carbaldehyde in 77% yield as a slightly white solid.
Reaction SMILES: O[CH2:2][CH:3]1[CH2:7][O:6][C:5](=[O:8])[O:4]1.Cl[C:10]([O:12][CH3:13])=[O:11]>N1C=CC=CC=1>[C:10]([CH2:2][CH:3]1[CH2:7][O:6][C:5](=[O:8])[O:4]1)([O:12][CH3:13])=[O:11]
Reactant: O=C1OCC(CO)O1
Reactant: COC(=O)Cl
Solvent: c1ccncc1
Product: COC(=O)CC1COC(=O)O1
Yield: 30.3 %

Procedure:
To 73 g of 4-hydroxymethyl-1,3-dioxolan-2-one was added 63.3 g of pyridine with stirring and 75.6 g of methyl chloroformate was added at 0° C. for 1 hr, then the reaction mixture stirred at room temperature for 16 hrs. The reaction solution was passed through a glass filter to remove pyridine HCl salts, and then extracted with methylene chloride and distilled water. Recrystallization was carried out in toluene to obtain 30 g of 4-carbomethoxymethyl-1,3-dioxolan-2-one as a final product.
Reaction SMILES: Cl[C:2]1[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=[C:6]([Cl:8])[N:7]=1.[NH3:11]>O1CCOCC1>[NH2:11][C:2]1[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=[C:6]([Cl:8])[N:7]=1
Reactant: Cn1cc(Cl)nc(Cl)c1=O
Reactant: N
Solvent: C1COCCO1
Product: Cn1cc(Cl)nc(N)c1=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 3,5-dichloro-1-methyl-2(1H)-pyrazinone (7.16 g, 0.040 mol) in dioxane (120 mL) was treated with a concentrated aqueous solution of ammonia (28%, 16 mL, 0.24 mol). After stirring at room temperature for three days a suspension of solid had formed. The solid was collected, rinsed with a little water, ether, and hexanes and air dried. The product, 3-amino-5-chloro-1-methyl-2(1H)-pyrazinone, was obtained as a white crystalline powder (4.81 g) melting above 250° C.
Reaction SMILES: [CH3:1][C:2]([N:10]=[C:11]=[O:12])([CH3:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16][NH2:17]>>[Cl:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16][NH:17][C:11]([NH:10][C:2]([CH3:1])([CH3:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[O:12]
Reactant: CC(C)(N=C=O)c1ccccc1
Reactant: NCc1ccccc1Cl
Product: CC(C)(NC(=O)NCc1ccccc1Cl)c1ccccc1
Reaction time: 2 h
Yield: 93.9 %

Procedure:
A mixture consisting of 18.1 g of α,α-dimethylbenzyl-isocyanate and 14.2 g of 2-chlorobenzylamine was allowed to stand for 2 hours at room temperature. The white deposit formed was then filtered off. Washing with n-hexane and recrystallization from ethanol gave 28.5 g of colorless crystal product, m.p. 165°-166° C.
Reaction SMILES: O[C:2]1[N:7]2[N:8]=[C:9]3[C:14]([CH:13]=[CH:12][CH:11]=[CH:10]3)=[C:6]2[N:5]=[C:4]([CH3:15])[C:3]=1[CH2:16][C:17]([O:19][CH3:20])=[O:18].CN(C)C1C=CC=CC=1.P(Cl)(Cl)([Cl:32])=O>>[Cl:32][C:2]1[N:7]2[N:8]=[C:9]3[C:14]([CH:13]=[CH:12][CH:11]=[CH:10]3)=[C:6]2[N:5]=[C:4]([CH3:15])[C:3]=1[CH2:16][C:17]([O:19][CH3:20])=[O:18]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)Cc1c(C)nc2c3ccccc3nn2c1O
Solvent: CN(C)c1ccccc1
Product: COC(=O)Cc1c(C)nc2c3ccccc3nn2c1Cl
Temperature: 60 °C
Yield: 46 %

Procedure:
The methyl 2-(4-hydroxy-2-methylpyrimido[1,2-b]indazol-3-yl)acetate (1.34 g; 4.94 mmol) was suspended in phosphorus oxychloride (5.1 mL) and dimethylaniline (0.96 mL) was added under nitrogen atmosphere. The well-stirred reaction mixture was heated at 60° C. for 3 days. Phosphorus oxychloride in excess was removed under reduced pressure and the remaining oil was placed in an ice-bath. A cold saturated sodium hydrogenocarbonate solution was carefully added until neutralization. The aqueous layer was extracted with ethyl acetate, the organics were combined, dried over sodium sulfate, concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (1-20%) in dichloromethane furnished 0.659 g (46%) of methyl 2-(4-chloro-2-methylpyrimido[1,2-b]indazol-3-yl)acetate as a light yellow solid. ESI/APCI(+): 290-292 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1)#[N:2].[Br:12][C:13]1[CH:18]=[CH:17][C:16](I)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.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>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=2)=[CH:15][CH:14]=1
Reactant: Brc1ccc(I)cc1
Reactant: N#Cc1cccc(B(O)O)c1
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: CN(C)C=O
Product: N#Cc1cccc(-c2ccc(Br)cc2)c1
Temperature: 75 °C
Yield: 39.5 %

Procedure:
To a magnetically stirring solution of 3-cyanophenyl boronic acid (0.62 g, 4.24 mmol) and 1-bromo-4-iodobenzene (1.0 g, 3.53 mmol) in anhydrous DMF (7.0 mL), under argon at room temperature, was added 2M sodium carbonate solution (7.0 mL) followed by Pd(PPh3)4 (0.21 g, 0.18 mmol). The resulting mixture was heated to 75° C. overnight. The resulting dark reaction mixture was cooled to room temperature filtered to remove the solids and the resultant filtrate was poured into water (50 mL) and extracted with EtOAc (2×25 mL). The organics were washed with water (50 mL) and brine (50 mL) then dried over Na2SO4, filtered and concentrated. The crude residue was purified by flash chromatography (5% EtOAc in Hexanes) to yield the intermediate bromide as a white solid (0.36 g, 33%).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[N:20]=[CH:19][C:18]([CH2:21][OH:22])=[CH:17][CH:16]=1.O[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][C:31]([O:33][CH3:34])=[O:32].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[N:20]=[CH:19][C:18]([CH2:21][O:22][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:17][CH:16]=1
Reactant: COC(=O)Cc1ccccc1O
Reactant: Cc1sc(-c2ccccc2)nc1COc1ccc(CO)cn1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COC(=O)Cc1ccccc1OCc1ccc(OCc2nc(-c3ccccc3)sc2C)nc1
Reaction time: 15 h
Yield: 86.6 %

Procedure:
To a mixture of [6-[(5-methyl-2-phenyl-4-thiazolyl)methoxy]-3-pyridyl]methanol (1.00 g), methyl 2-(2-hydroxyphenyl)acetate (0.50 g), tributylphosphine (1.21 g) and tetrahydrofuran (100 mL) was added 1,1′-(azodicarbonyl)dipiperidine (1.51 g) at room temperature and the mixture was stirred for 15 hrs. The precipitated crystals were filtered off. The filtrate was concentrated and the residue was subjected to silica gel column chromatography to give crystals (1.20 g, 87%) of methyl 2-[2-[[6-[(5-methyl-2-phenyl-4-thiazolyl)methoxy]-3-pyridyl]methoxy]phenyl]acetate from a fraction eluted with ethyl acetate-hexane (1:6, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 119-120° C.
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]2[CH2:11][CH:10]([OH:12])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Cl)=[CH:24][CH:23]=1>CN(C=O)C>[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][O:12][CH:10]2[CH2:11][N:8]([CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:9]2)=[CH:24][CH:23]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ccc(COC2CN(C(c3ccccc3)c3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.2 %

Procedure:
A solution of 1-diphenylmethyl-3-azetidinol (25 mmol) in DMF (100 mL) was added at 0° C. to a suspension of NaH (60% disp.in oil, 30 mmol) in DMF (50 mL). The reaction mixture was stirred at room temperature for 1 h, then 4-chlorobenzylchloride (25 mmol) was added dropwise at 0° C. and the reaction mixture stirred at room temperature for 3 h. The reaction was quenched with water and extracted with ethyl acetate (3×50 mL), the extracts were washed with water and brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by chromatography [SiO2; hexane-ethyl acetate (9:1)] to yield the product as a yellow oil (7.3 g, 80%). The material was used in the next step without further purification.
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([Cl:13])[CH:12]=1)[NH:9][C:8](=[O:14])[CH:7]=[N:6]2.I[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].Cl>C(O)C>[CH2:20]([O:19][C:17]([CH2:16][N:9]1[C:10]2[C:5](=[CH:4][C:3]([Cl:2])=[CH:12][C:11]=2[Cl:13])[N:6]=[CH:7][C:8]1=[O:14])=[O:18])[CH3:21]
Reactant: CCOC(=O)CI
Reactant: O=c1cnc2cc(Cl)cc(Cl)c2[nH]1
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)Cn1c(=O)cnc2cc(Cl)cc(Cl)c21
Temperature: 25 °C

Procedure:
Under a nitrogen atmosphere sodium (0.13 g, 5.62 mmol) was dissolved in 25 ml of abs. ethanol and 6,8-dichloroquinoxalin-2(1H)-one (1.10 g, 5.11 mmol) was added. The mixture was refluxed for 20 min., and ethyl iodoacetate (0.729 ml, 6.13 mmol) was added. The reaction mixture was refluxed for 72 h, cooled to room temperature, then poured onto crushed ice and acidified by dilute hydrochloric acid (pH=2). The precipitated compound was extracted with dichloromethane (4×30 ml) and purified by column chromatography on silica gel (eluent 10% THF in heptane) to give 1-ethoxycarbonylmethyl-6,8-dichloroquinoxalin-2(1H)-one. 1H-NMR (DMSO-d6):δ1.23 (t, 3H), 4.22 (q, 2H), 5.29 (s, 2H), 7.97 (dd, 2H), 8.45 (s, 1H).
Reaction SMILES: C([O:5][CH2:6][CH:7]1[C:11](=[O:12])[N:10]([C:13]2[CH:42]=[CH:41][C:16]([CH2:17][C:18]3[NH:26][C:25]4[C:24](=[O:27])[N:23]([CH2:28][C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=5[F:35])[C:22](=[O:36])[N:21]([CH2:37][CH:38]5[CH2:40][CH2:39]5)[C:20]=4[N:19]=3)=[CH:15][CH:14]=2)[C:9](=[O:43])[NH:8]1)(C)(C)C.FC(F)(F)C(O)=O>>[CH:38]1([CH2:37][N:21]2[C:20]3[N:19]=[C:18]([CH2:17][C:16]4[CH:41]=[CH:42][C:13]([N:10]5[C:11](=[O:12])[C@H:7]([CH2:6][OH:5])[NH:8][C:9]5=[O:43])=[CH:14][CH:15]=4)[NH:26][C:25]=3[C:24](=[O:27])[N:23]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[F:35])[C:22]2=[O:36])[CH2:40][CH2:39]1
Reactant: CC(C)(C)OCC1NC(=O)N(c2ccc(Cc3nc4c([nH]3)c(=O)n(Cc3ccccc3F)c(=O)n4CC3CC3)cc2)C1=O
Solvent: O=C(O)C(F)(F)F
Product: O=C1N[C@@H](CO)C(=O)N1c1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
8-[4-(4-tert-Butoxymethyl-2,5-dioxo-imidazolidin-1-yl)-benzyl]-3-cyclopropylmethyl-1-(2-fluorobenzyl)-3,7-dihydro-purine-2,6-dione was treated with trifluoroacetic acid (2 mL). After stirring at room temperature for 2 h, the reaction was concentrated and the residue was purified by reverse phase HPLC. LCMS, m/z(M+H)=533.12.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:6]=1.CN(CCN(C)C)C.[Li]CCCC.CN(C)[C:28](=O)[O:29]CC.[NH4+].[Cl-]>C(OCC)C.CCCCCC>[CH3:1][C:2]1[S:3][C:4]2[C:28](=[O:29])[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[C:5]=2[CH:6]=1
Reactant: Cc1cc(-c2ccccc2)cs1
Reactant: CCOC(=O)N(C)C
Agent: CN(C)CCN(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: Cc1cc2c(s1)C(=O)c1ccccc1-2
Temperature: -40 °C

Procedure:
A solution of 12.88 g (0.074 mol) of 2-methyl-4-phenylthiophene, 23.4 mL (0.16 mol) of TMEDA in 200 mL of diethyl ether (ether) was treated with 100 mL (0.16 mol) of 1.6M BuLi in hexane under stirring at −40° C. Then the reaction mixture was allowed to warm up to room temperature (r.t.) and was stirred for 3 h (white precipitate forms). The reaction mixture was cooled to −40° C. and treated with 8.76 g (0.075 mol) of ethyl N,N-dimethylcarbamate in 25 mL of ether. Then the reaction mixture was allowed to warm up to r.t. and was stirred overnight. Resulting mixture was treated with 10% aqueous NH4Cl, the organic layer was separated and the organic phase was washed with 10% aqueous solution of NH4Cl and then dried by anhydrous Na2SO4. Solvent was evaporated and the residue was washed with methanol. Yield 6.8 g (46%) of red crystals.
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH:16]=[CH:17][C:18](=[O:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+].O>C(C(C)=O)C>[CH2:1]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH:16]=[CH:17][C:18](=[O:20])[CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1ccccc1
Reactant: CC(=O)C=Cc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: CC(=O)C=Cc1ccccc1OCc1ccccc1
Yield: 85.5 %

Procedure:
A mixture of benzylchloride (8.8 g), 4-(2-hydroxy phenyl)-but-3-en-2-one (11.4 g) and anhydrous potassium carbonate (11.0 g) in methyl ethyl ketone (100 ml) was stirred and heated under reflux for 5 hours. The mixture was poured into water (300 ml) and extracted with chloroform (200 ml). The chloroform extracts were washed with dilute sodium hydroxide solution and then dried over magnesium sulphate and evaporated to give 4-(2-benzyloxyphenyl)-but-3-en-2-one (15 g) as a pale yellow oil.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][NH:4][C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]1=2.[C:11]([N:18]1[CH2:22][CH2:21][C:20](=O)[CH2:19]1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[S:1]1[CH2:6][CH2:5][N:4]([CH:21]2[CH2:20][CH2:19][N:18]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:22]2)[C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]1=2
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Reactant: c1ccc2c(c1)NCCS2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC(N2CCSc3ccccc32)C1
Temperature: 0 °C
Reaction time: 11 h
Yield: 19.4 %

Procedure:
A mixture of 3,4-dihydro-2H-benzo[b][1,4]thiazine (1.00 g, 6.61 mmol), N-boc-3-pyrrolidinone (1.34 g, 7.27 mmol), and acetic acid (0.94 mL, 16.52 mmol) in 1,2-dichloroethane (20 mL) was cooled to 0° C. and then treated with solid sodium triacetoxyborohydride (2.10 g, 9.92 mmol). The reaction was brought to room temperature and was stirred for 11 hours. Additional equivalents of each of sodium triacetoxyborohydride (1.40 g, 6.61 mmol) and N-boc-3-pyrrolidinone (1.22 g, 6.61 mmol) were added to the reaction mixture. The reaction was stirred for 2 more days and was then quenched with 3 N NaOH (50 mL). The mixture was transferred to a separatory funnel and extracted with EtOAc (2×50 mL). The organic phase was washed with brine (50 mL) and dried (Na2SO4). The crude material was subject to flash chromatography on silica gel (10% EtOAc/hexanes then 20% EtOAc/hexanes). The sample was subject to additional flash chromatography on silica gel (7.5-15% EtOAc/hexanes) to give viscous oil (0.41 g, 19%). 1H NMR (CDCl3) δ 7.08 (dd, J=0.9, 7.5 Hz, 1H), 7.04-6.99 (m, 1H), 6.77 (d, J=8.1 Hz, 1H), 6.67-6.72 (m, 1H), 4.39-4.36 (m, 1H), 3.73-3.72 (m, 6H), 3.10-3.06 (m, 2H), 2.20-2.00 (m, 2H), 1.47 (s, 9H); ESI-MS (m/z, %): 345, 343 (M+Na, 4), 322, 320 (MH+, 3), 267, 265 (100).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]#[N:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[C:17]([O:21][C:22]([NH:24][C@@H:25]1[CH2:31][CH2:30][C:29]2[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=2[NH:27][C:26]1=[O:36])=[O:23])([CH3:20])([CH3:19])[CH3:18]>>[C:17]([O:21][C:22]([NH:24][C@@H:25]1[CH2:31][CH2:30][C:29]2[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=2[N:27]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:15]#[N:16])=[CH:5][CH:4]=2)[C:26]1=[O:36])=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCc2ccccc2NC1=O
Product: CC(C)(C)OC(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3C#N)cc2)C1=O

Procedure:
Prepared from 4'-bromomethyl-1,1'-biphenyl-2-nitrile (prepared by the method of M. Fisher, et al, U.S. Pat. No. 5,206,235) and 3(R)-t-butoxycarbonylamino-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (Step A) by the procedure described in Example 1, Step Q. 1H NMR (400 MHz, CDCl3): δ 1.39 (s, 9H), 1.90 (m, 1H), 2.40-2.60 (m, 3H), 4.28 (m, 1H), 4.94 (d, 15 Hz, 1H), 5.20 (d, 15 Hz, 1H), 5.43 (d, 7 Hz, 1H), 7.1-7.3 (m, 4H), 7.33 (d, 8 Hz, 2H), 7.35-7.50 (m, 4H), 7.60 (t, 8 Hz, 1H), 7.72 (d, 8 Hz, 1H). FAB-MS: calculated for C29H29N3O3 467; found 468 (M+H, 15%), 368 (M-BOC, 100%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[C:9]([C:26](=[O:28])[CH3:27])[C:10]([O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24]Br)=[CH:11][CH:12]=2)[CH:7]=1.[OH:30][C:31]1[C:36]([CH2:37][CH2:38][CH3:39])=[C:35]([OH:40])[CH:34]=[CH:33][C:32]=1[C:41](=[O:43])[CH3:42].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C)C=O>[CH3:1][O:2][C:3](=[O:29])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[C:9]([C:26](=[O:28])[CH3:27])[C:10]([O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:40][C:35]3[CH:34]=[CH:33][C:32]([C:41](=[O:43])[CH3:42])=[C:31]([OH:30])[C:36]=3[CH2:37][CH2:38][CH3:39])=[CH:11][CH:12]=2)[CH:7]=1
Reactant: COC(=O)COc1ccc2ccc(OCCOCCOCCBr)c(C(C)=O)c2c1
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCCc1c(OCCOCCOCCOc2ccc3ccc(OCC(=O)OC)cc3c2C(C)=O)ccc(C(C)=O)c1O
Yield: 72.5 %

Procedure:
A mixture of 2 g of [[8-acetyl-7-[2-[2-(2-bromoethoxy)ethoxy]ethoxy]-2-naphthalenyl]oxy]acetic acid methyl ester, 1.0 g of 1-(2,4-dihydroxy-3-propylphenyl)ethanone and 0.9 g of anhydrous potassium carbonate in 40 ml of anhydrous acetone and 14 ml of anhydrous dimethylformamide was stirred at reflux for 16 hours. The solvent was removed in vacuo and residue was dissolved in ethyl acetate, washed with water, dried (magnesium sulfate) and concentrated in vacuo to give an oil which was purified by high pressure liquid chromatography (60% ethyl acetate-hexane) to yield 1.8 g (73%) of [[8-acetyl-7-[2-[2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]ethoxy]-2-naphthalenyl]oxy]acetic acid methyl ester as an oil.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[C:18]([NH:20][N:21]=[C:22]([C:24]2[CH:29]=[CH:28][C:27]([N:30]([CH3:32])[CH3:31])=[CH:26][CH:25]=2)[CH3:23])[N:17]=[C:16]([CH3:33])[N:15]=1)(C)(C)C>FC(F)(F)C(O)=O.ClCCl>[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[N:15]=[C:16]([CH3:33])[N:17]=[C:18]([NH:20][N:21]=[C:22]([C:24]2[CH:25]=[CH:26][C:27]([N:30]([CH3:32])[CH3:31])=[CH:28][CH:29]=2)[CH3:23])[CH:19]=1
Reactant: CC(=NNc1cc(-c2ccccc2NC(=O)OC(C)(C)C)nc(C)n1)c1ccc(N(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=NNc1cc(-c2ccccc2N)nc(C)n1)c1ccc(N(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
[2-(6-{N′-[1-(4-dimethylamino-phenyl)-ethylidene]-hydrazino}-2-methyl-pyrimidin-4-yl)-phenyl]-carbamic acid tert-butyl ester was dissolved in 10 mL of 5% trifluoroacetic acid in dichloromethane. The resultant reaction mixture was stirred at room temperature for 2 hours before being concentrated in vacuo. The residue was dissolved in methanol and the pH was adjusted to 7 with potassium bicarbonate. After filtration the methanol was concentrated in vacuo and the residue was purified by Si gel chromatography (1:1 ethyl acetate:hexanes) yielding 140 mg (60%) of the title compound as a brown solid. HPLC Purity: 95%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[O:16][C:15]([C:17]3[CH:33]=[CH:32][C:20]4[N:21]=[C:22]([NH:24]C(=O)OC(C)(C)C)[S:23][C:19]=4[CH:18]=3)=[N:14][N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[NH2:24][C:22]1[S:23][C:19]2[CH:18]=[C:17]([C:15]3[O:16][C:12]([NH:11][S:8]([C:5]4[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=4)(=[O:10])=[O:9])=[N:13][N:14]=3)[CH:33]=[CH:32][C:20]=2[N:21]=1
Reactant: Cc1ccc(S(=O)(=O)Nc2nnc(-c3ccc4nc(NC(=O)OC(C)(C)C)sc4c3)o2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)Nc2nnc(-c3ccc4nc(N)sc4c3)o2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.4 %

Procedure:
A mixture of tert-butyl 6-(5-(4-methylphenylsulfonamido)-1,3,4-oxadiazol-2-yl)benzo[d]thiazol-2-ylcarbamate (0.40 g, 0.82 mmol) in 1:1 solution of TFA/CH2Cl2 was stirred at room temperature for 4 hours. The solution was concentrated in vacuo to give the desired product as white solid N-(5-(2-aminobenzo[d]thiazol-6-yl)-1,3,4-oxadiazol-2-yl)-4-methylbenzenesulfonamide (0.30 g, 94% yield). MS (ESI pos. ion) m/z: calc'd for C16H13N5O3S2: 387.0. found: 387.9 (MH+). 1H NMR (300 MHz, MeOH) δ ppm 2.41 (s, 3H) 7.37 (d, J=8.04 Hz, 2H) 7.54 (d, J=8.48 Hz, 1H) 7.82-7.94 (m, 3H) 8.22 (d, J=1.46 Hz, 1H).
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[Br:12][C:13]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:14]=1[CH2:15][OH:16]>C(Cl)Cl>[Br:12][C:13]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:14]=1[CH:15]=[O:16]
Reactant: COc1ccc(Br)c(CO)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COc1ccc(Br)c(C=O)c1
Reaction time: 3 h

Procedure:
Pyridinium Chlorochromate (1.2 eq) was added to a solution of 2-bromo-5-methoxybenzyl alcohol (1 eq) and Celite (1.2 eq) in methylene chloride (0.30 M) at RT and the resulting mixture was stirred under nitrogen for 3 h. The mixture was filtered through a plug of silica rinsing with methylene chloride and concentrated in vacuo to give 2-bromo-5-methoxy benzaldehyde as a white solid. EI-MS m/z 232, 234 (M+NH4)+