Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:19])[C:10]([C:12]1[CH:17]=[CH:16][NH:15][C:14](=[O:18])[CH:13]=1)=[O:11].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1C=CC=CC=1.C(=O)([O-])[O-].[Ag+2]>[CH2:20]([O:18][C:14]1[CH:13]=[C:12]([C:10](=[O:11])[CH:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[CH3:19])[CH:17]=[CH:16][N:15]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C(=O)c1cc[nH]c(=O)c1)c1ccc(Cl)cc1Cl
Reactant: BrCc1ccccc1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: c1ccccc1
Product: CC(C(=O)c1ccnc(OCc2ccccc2)c1)c1ccc(Cl)cc1Cl
Temperature: 50 °C
Yield: 59.8 %

Procedure:
This material was re-benzylated as follows: 4-[2-(2,4-Dichloro-phenyl)-propionyl]-1H-pyridin-2-one (100 mg) was dissolved in absolute benzene (6 mL) and silver carbonate (65 mg) and benzyl bromide (70 mg, 0.05 mL) were added. The mixture was stirred at 50° C. over night and was then poured into ice water. The aqueous phase was extracted with ethyl acetate and the organic layer was washed with brine, dried over Na2SO4 and evaporated. The residue was purified by flash chromatography (20 g silica gel, gradient of ethyl aceate in heptane (0 to 20%)) to give 1-(2-benzyloxy-pyridin-4-yl)-2-(2,4-dichloro-phenyl)-propan-1-one (78 mg) as a colorless oil. MS (m/e)=386.0 [MH+].
Reaction SMILES: [C:1](=[S:3])=S.[NH2:4][C:5]1[CH:6]=[CH:7][C:8]([OH:14])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11].C(N(CC)CC)C.II.Cl.S([O-])([O-])=O.[Na+].[Na+]>C(OCC)(=O)C.O1CCCC1.O>[N:4]([C:5]1[CH:6]=[CH:7][C:8]([OH:14])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])=[C:1]=[S:3]
Reactant: S=C=S
Reactant: Nc1ccc(O)c(C(=O)O)c1
Agent: Cl
Agent: II
Agent: O=S([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(O)c1cc(N=C=S)ccc1O
Temperature: 25 °C
Reaction time: 17 h
Yield: 100 %

Procedure:
Carbon disulfide (0.26 mL, 4.4 mmol) was added to a mixture comprising 5-amino-2-hydroxybenzoic acid (0.23 g, 1.5 mmol), tetrahydrofuran (1.0 mL), water (1.0 mL) and triethylamine (0.51 mL, 3.6 mmol), followed by stirring at room temperature for 17 hours. The obtained reaction mixture was dropwise added to a tetrahydrofuran (1.0 mL) solution of iodine (0.41 g, 1.6 mmol) over a period of 5 minutes at 0° C., followed by stirring at 0° C. for further 2.5 hours. Thereafter, 1M hydrochloric acid (1.5 mL) and sodium sulfite (38 mg, 0.30 mmol) were added and mixed. Then, ethyl acetate (6 mL) was added, and the organic layer was separated and concentrated under reduced pressure to dryness. To the residue, ethyl acetate (6 mL) and water (1 mL) were added, and the organic layer was concentrated under reduced pressure to dryness to obtain 5-isothiocyanato-2-hydroxybenzoic acid as a gray solid (0.29 g, yield: 100%, HPLC purity: 97%, HPLC retention time: 4.3 min). LC-MS ES-194 (retention time: 4.4 min, condition 1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15]O)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:19])=O>C1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][Cl:19])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1cccc(OCc2ccccc2)n1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: ClCc1cccc(OCc2ccccc2)n1
Reaction time: 8 h

Procedure:
A mixture of 2-benzyloxy-6-hydroxymethylpyridine (1.5 g, 7.0 mmol) and thionyl chloride (10 mL, 137 mmol) in benzene (25 mL) was stirred at room temp. overnight. The product mixture was concentrated under vacuum. The residue was partitioned between chloroform and aqueous sodium bicarbonate. The organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 5% methanol in chloroform. Collection and concentration of appropriate fractions provided 2-benzyloxy-6-chloromethylpyridine as clear, colorless oil. This alkylating reagent was passed through a small plug of activated basic alumina immediately before use.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:4]=1[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][N:8]=1.[Cl:19][C:20]1[C:21]([F:31])=[CH:22][C:23]([F:30])=[C:24]([S:26](Cl)(=[O:28])=[O:27])[CH:25]=1.N12CCN(CC1)CC2>C(#N)C>[Cl:19][C:20]1[C:21]([F:31])=[CH:22][C:23]([F:30])=[C:24]([S:26]([N:6]([CH2:5][C:4]2[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:3]=2[O:2][CH3:1])[C:7]2[CH:12]=[CH:11][N:10]=[CH:9][N:8]=2)(=[O:28])=[O:27])[CH:25]=1
Reactant: O=S(=O)(Cl)c1cc(Cl)c(F)cc1F
Reactant: COc1ccc(CNc2ccncn2)c(OC)c1
Agent: C1CN2CCN1CC2
Solvent: CC#N
Product: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(Cl)c(F)cc2F)c(OC)c1
Yield: 25.7 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 14b by using the N-(2,4-dimethoxybenzyl)pyrimidine-4-amine (150 mg, 0.611 mmol) prepared in Example 14, 5-chloro-2,4-difluorobenzenesulfonyl chloride (302 mg, 1.22 mmol), 1,4-diazabicyclo[2.2.2]octane (137 mg, 1.22 mmol) and acetonitrile (5.0 mL), to yield the title compound (71.7 mg, 26%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C1(=O)O[CH2:12][CH2:11][O:10]1>[I-].C([N+](CC)(CC)CC)C.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:12][CH2:11][OH:10])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: O=C1OCCO1
Agent: CC[N+](CC)(CC)CC
Agent: [I-]
Solvent: ClC(Cl)Cl
Product: OCCOc1ccc(Cl)cc1
Temperature: 160 °C
Yield: 105.3 %

Procedure:
A mixture of 4-chlorophenol (28.3 g, 0.22 mol), ethylene carbonate (19.4 g, 0.22 mol) and tetraethylammonium iodide (10 g, 3.6 mmol) was heated at 160° C. for 3 hours and then cooled to room temperature. Chloroform (500 ml) was added and the resultant solution was washed with water and then dried over anhydrous sodium sulphate. Evaporation of the solvent gave 2-(4-chlorophenoxy)ethanol (40.0 g) which was dissolved in ether (400 ml) containing triethylamine (20 g, 0.2 mol). A solution of 4-chlorophenylsulphonyl chloride (42.0 g, 0.2 mol) in ether (150 ml) was added dropwise and the resultant mixture was refluxed for 40 hours and then cooled. The precipitate was filtered off and washed well with dichloromethane. The combined filtrate and washings were dried over anhydrous sodium sulphate. After removal of the solvent by evaporation, the residue was recrystallised from ethyl acetate to give 2-(4-chlorophenoxy)-1-(4-chlorophenylsulphonyl)ethane as a white solid (34.6 g, m.pt. 108° C.
Reaction SMILES: O[N:2]=[CH:3][C@:4]1([CH2:18][OH:19])[O:8][C@@H:7]([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[CH2:6][CH2:5]1.[CH3:20][C:21]([O-])=[O:22].[Na+]>C(OC(=O)C)(=O)C>[C:3]([C@:4]1([CH2:18][O:19][C:21](=[O:22])[CH3:20])[O:8][C@@H:7]([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[CH2:6][CH2:5]1)#[N:2]
Reactant: Cc1cn([C@H]2CC[C@@](C=NO)(CO)O2)c(=O)[nH]c1=O
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)OC[C@]1(C#N)CC[C@H](n2cc(C)c(=O)[nH]c2=O)O1
Temperature: 100 °C
Reaction time: 24 h
Yield: 149.2 %

Procedure:
To a solution of the 4'-α and 4'-β isomers of 3'-deoxy-4'-hydroxyiminomethylthymidine (40 mg, 0.15 mM) (Formula 24) in 0.5 ml acetic anhydride, was added NaOAc (6 mg, 0.07 mM) and stir at 100° C. for 24 hours. The solvent was removed by evaporation and the residue chromatographed on silica gel using 4% CH3OH/CH2Cl2, affording the 4'-α and 4'-β isomers of 3'-deoxy-4'-cyano-5'-O-acetylthymidine (32 mg, 0.11 mM).
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][C:6]([NH:9][C:10](=[O:17])[CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[N:7][CH:8]=1)#[N:2].[N-:18]=[N+:19]=[N-:20].[Na+].[Cl-].C([NH+](CC)CC)C>CN1CCCC1=O.O>[O:17]=[C:10]([NH:9][C:6]1[CH:5]=[N:4][C:3]([C:1]2[NH:20][N:19]=[N:18][N:2]=2)=[CH:8][N:7]=1)[CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)CCC(=O)Nc1cnc(C#N)cn1
Agent: CC[NH+](CC)CC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: COC(=O)CCC(=O)Nc1cnc(-c2nnn[nH]2)cn1
Yield: 43 %

Procedure:
A mixture of methyl 4-[(5-cyanopyrazin-2-yl)amino]-4-oxo-butanoate A4 (0.168 g, 0.7173 mmol), sodium azide (0.141 g, 0.076 mL, 2.15 mmol) and triethylammonium chloride (0.156 g, 0.146 mL, 1.11 mmol) was stirred 4 h at 150° C. in 1-methyl-2-pyrrolidinone (10 mL). The mixture was cooled down and diluted with water. After acidification with aqueous hydrochloric acid (1N), the filtrate was extracted twice with ethyl acetate. The combined organic phases were combinated, dried over sodium sulfate and concentrated. The residue was suspended in ethyl acetate and filtered to methyl 4-oxo-4-[[5-(1H-tetrazol-5-yl)pyrazin-2-yl]amino]butanoate A36 (0.085 g, 43% yield). M.p.: 270-274° C. LC-MS (Method F): RT 0.49, 278 (M+H+)
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9]/[CH:10]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13].ClC(Cl)(Cl)[C:19]([C:21]1[NH:22][CH:23]=[C:24]([I:26])[CH:25]=1)=[O:20].C(N(CC)C(C)C)(C)C>ClCCl>[I:26][C:24]1[CH:25]=[C:21]([C:19]([NH:8][CH2:9]/[CH:10]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:20])[NH:22][CH:23]=1
Reactant: CCOC(=O)/C=C/CN
Reactant: O=C(c1cc(I)c[nH]1)C(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)/C=C/CNC(=O)c1cc(I)c[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.9 %

Procedure:
Ethyl (2E)-4-aminobut-2-enoate trifluoroacetate (IV) (0.97 g, 4 mmol) was added to a solution of 2,2,2-trichloro-1-(4-iodo-1H-pyrrol-2-yl)ethanone (IX) (0.68 g, 2 mmol) and N,N-diisopropylethylamine (DIPEA) (2.7 mL, 16 mmol) in dichloromethane (20 mL) and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated under vacuum and the residue purified by flash chromatography (SiO2, hexane-EtOAc 1:1) to obtain compound ethyl (2E)-4-{[(4-iodo-1H-pyrrol-2-yl)carbonyl]amino}but-2-enoate (X, where R1=OCH2CH3) as an off-white solid (0.48 g, 68% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5](O)=[O:6].S(Cl)([Cl:16])=O>>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([Cl:16])=[O:6]
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(F)c1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1ccc([N+](=O)[O-])c(F)c1
Yield: 99 %

Procedure:
A stirred solution of 3-fluoro-4-nitro-benzoic acid (1.65 g, 8.91 mmol) in thionyl chloride (10 mL) was heated at reflux for 2 h. Excess thionyl chloride was evaporated in vacuo and the residue azeotroped with toluene to afford 3-fluoro-4-nitro-benzoyl chloride (1.7 g, 99%) as a brown oil.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]([C@H:13]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:14]([NH2:16])=[O:15])[C:7]2=[O:12].CN(C)C=O.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.[Cl:61][C:62]1[CH:67]=[CH:66][C:65]([C@H:68]([CH3:72])[C:69](O)=[O:70])=[CH:64][CH:63]=1>>[NH2:16][C:14](=[O:15])[C@H:13]([N:6]1[CH:5]=[CH:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[NH:1][C:69](=[O:70])[C@H:68]([C:65]2[CH:66]=[CH:67][C:62]([Cl:61])=[CH:63][CH:64]=2)[CH3:72])[C:7]1=[O:12])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: C[C@H](C(=O)O)c1ccc(Cl)cc1
Reactant: NC(=O)[C@@H](c1ccccc1)n1ccc2c(N)cccc2c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H](C(=O)Nc1cccc2c(=O)n([C@@H](C(N)=O)c3ccccc3)ccc12)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
A mixture of (R)-2-(5-amino-1-oxoisoquinolin-2(1H)-yl)-2-phenylacetamide (120 mg, 0.00041 mol), N,N-dimethylformamide (1.5 mL, 0.019 mol), N,N-diisopropylethylamine (0.1 mL, 0.0008 mol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.3 g, 0.0008 mol) and (S)-2-(4-chlorophenyl)propanoic acid (0.091 g, 0.00049 mol) was allowed to stir over night at room temperature. The solvent was removed and the residue purified by flash chromatography (12 g silica gel, 0-10% MeOH/DCM) and again by preparative HPLC (reverse phase) to obtain the product as an off white solid. MS m/z=460.3 (M+H). 1H NMR (400 MHz; DMSO-d6) δ 9.95 (s, 1H), 8.13-8.11 (d, J=7.99 Hz, 1H), 8.02 (s, 1H), 7.74-7.72 (d, J=7.60 Hz, 1H), 7.71-7.69 (d, J=8.03 Hz, 1H), 7.55 (s, 1H), 7.50-7.32 (m, 10H), 6.99-6.97 (dd, J=7.89&1.86 Hz, 1H), 6.74 (s, 1H), 6.39-6.37 (d, J=8.02 Hz, 1H), 4.00-3.94 (q, J=6.97 Hz, 1H), 1.44-1.41 (d, J=7.11 Hz, 3H).
Reaction SMILES: [O:1]([CH2:8][C:9]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)[C:12]2[CH:26]=[CH:27][C:28]([C:30](O)=[O:31])=[CH:29][C:11]=2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)N=C=NC(C)C.[CH2:42]([NH2:48])[CH2:43][CH2:44][CH2:45][CH2:46][CH3:47]>C1COCC1>[CH2:42]([NH:48][C:30]([C:28]1[CH:27]=[CH:26][C:12]2[N:13]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:23])([F:25])[F:24])=[CH:17][CH:16]=3)[C:9]([CH2:8][O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[N:10][C:11]=2[CH:29]=1)=[O:31])[CH2:43][CH2:44][CH2:45][CH2:46][CH3:47]
Reactant: O=C(O)c1ccc2c(c1)nc(COc1ccccc1)n2Cc1ccc(OC(F)(F)F)cc1
Reactant: CCCCCCN
Agent: CC(C)N=C=NC(C)C
Solvent: C1CCOC1
Product: CCCCCCNC(=O)c1ccc2c(c1)nc(COc1ccccc1)n2Cc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.16 mmol of 2-phenoxymethyl-1-(4-trifluoromethoxy-benzyl)-1H-benzoimidazole-5-carboxylic acid were dissolved in 1 ml THF with 1 eq. DIC. After 15 min 1.5 eq of hexylamine were added and the reaction stirred at room temperature for 16 h. The crude material was purified via reversed phase preparative HPLC. MS(ISP): 526.3 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([OH:8])([CH3:7])[C:4](O)=[O:5].S(Cl)(Cl)=O.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22](=[O:31])[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=2[F:30])=[CH:18][CH:17]=1.O>CN(C)C(=O)C>[F:30][C:24]1[C:25]([F:29])=[CH:26][CH:27]=[CH:28][C:23]=1[C:22]([C:19]1[CH:18]=[CH:17][C:16]([NH:15][C:4](=[O:5])[C:3]([OH:8])([CH3:7])[C:2]([F:10])([F:9])[F:1])=[CH:21][CH:20]=1)=[O:31]
Reactant: CC(O)(C(=O)O)C(F)(F)F
Reactant: Nc1ccc(C(=O)c2cccc(F)c2F)cc1
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: O=S(Cl)Cl
Product: CC(O)(C(=O)Nc1ccc(C(=O)c2cccc(F)c2F)cc1)C(F)(F)F
Reaction time: 1 h
Yield: 70.4 %

Procedure:
To a stirred, cooled (-20° C.) solution of 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (1.02 g, 6.4 mmol) in N,N-dimethylacetamide (10 mL) was added thionyl chloride (0.77 g, 6.4 mmol) and the mixture stirred at -10° to -15° C. for 1 hour. 4'-Amino-2,3-difluorobenzophenone (1.00 g, 4.3 mmol) was added in one portion and the reaction mixture stirred at room temperature overnight. The mixture was poured into water and the aqueous solution extracted with methylene chloride (2×50 mL). The combined organics were washed with water and 3N HCl (1×50 mL), dried (MgSO4) and concentrated in vacuo to yield a tan solid. The solid was purified by flash column chromatography (5% v/v ethyl acetate/methylene chloride). Recrystallization of the resulting solid from methylene chloride/hexane yielded the title propanamide as a white solid (1.13 g, 70%); mp 154°-155° C. 1H--NMR (250 MHz, d6--DMSO): 1.60 (s, 3H, CH3) 7.36-7.40 (m, 2H, aromatic) 7.57 (s, 1H, OH) 7.65-7.72 (m, 1H, aromatic) 7.89 (d, 2H, J=8.6 Hz, aromatic) 7.98 (d, 2H, J=8.6 Hz, aromatic) 10.40 (s, 1H, NH). MS (CI, CH4): 374 (M+1).
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16]3[O:20][N:19]=[C:18]4[C:21]5[C:26]([CH2:27][CH2:28][C:17]=34)=[CH:25][C:24]([CH2:29][N:30]3[CH2:33][CH:32]([C:34]([O:36]C(C)(C)C)=[O:35])[CH2:31]3)=[CH:23][CH:22]=5)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O>ClCCl>[C:1]1([C:7]2[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16]3[O:20][N:19]=[C:18]4[C:21]5[C:26]([CH2:27][CH2:28][C:17]=34)=[CH:25][C:24]([CH2:29][N:30]3[CH2:33][CH:32]([C:34]([OH:36])=[O:35])[CH2:31]3)=[CH:23][CH:22]=5)[O:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)C1CN(Cc2ccc3c(c2)CCc2c-3noc2-c2onc(-c3ccccc3)c2C(F)(F)F)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C1CN(Cc2ccc3c(c2)CCc2c-3noc2-c2onc(-c3ccccc3)c2C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of tert-butyl 1-((3-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)methyl)azetidine-3-carboxylate (7C, 2.24 g, 4.06 mmol) in dichloromethane (4 mL) was added TFA (4 mL) slowly at room temperature. The reaction mixture was stirred at room temperature for 2 hr. The mixture was concentrated to remove dichloromethane and TFA (6 mL) was added. The mixture was stirred at room temperature till the starting material was observed to disappear. Dichloroethane (6 mL) was added and the mixture was concentrated under reduced pressure. The residue was mixed with water (10 mL), basified with 1 N aqueous NaOH to pH=8 and acidified with 1N aqueous HCl to pH=5. The mixture was sonicated for 30 min. The solid was filtered and washed with water (4×10 mL). The wet solid was mixed with methanol (40 mL), sonicated for 30 min, filtered, washed with methanol (3×10 mL), and dried to give 1-((3-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)methyl)azetidine-3-carboxylic acid as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([NH2:17])[CH:12]=2)=[N:8][CH:9]=1)([O-])=O.C(=O)=O>[Pd].CO>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([NH2:17])[CH:12]=2)=[N:8][CH:9]=1
Reactant: Nc1cccc(Nc2ccc([N+](=O)[O-])cn2)c1
Agent: [Pd]
Agent: O=C=O
Solvent: CO
Product: Nc1ccc(Nc2cccc(N)c2)nc1
Reaction time: 2 h

Procedure:
m-Phenylenediamine (2.8 mmol, 0.30 g) and 2-fluoro-5-nitropyridine (0.92 mmol, 0.13 g) were dissolved in 6 mL of DMSO. The solution was heated to 80° C. for 18 hours. The solution eventually turned dark red. The reaction mixture was cooled to room temperature and purified directly by flash column chromatography (silica, EtOAc:Hexanes=1:3) to give N1-(5-nitropyridin-2-yl)benzene-1,3-diamine as a reddish crystalline compound (0.19 g, 89% yield): 1H NMR (500 MHz, CDCl3) δ 9.08 (d, 1H, J=2.5 Hz), 8.24 (dd, 1H, J1=2.5 Hz, J2=9.5 Hz), 7.281 (s, 1H), 7.19 (t, 1H, J=8.0 Hz), 6.82 (d, 1H, J=9.5 Hz), 6.74 (s, 1H), 6.70 (d, 1H, J=8.0 Hz), 6.56 (d, 1H, J=7.5 Hz), 3.80 (br, 2H); 13C NMR (125 MHz, CDCl3) δ 159.91, 148.05, 146.93, 139.09, 137.15, 133.59, 130.77, 112.80, 112.66, 109.13, 106.67. The nitro compound (0.43 mmol, 0.10 g) and 10% Pd/C (10 mg) were added to a 20 mL test tube equipped with a stir bar, dry ice (0.5 g) was added to the mixture just before MeOH (7 mL) was added. The suspension was then put into a pressure vessel under 80 psi of H2. The reaction mixture was stirred for 2 hours. The solution turned from yellow to colorless. The reaction mixture was transferred into a 10 mL syringe and filtered through an Acrodisc syringe Filter into a 100 mL round bottom flask containing 37% aqueous HCl (3 mL). The solvent was then evaporated and azeotroped to dryness with toluene and absolute ethanol (3×30 mL of 1:1 mixture). The product was obtained as a grayish yellow powder in quantitative yield. B. Primary Intermediates of Formula (5)
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][C:10]2[CH:11]=[N:12][N:13]([CH3:32])[C:14]=2[C@H:15]2[O:21][CH2:20][C@H:19]([O:22][CH3:23])[C@H:18]([NH:24]C(=O)OC(C)(C)C)[CH2:17][CH2:16]2)=[O:8])[N:6]=1.[F:33][C:34]1[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[C:36]([F:42])[C:35]=1B(O)O>>[NH2:24][C@H:18]1[C@@H:19]([O:22][CH3:23])[CH2:20][O:21][C@H:15]([C:14]2[N:13]([CH3:32])[N:12]=[CH:11][C:10]=2[NH:9][C:7]([C:5]2[N:6]=[C:2]([C:35]3[C:34]([F:33])=[CH:39][C:38]([O:40][CH3:41])=[CH:37][C:36]=3[F:42])[S:3][CH:4]=2)=[O:8])[CH2:16][CH2:17]1
Reactant: CO[C@H]1CO[C@H](c2c(NC(=O)c3csc(Br)n3)cnn2C)CC[C@H]1NC(=O)OC(C)(C)C
Reactant: COc1cc(F)c(B(O)O)c(F)c1
Product: COc1cc(F)c(-c2nc(C(=O)Nc3cnn(C)c3[C@@H]3CC[C@@H](N)[C@@H](OC)CO3)cs2)c(F)c1

Procedure:
Following the procedure for Example 101 starting from tert-butyl ((3R,4R,7S)-7-(4-(2-bromothiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)-3-methoxyoxepan-4-yl)carbamate (Intermediate 101), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (2,6-difluoro-4-methoxyphenyl)boronic acid gave 265. 1H NMR (400 MHz, DMSO-d6) δ 10.12 (s, 1H), 8.56 (s, 1H), 7.94 (s, 1H), 7.08-6.97 (m, 2H), 5.11 (t, J=5.5 Hz, 1H), 3.88 (s, 3H), 3.84-3.75 (m, 1H), 3.71 (s, 3H), 3.47-3.38 (m, 1H), 3.31-3.22 (m, 1H), 3.04 (s, 3H), 2.49-2.36 (m, 1H), 1.75-1.49 (m, 3H), 1.41 (br, 2H). LCMS (ES+) m/z 494 (M+1).
Reaction SMILES: [CH2:1]([N:5]1[CH2:9][CH2:8][CH:7]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH2:6]1)[CH2:2][CH:3]=[CH2:4].CN(C=O)C.Br[C:26]1[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.B1C2CCCC1CCC2>[C:28]1([CH3:32])[CH:29]=[CH:30][CH:31]=[C:26]([CH2:4][CH2:3][CH2:2][CH2:1][N:5]2[CH2:9][CH2:8][CH:7]([S:10]([C:13]3[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=3)(=[O:12])=[O:11])[CH2:6]2)[CH:27]=1
Reactant: Cc1cccc(Br)c1
Reactant: C=CCCN1CCC(S(=O)(=O)c2ccc(O)cc2)C1
Agent: B1C2CCCC1CCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1cccc(CCCCN2CCC(S(=O)(=O)c3ccc(O)cc3)C2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 46.9 %

Procedure:
To a 0° C. solution of (RS)-4-(1-but-3-enyl-pyrrolidine-3-sulfonyl)-phenol (0.106 g, 0.378 mmol) in THF (0.5 ml), 9-BBN (1.66 ml, 0.74 ml, 0.5 M solution in THF) was added dropwise. The reaction mixture was allowed to warm up slowly to room temperature. After 4 hours stirring, the reaction mixture was treated successively with DMF (1.5 ml), 3-bromotoluene (0.046 ml, 0.377 mmol), PdCl2(dppf)2-dichloromethane complex (9.3 mg, 0.01 mmol), and K2CO3 (95 mg, 0.69 mmol). After 5 hours stirring at 60° C., the reaction mixture was cooled to room temperature, quenched with ethylacetate and H2O. The aqueous phase was extracted with ethylacetate. The combined organic phases were washed with H2O, dried over Na2SO4, filtered and concentrated. The residue was chromatographed over silica gel (CH2Cl2—MeOH, 98:2) to provide (RS)-4-[1-(4-m-tolyl-butyl)-pyrrolidine-3-sulfonyl]-phenol (66 mg, 47%) as a light yellow foam, MS: m/e=374.4 (M+H+).
Reaction SMILES: [Br-:1].[CH3:2][C:3]1[CH2:11][CH2:10][N+:9]2[C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[S:6][C:5]=2[C:4]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CS(C)=O.[Br-].C(CC[N+]1C2C=CC=CC=2SC=1C)(=O)C.[Br-].CC1C=C[N+]2C3C=CC=CC=3SC=2C=1>C(O)C.CCOCC>[Br-:1].[CH3:2][C:3]1[CH:11]=[CH:10][N+:9]2[C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[S:6][C:5]=2[C:4]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC1=C(c2ccccc2)c2sc3ccccc3[n+]2CC1
Agent: CC(=O)CC[n+]1c(C)sc2ccccc21
Agent: Cc1cc[n+]2c(c1)sc1ccccc12
Agent: [Br-]
Solvent: CS(C)=O
Solvent: CCOCC
Solvent: CCO
Product: Cc1cc[n+]2c(sc3ccccc32)c1-c1ccccc1

Procedure:
1,2-Dihydro-3-methyl-4-phenylpyrido[2,1-b]benzothiazolium bromide is prepared by reacting 3-(2-acetylethyl)-2-benzylbenzothiazolium bromide (1.0 g.) dissolved in 25 ml. of dimethyl sulfoxide. The reaction mixture is heated to reflux for several minutes and cooled. The resulting tan solid precipitate is filtered, washed with ether and dried to give 0.7 g. (72% yield) of product having a melting point of 208°-210° C. 1,2-Dihydro-3-methyl-4-phenylpyrido[2,1-b]benzothiazolium bromide (1.0 g.) is heated in 15 ml. of dimethylsulfoxide to 160° C and held for several minutes. As the mixture cools, 5 ml. each of ether and ethanol are added, precipitating some of the starting material. The addition of more ether causes the slow crystallization of the product, which on recrystallization from ethanol, is obtained in 30% yield (0.3 g.). The product has a melting point of 285°-287° C with decomposition. The NMR spectrum verifies a completely aromatic ring system. When this example is repeated, except that 3-(2-acetylethyl)-2-methylbenzothiazolium bromide is used as the starting material, there is obtained, in somewhat lower yield, 3-methylpyrido[2,1-b]benzothiazolium bromide, which is a useful intermediate in preparing dyes in accordance with this invention.