Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:2]([C:11]([OH:13])=O)[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1.[NH:21]([CH3:46])[C@H:22]([C:26]([N:28]([CH3:45])[C@H:29]([C:42]([NH2:44])=[O:43])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[C:33]([C:38]([CH3:41])([CH3:40])[CH3:39])[CH:32]=1)=[O:27])[CH:23]([CH3:25])[CH3:24].O>C1COCC1>[NH:1]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:2]([C:11]([N:21]([CH3:46])[C@H:22]([C:26]([N:28]([CH3:45])[C@H:29]([C:42]([NH2:44])=[O:43])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[C:33]([C:38]([CH3:41])([CH3:39])[CH3:40])[CH:32]=1)=[O:27])[CH:23]([CH3:25])[CH3:24])=[O:13])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([Cl:10])=[CH:8][CH:9]=1
Reactant: CN[C@H](C(=O)N(C)[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O)C(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(Cl)cc1)C(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)[C@@H](C(=O)N(C)[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O)N(C)C(=O)[C@H](Cc1ccc(Cl)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.8 %

Procedure:
To a solution of Boc-Phe(4-Cl)-OH (354 mg, 1.18 mmol), N-Me-Val-N-Me-Tyr(3-tBu)-NH2 (0.33 g, 0.908 mmol) and CMPI (301 mg, 1.18 mmol) in THF (8 ml), TEA (0.38 ml, 2.72 mmol) was added under cooling with ice and stirred at room temperature overnight. The reaction mixture was mixed with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated to remove the solvent under reduced pressure; the thus obtained residue was subjected to silica gel column chromatography (developing solvent: chloroform:methanol:aqueous ammonia=40:1:0.05) to give Boc-Phe(4-Cl)-N-Me-Val-N-Me-Tyr(3-tBu)-NH2 (0.45 g, 77%).
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH3:40])[C:4]([C:34]2[N:38]([CH3:39])[N:37]=[CH:36][CH:35]=2)=[CH:5][C:6]=1[C:7]([NH:9][C@@H:10]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]([F:33])([F:32])[F:31])[CH2:11][N:12]1C(=O)C2C(=CC=CC=2)C1=O)=[O:8].NN>O1CCCC1.CO>[NH2:12][CH2:11][C@@H:10]([NH:9][C:7]([C:6]1[CH:5]=[C:4]([C:34]2[N:38]([CH3:39])[N:37]=[CH:36][CH:35]=2)[N:3]([CH3:40])[C:2]=1[Cl:1])=[O:8])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]([F:33])([F:32])[F:31]
Reactant: Cn1nccc1-c1cc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)c(Cl)n1C
Agent: NN
Solvent: CO
Solvent: C1CCOC1
Product: Cn1nccc1-c1cc(C(=O)N[C@H](CN)Cc2ccccc2C(F)(F)F)c(Cl)n1C
Yield: 59.1 %

Procedure:
To a solution of 2-chloro-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-1-methyl-5-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrole-3-carboxamide (125 mg, 0.22 mmol) in tetrahydrofuran (1.1 ml) and methanol (1.1 ml) at 25° C. was added hydrazine (0.06 ml, 1.76 mmol) dropwise. After 12 h the solution was concentrated, dry loaded onto silica and purified by column chromatography (2% MeOH in DCM (1% NH4OH)). The free base was transferred to the HCl salt by addition of excess 2M HCl in Ether (20 ml) to the residue in DCM (40 ml) affording the HCl salt of N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-2-chloro-1-methyl-5-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrole-3-carboxamide (70 mg, 0.13 mmol, 57% yield) as a white solid: LCMS (ES) m/z=440, 442 (M, M+2)+, 1H NMR (400 MHz, DMSO-d6) δ ppm 8.17 (d, J=9.09 Hz, 1 H) 8.08 (br. s., 2 H) 7.69 (d, J=8.08 Hz, 1 H) 7.58 (br. s., 1 H) 7.57 (d, J=2.02 Hz, 1 H) 7.40-7.43 (m, 1 H) 7.02 (s, 1 H) 6.48 (d, J=2.02 Hz, 1 H) 4.50-4.57 (m, 1 H) 3.78 (s, 3 H) 3.44 (s, 3 H) 2.98-3.07 (m, 4 H).
Reaction SMILES: [OH:1]/[N:2]=[C:3](/[C:9](=[O:11])[CH3:10])\[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:12][C@H:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]1O>>[CH3:12][C@@H:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]1[O:1]/[N:2]=[C:3](/[C:9](=[O:11])[CH3:10])\[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: C[C@H]1CCCC[C@H]1O
Reactant: CCOC(=O)/C(=N\O)C(C)=O
Product: CCOC(=O)/C(=N\O[C@@H]1CCCC[C@H]1C)C(C)=O

Procedure:
Ethvl (Z)-2-hydroxyimino-3-oxobutyrate (1.59 g) was alkylated with cis-2-methylcyclohexan-1-ol (1.71 g) as described in Example 4, method 3. The pure title compound was otained as a pale yellow oil (0.506 g). (Found: M+, 256.1552. C13H21NO4 requires M 256.1549); νmax (film) 1745, 1695 and 1595 cm-1 ; δH (CDCl3) 1.02 (3H, d, J 6 Hz), 1.35 (3H, t, J 7 Hz), ca 1.2-2.3 (9H, m), 2.40 (3H, s), 3.95 (1H, m) and 4.42 (2H, q, J 7 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=2[F:16])[CH:5]=[CH:6][C:7]=1[Cl:8].[Br:17]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.S([O-])([O-])=O.[Na+].[Na+]>C(#N)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][Br:17])=[CH:11][C:10]=2[F:16])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2ccc(Cl)c(Cl)c2)c(F)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: Fc1cc(CBr)ccc1-c1ccc(Cl)c(Cl)c1
Reaction time: 0.5 h

Procedure:
3′,4′-dichloro-2-fluoro-4-methyl-biphenyl (29 g, 0.114 mol), N-bromosuccinimide (21.2 g, 0.119 mol), benzoyl peroxide (1.4 g, 0.004 mol) were dissolved in acetonitrile (190 ml). The mixture was refluxed for 3 hours, then cooled, mixed with a solution of sodium sulphite (2.2 g) in water (54 ml), stirred for 30 minutes and then allowed to rest to separate the phases. The lower aqueous phase was separated and extracted with dichloromethane (29 ml). The upper phase was concentrated under vacuum, mixed with water (10 ml), and dichloromethane (58 ml) and stirred. The organic phases were separated and put together, washed twice with water (29 ml), and concentrated under vacuum. The compound 3′,4′-dichloro-2-fluoro-4-bromomethyl-biphenyl was isolated as an orange oil (35.7 g, 94% yield).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15](CC3C=CC(OC)=CC=3OC)[C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[C:5]([C:32]#[N:33])=[CH:4][N:3]=1.[Cl:34][C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[C:37]([O:44][CH3:45])[CH:36]=1>>[Cl:34][C:35]1[CH:40]=[CH:39][C:38]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([S:12]([NH:15][C:16]4[S:17][CH:18]=[CH:19][N:20]=4)(=[O:13])=[O:14])=[CH:9][CH:10]=3)[C:5]([C:32]#[N:33])=[CH:4][N:3]=2)=[C:37]([O:44][CH3:45])[CH:36]=1
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(Cl)ncc(C#N)c3c2)c(OC)c1
Reactant: COc1cc(Cl)ccc1B(O)O
Product: COc1cc(Cl)ccc1-c1ncc(C#N)c2cc(S(=O)(=O)Nc3nccs3)ccc12

Procedure:
Example 241 was synthesized in a similar manner to Example 228, except that 1-chloro-4-cyano-N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide and (4-chloro-2-methoxyphenyl)boronic acid were used as the coupling partners. The final compound was purified via column chromatography (12 g silica gel column, gradient elution 25 to 100% EtOAc:Heptane) to afford 1-(4-chloro-2-methoxyphenyl)-4-cyano-N-(thiazol-2-yl)isoquinoline-6-sulfonamide as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm=13.06 (s, 1H), 9.26 (s, 1H), 8.58-8.43 (m, 1H), 8.06 (dd, J=1.8, 8.9 Hz, 1H), 7.94 (dd, J=0.6, 8.9 Hz, 1H), 7.42 (d, J=8.1 Hz, 1H), 7.37 (d, J=1.9 Hz, 1H), 7.32 (d, J=4.6 Hz, 1H), 7.24 (dd, J=1.9, 8.1 Hz, 1H), 6.92 (d, J=4.6 Hz, 1H), 3.69 (s, 3H). m/z (ESI) 457.2 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[CH:32]=[CH:31][C:6]([C:7]([N:9]2[CH2:30][CH2:29][C:12]3([C:17]4=[CH:18][CH:19]=[CH:20][N:16]4[C:15]4[CH:21]=[CH:22][C:23]([C:25]([O:27]C)=[O:26])=[CH:24][C:14]=4[O:13]3)[CH2:11][CH2:10]2)=[O:8])=[CH:5][C:4]=1[O:33][CH3:34])[CH3:2].[Li+].[OH-]>O1CCOCC1.C(OCC)(=O)C>[CH2:1]([C:3]1[CH:32]=[CH:31][C:6]([C:7]([N:9]2[CH2:10][CH2:11][C:12]3([O:13][C:14]4[CH:24]=[C:23]([C:25]([OH:27])=[O:26])[CH:22]=[CH:21][C:15]=4[N:16]4[CH:20]=[CH:19][CH:18]=[C:17]34)[CH2:29][CH2:30]2)=[O:8])=[CH:5][C:4]=1[O:33][CH3:34])[CH3:2]
Reactant: CCc1ccc(C(=O)N2CCC3(CC2)Oc2cc(C(=O)OC)ccc2-n2cccc23)cc1OC
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCc1ccc(C(=O)N2CCC3(CC2)Oc2cc(C(=O)O)ccc2-n2cccc23)cc1OC

Procedure:
A solution of methyl 1-(4-ethyl-3-methoxy-benzoyl)spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-7′-carboxylate (1.1 g, 2.5 mmol) in LiOH (2.5 mL of 4.0 M, 9.9 mmol) and dioxane (5 mL) was stirred at 50° C. for 1 hour. The reaction was diluted with ethyl acetate and washed with water. The aqueous was acidified with 1N HCl and the product was extracted into ethyl acetate. The organics were dried over sodium sulfate, filtered and evaporated to yield a crude product that was used in the next step without further purification (0.60 g, 53%). ESI-MS m/z calc. 446.5, found 447.5 (M+1)+; Retention time: 1.84 minutes (3 min run).
Reaction SMILES: [CH2:1]([C:4]1[C:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[C:22]([O:24][CH3:25])=[O:23])[CH:2]=C.[O:26]=[O+][O-]>C(Cl)Cl.CO>[CH2:15]([O:14][C:13]1[C:4]([CH2:1][CH:2]=[O:26])=[C:5]([C:22]([O:24][CH3:25])=[O:23])[CH:6]=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=[O+][O-]
Reactant: C=CCc1c(OCc2ccccc2)cc(C(=O)OC)cc1C(=O)OC
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1cc(OCc2ccccc2)c(CC=O)c(C(=O)OC)c1
Temperature: 25 °C
Yield: 98 %

Procedure:
A solution of dimethyl 4-allyl-5-(benzyloxy)isophthalate (3.5 g, 10.28 mmol) in CH2Cl2 and methanol was cooled to −78° C. and treated with ozone until the solution appeared blue (20 min). Nitrogen was bubbled through the solution until the blue color dissipated. Dimethylsulfide (1.0 mL) was added and the cold-bath was removed allowing the reaction mixture to warm to room temperature overnight. Concentration of the solution under vacuum provided an oil which was purified by column chromatography on silica gel eluted with 10-30% EtOAc in hexanes to afford the aldehyde (3.0g, 98%) as a white solid. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 3.90 (s, 3 H) 3.95 (s, 3 H) 4.29 (s, 2 H) 5.14 (s, 2 H) 7.31-7.56 (m, 5 H) 7.81 (d, J=1.32 Hz, 1 H) 8.29 (d, J=1.51 Hz, 1 H) 9.75 (s, 1 H); MS (ESI, pos): 343.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.C([O:15][C:16](=O)[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[CH:31]=[C:30]([CH3:32])[N:29]=[C:28]([CH3:33])[CH:27]=2)[CH:21]=1)=O)(C)(C)C>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]2[NH:9][C:16](=[O:15])[CH2:17][C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]4[CH:27]=[C:28]([CH3:33])[N:29]=[C:30]([CH3:32])[CH:31]=4)[CH:21]=3)=[N:10][C:4]=2[CH:3]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cc(C)n1
Reactant: Nc1cc(Cl)c(Cl)cc1N
Solvent: Cc1ccccc1C
Product: Cc1cc(-c2cccc(C3=Nc4cc(Cl)c(Cl)cc4NC(=O)C3)c2)cc(C)n1

Procedure:
The title compound was prepared from commercially available 4,5-dichloro-1,2-phenylendiamine (109 mg, 0.61 mmol) and 3-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K15) (200 mg, 0.61 mmol) in xylene (10 ml) under reflux conditions for 2 h according to the general procedure M. Obtained as a light brown solid (173 mg, 69%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[S:8][CH:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:5]2=[C:4]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH:3]=1.[CH2:25]([CH2:27][NH2:28])[OH:26]>C(Cl)Cl>[C:11]1([C:10]2[C:5]3[C:6](=[N:7][C:2]([NH:28][CH2:27][CH2:25][OH:26])=[CH:3][C:4]=3[NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[S:8][CH:9]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Clc1cc(NCc2ccccn2)c2c(-c3ccccc3)csc2n1
Reactant: NCCO
Solvent: ClCCl
Product: OCCNc1cc(NCc2ccccn2)c2c(-c3ccccc3)csc2n1
Temperature: 200 °C

Procedure:
A mixture of (6-chloro-3-phenyl-thieno[2,3-b]pyridin-4-yl)-pyridin-2-ylmethyl-amine (20 mg, 0.57 mmol) and ethanolamine (1 ml) were heated to 200° C. in the microwave and maintained at this temperature for 90 min. On cooling, the reaction mixture was poured into DCM (50 ml) and washed with water (2×50 ml), dried (Na2SO4), and concentrated. The residue was purified on silica (ethyl acetate, 100%) to give 2-{3-phenyl-4-[(pyridin-2-ylmethyl)-amino]-thieno[2,3-b]pyridin-6-ylamino}-ethanol as a white solid. Yield=18 mg (83.9%).
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:12][C:13]2[CH:18]=[C:17]([OH:19])[CH:16]=[CH:15][C:14]=2[C:20]([F:23])([F:22])[F:21])[N:8]=1)=[O:5].CC(C)([O-])C.[K+].Br[CH2:36][CH:37]1[CH2:39][CH2:38]1>CS(C)=O.CO>[CH:37]1([CH2:36][O:19][C:17]2[CH:16]=[CH:15][C:14]([C:20]([F:23])([F:21])[F:22])=[C:13]([CH2:12][N:9]3[CH:10]=[CH:11][C:7]([NH:6][C:4](=[O:5])[C:3]4[C:2]([F:1])=[CH:27][CH:26]=[CH:25][C:24]=4[F:28])=[N:8]3)[CH:18]=2)[CH2:39][CH2:38]1
Reactant: O=C(Nc1ccn(Cc2cc(O)ccc2C(F)(F)F)n1)c1c(F)cccc1F
Reactant: BrCC1CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CO
Product: O=C(Nc1ccn(Cc2cc(OCC3CC3)ccc2C(F)(F)F)n1)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2,6-difluoro-N-(1-{[5-hydroxy-2-(trifluoromethyl)phenyl]methyl}-1H-pyrazol-3-yl)benzamide (for a preparation see Intermediate 42)(75 mg, 0.189 mmol) in DMSO (1 ml) was added potassium t-butoxide (23 mg, 0.205 mmol, Aldrich). The solution was stirred at ambient temperature for 5 min. To the solution was added (bromomethyl)cyclopropane (0.023 ml, 0.245 mmol, Alfa Aesar) and the mixture stirred overnight at ambient temperature under nitrogen. The solution was diluted with methanol (1 ml) and purified by MDAP on Sunfire C18 column (Method B) using Acetonitrile-Water with a Formic acid modifier. The solvent was evaporated in vacuo to give the title compound as a white solid (36 mg); LCMS: (System 4) MH+=452, tRET=3.18 min.
Reaction SMILES: [CH3:1][C@@H:2]1[C@@H:16]2[C:11](=[C:12]([OH:31])[C@:13]3([OH:30])[C:21](=[O:22])[C:20]([C:23]([NH2:25])=[O:24])=[C:19]([OH:26])[C@@H:18]([N:27]([CH3:29])[CH3:28])[C@@H:14]3[C@H:15]2[OH:17])[C:9](=[O:10])[C:8]2[C:7]([OH:32])=[CH:6][CH:5]=[CH:4][C:3]1=2.C1(C)C=CC([S:39]([O-:42])(=[O:41])=[O:40])=CC=1.C(N(CC)CC)C.C([OH:53])C>O>[CH3:1][C@@H:2]1[C@@H:16]2[C:11](=[C:12]([OH:31])[C@:13]3([OH:30])[C:21](=[O:22])[C:20]([C:23]([NH2:25])=[O:24])=[C:19]([OH:26])[C@@H:18]([N:27]([CH3:28])[CH3:29])[C@@H:14]3[C@H:15]2[OH:17])[C:9](=[O:10])[C:8]2[C:7]([OH:32])=[CH:6][CH:5]=[CH:4][C:3]1=2.[S:39]([O:22][C:21]1[C:20](=[CH:19][CH:18]=[CH:14][CH:13]=1)[C:23]([O-:24])=[O:53])([OH:42])(=[O:41])=[O:40]
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Reactant: CCO
Agent: C[C@H]1c2cccc(O)c2C(=O)C2=C(O)[C@]3(O)C(=O)C(C(N)=O)=C(O)[C@@H](N(C)C)[C@@H]3[C@@H](O)[C@@H]21
Solvent: CCN(CC)CC
Solvent: O
Product: O=C([O-])c1ccccc1OS(=O)(=O)O

Procedure:
Doxycycline p-toluenesulphonate (40.0 g) prepared according to the process above was suspended in a mixture of ethanol (72.0 ml) and water (24.0 ml), with stirring. A solution of triethylamine (9.04 ml) in ethanol (9.04 ml) was added, causing dissolution followed by crystallisation. After stirring for 20 minutes, ethanol (144 ml) was added and the mixture stirred for a further 1 hour 30 minutes. The crystals were filtered, washed with ethanol (25 ml), then with acetone (12.5 ml) and dried at 35° C. The product, doxycycline monohydrate, weighed 22.12 g and complied with the U.S. Pharmacopoeia monograph requirements. The mother liquors were diluted with an equal volume of water and 5-sulphosalicylic acid (2.0 g) was added. After stirring overnight, the deposited solid was filtered, washed with 66% aqueous methanol and then with acetone, dried at 35° C., and gave 1.53 g of doxycycline sulphosalicylate.
Reaction SMILES: [F:1][C:2]1[C:3]([N:9]=[CH:10][N:11]([CH3:13])[CH3:12])=[N:4][C:5]([OH:8])=[N:6][CH:7]=1.[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>N1C=CC=CC=1>[C:14]1([S:20]([N:6]2[CH:7]=[C:2]([F:1])[C:3]([N:9]=[CH:10][N:11]([CH3:13])[CH3:12])=[N:4][C:5]2=[O:8])(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CN(C)C=Nc1nc(O)ncc1F
Solvent: c1ccncc1
Product: CN(C)C=Nc1nc(=O)n(S(=O)(=O)c2ccccc2)cc1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 18.8 %

Procedure:
To an 8 mL screw-cap vial were added pyridine (2 mL), N′-(5-fluoro-2-hydroxy-pyrimidin-4-yl)-N,N-dimethylformamidine (100 mg, 0.54 mmol), and benzenesulfonyl chloride (106 mg, 0.60 mmol), and the mixture was shaken at room temperature for 24 hours (h). The crude mixture was partitioned between ethyl acetate (EtOAc) and saturated aqueous sodium bicarbonate (satd aq NaHCO3), and the organic phase was dried over magnesium sulfate (MgSO4), filtered, and evaporated to yield 153 mg of crude material. Reverse phase chromatography furnished the title product as a white solid (33 mg, 19%): mp 203-204° C.; 1H NMR (300 MHz, CDCl3) δ 8.77 (s, 1H), 8.16-8.11 (m, 3H), 7.72-7.65 (m, 1H) 7.60-7.53 (m, 2H), 3.24 (s, 3H), 3.23 (s, 3H); ESIMS m/z 325 ([M+H]+).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][S:5][C:6]=1[CH3:7].[C:12](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[CH3:12][O:1][C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][S:5][C:6]=1[CH3:7]
Reactant: COC(=O)c1csc(C)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: COC(=O)c1csc(C)c1OC

Procedure:
Methyl 4-hydroxy-5-methyl-3-thiophenecarboxylate (34 g), potassium carbonate (37 g) and dimethyl sulphate (33.67 g) were stirred in anhydrous acetone (200 ml) at room temperature for 20 days. The reaction mixture was filtered and the solvent removed.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4](O)([C:20]([F:23])([F:22])[F:21])[C:5]1[C:9](=[O:10])[N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH3:18])[NH:7][C:6]=1[CH3:19].S(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:25])[C:4](=[C:5]1[C:9](=[O:10])[N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH3:18])[N:7]=[C:6]1[CH3:19])[C:20]([F:23])([F:21])[F:22]
Reactant: COC(=O)C(O)(c1c(C)[nH]n(-c2ccccc2OC)c1=O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: COC(=O)C(=C1C(=O)N(c2ccccc2OC)N=C1C)C(F)(F)F

Procedure:
To a toluene solution (5 ml) of 2,5-dihydro-α-hydroxy-1-(2-methoxyphenyl)-3-methyl-5-oxo-α-trifluoromethyl-1H-pyrazole-4-acetic acid methyl ester (180 mg, 0.5 mmol), thionyl chloride (0.365 ml, 5.0 mmol) was added and the mixture was stirred under reflux for 3 hours. After concentrating the liquid reaction mixture under reduced pressure, the title compound was obtained as a reddish brown solid (171 mg).
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)CCC.Br[C:20]1[CH:32]=[CH:31][C:30]2[C:29]3[C:24](=[CH:25][C:26](Br)=[CH:27][CH:28]=3)[C:23]([CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[C:22]=2[CH:21]=1>C1(C)C=CC=CC=1.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>[S:7]1[CH:8]=[CH:9][CH:10]=[C:6]1[C:26]1[CH:27]=[CH:28][C:29]2[C:30]3[C:22](=[CH:21][C:20]([C:6]4[S:7][CH:8]=[CH:9][CH:10]=4)=[CH:32][CH:31]=3)[C:23]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])([CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[C:24]=2[CH:25]=1
Reactant: CCCCCCCCCCC1(CCCCCCCCCC)c2cc(Br)ccc2-c2ccc(Br)cc21
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCC1(CCCCCCCCCC)c2cc(-c3cccs3)ccc2-c2ccc(-c3cccs3)cc21
Reaction time: 3 h
Yield: 70 %

Procedure:
2-(tributylstannyl)thiophene (5.80 ml, 0.018 mol) was added under nitrogen directly to a single-necked round bottom flask equipped with a condenser and a magnetic stir bar that had been previously dried in an oven at 110° C. The 2,7-dibromo-9,9-di-n-decyl-9H-fluorene (5.26 g, 8.70 mmol) was weighed into a beaker and dissolved in toluene (14 ml) which had been freshly distilled and degassed with nitrogen. The resulting fluorene solution was pipetted into the round bottom flask and the beaker rinsed twice with 3 ml portions of degassed toluene. Pd(PPh3)4 (0.50 g, 0.43 mmol) and PdCl2 (PPh3)2 (0.31 g, 0.44 mmol) were added to the reaction flask and the solution refluxed until it turned black. The toluene was removed under reduced pressure and the residue dissolved in hexane. The hexane solution was stirred vigorously with a 100 ml of a 2% aqueous KF solution for 3 hours. The organic layer was separated, washed twice with an equal volume of water, dried over anhydrous MgSO4, filtered and concentrated. The crude product was purified by column chromotography on silica gel using hexane as the eluent. The purified waxy solid compound (mp 59.9°-60.8° C.) was isolated in a 70% yield. Mass Spec. m/z 610 (M+), 469 (M--C10H21), Elemental Analysis: Calculated for C41H52S2 : C, 80.60, H, 8.91, S, 10.49. Found: C, 80.55, H, 8.97, S, 10.08.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:15])[CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:23](Cl)(=[O:25])[CH3:24]>C(OCC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:15][C:23](=[O:25])[CH3:24])[CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:4][CH:3]=1
Reactant: CC(=O)Cl
Reactant: OC(Cn1cncn1)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(=O)OC(Cn1cncn1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1-p-Chlorophenyl-2-(1,2,4-triazol-1-yl)-ethanol (2.24 g) and triethylamine (1.1 g) in dry diethyl ether (50 ml) were treated with acetyl chloride (0.8 g) in dry diethyl ether (5 ml) and the mixture was stirred for 3 hours at room temperature to give a white solid which was filtered off and washed with ether. The solvent was removed from the filtrate to give a brown oil. The oil was distilled to give the title compound as a semi-solid which could not be purified further.
Reaction SMILES: [Na].[C:2]([O:9][CH2:10][CH3:11])(=[O:8])[C:3]([O:5]CC)=O.[C:12]1(=[O:18])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>C(O)C>[CH2:10]([O:9][C:2](=[O:8])[C:3](=[O:5])[CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17][C:12]1=[O:18])[CH3:11]
Reactant: CCOC(=O)C(=O)OCC
Reactant: O=C1CCCCC1
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(=O)C1CCCCC1=O
Temperature: 60 °C

Procedure:
A solution of sodium (1.75 g) in ethanol (100 ml) was treated with a mixture of diethyl oxalate (9.41 ml) and cyclohexanone (7.18 ml). The mixture was heated to 60° C. for 5 hours then cooled and then evaporated to yield oxo-(2-oxo-cyclohexyl)-acetic acid ethyl ester as a brown foam (16.635 g). LC-MS (METHOD B): RT=3.10 minutes; 197 (M−H)−. (b) 5-Methyl-2,4-dioxo-hexanoic acid ethyl ester