Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.[Cl:33][C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][C:41]=1[Cl:42])[CH2:37]Br>CN(C=O)C>[CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:37][C:36]2[CH:39]=[CH:40][C:41]([Cl:42])=[C:34]([Cl:33])[CH:35]=2)[CH:6]=1
Reactant: Clc1ccc(CBr)cc1Cl
Reactant: COC(=O)Cc1c[nH]c2ncccc12
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: CN(C)C=O
Product: COC(=O)Cc1cn(Cc2ccc(Cl)c(Cl)c2)c2ncccc12
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To an ice cold solution of (1H-pyrrolo[2,3-b]pyridine-3-yl)-acetic acid methyl ester (50 mg, 0.26 mmol) in DMF (1 mL), is added BEMP (0.122 mL, 0.42 mmol). The reaction mixture is stirred at ambient temperature for 40 minutes, then 3,4-dichlorobenzyl bromide (0.101 g, 0.42 mmol) is added and the reaction mixture is stirred for 16 hours at ambient temperature. The reaction mixture is poured into ice cold water (40 mL) and extracted with EtOAc, washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The crude product is purified by column chromatography on silica gel using a pre-packed Isolute™ silica column (2 g) eluting with 1:20 EtOAc/iso-hexane, furnishing [1-(3,4-dichloro-benzyl)-1H-pyrrolo[2,3-b]pyridine-3-yl]-acetic acid methyl ester; MH+=349.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]([CH2:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([C:27]([NH:29][C@@H:30]([CH2:34][CH2:35][CH2:36][NH:37][C@H:38]2[C:47]3[N:46]=[CH:45][CH:44]=[CH:43][C:42]=3[CH2:41][CH2:40][CH2:39]2)[C:31]([OH:33])=[O:32])=[O:28])=[CH:19][CH:18]=1)C(OC(C)(C)C)=O.[ClH:48].O1CCOCC1>CO>[ClH:48].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][CH2:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([C:27]([NH:29][C@@H:30]([CH2:34][CH2:35][CH2:36][NH:37][C@H:38]2[C:47]3[N:46]=[CH:45][CH:44]=[CH:43][C:42]=3[CH2:41][CH2:40][CH2:39]2)[C:31]([OH:33])=[O:32])=[O:28])=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccccn1)Cc1ccc(C(=O)N[C@@H](CCCN[C@@H]2CCCc3cccnc32)C(=O)O)c2ccccc12
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: O=C(N[C@@H](CCCN[C@@H]1CCCc2cccnc21)C(=O)O)c1ccc(CNCc2ccccn2)c2ccccc12
Reaction time: 2 h

Procedure:
The compound obtained in Example 54-3 (7.2 mg) was dissolved in methanol (0.15 ml) and 4 mol/l hydrochloric acid/dioxane solution (0.15 ml) was added. After 2 hours, the reaction solution was concentrated. The residue was purified by silica gel column chromatography (chloroform/methanol/water=7/3/0.5). After the addition of 1 mol/l hydrochloric acid, the residue was concentrated and subjected to azeotropic distillation with methanol to obtain hydrochloride of the title compound (6.3 mg) as a white solid.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][C:4]([C:7]2[N:12]=[C:11]3[CH2:13][CH2:14][CH2:15][C:10]3=[C:9]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:19][CH:18]=3)[CH:8]=2)=[CH:3]1>[Pd].C(OCC)(=O)C.C(O)C>[OH:1][CH:2]1[CH2:6][CH2:5][CH:4]([C:7]2[N:12]=[C:11]3[CH2:13][CH2:14][CH2:15][C:10]3=[C:9]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:21][CH:22]=3)[CH:8]=2)[CH2:3]1
Reactant: CCOC(=O)Cc1ccc(Nc2cc(C3=CC(O)CC3)nc3c2CCC3)cc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1ccc(Nc2cc(C3CCC(O)C3)nc3c2CCC3)cc1
Reaction time: 4 h

Procedure:
A 250-mL round bottom flask was charged with ethyl 2-(4-((2-(3-hydroxycyclopent-1-en-1-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetate (0.109 g, 0.29 mmol) and 10% palladium on carbon (0.028 g) in 1:1 ethyl acetate/ethanol (12 mL). This mixture was vigorously stirred under H2 (1 atm) for 4 h. After this time, the mixture was filtered through celite and the filtrate concentrated under reduced pressure. The residue was purified by preparative HPLC (water/acetonitrile with 0.05% TFA) to afford two diastereomers of the title compound:
Reaction SMILES: BrBr.[Cl:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[N:11]1[C:19]2[CH2:18][CH2:17][N:16]([N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:15](=[O:26])[C:14]=2[C:13]([CH3:27])=[C:12]1[C:28]1[CH:33]=[CH:32][C:31]([O:34][S:35]([CH2:38][CH2:39][C:40]([F:43])([F:42])[F:41])(=[O:37])=[O:36])=[CH:30][CH:29]=1>C(O)(=O)C.C1COCC1>[Cl:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[N:11]1[C:19]2[CH:18]=[CH:17][N:16]([N:20]3[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]3)[C:15](=[O:26])[C:14]=2[C:13]([CH3:27])=[C:12]1[C:28]1[CH:33]=[CH:32][C:31]([O:34][S:35]([CH2:38][CH2:39][C:40]([F:42])([F:43])[F:41])(=[O:36])=[O:37])=[CH:30][CH:29]=1
Reactant: Cc1c2c(n(-c3ccc(F)cc3Cl)c1-c1ccc(OS(=O)(=O)CCC(F)(F)F)cc1)CCN(N1CCCCC1)C2=O
Agent: BrBr
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1c(-c2ccc(OS(=O)(=O)CCC(F)(F)F)cc2)n(-c2ccc(F)cc2Cl)c2ccn(N3CCCCC3)c(=O)c12
Reaction time: 0.5 h
Yield: 29.5 %

Procedure:
Bromine (39.0 mg, 0.244 mmol) dissolved in acetic acid (0.556 ml) was added to a solution of 4-[1-(2-chloro-4-fluorophenyl)-3-methyl-4-oxo-5-piperidin- 1-yl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl]phenyl 3,3,3-trifluoropropane-1-sulfonate (75 mg, 0.122 mmol) (Example 3 ) in THF (3 ml) at −78° C. After 30 min at −78° C. the reaction mixture was allowed to reach rt. After 3 h at rt more bromine (19.5 mg, 0.122 mmol) dissolved in acetic acid (0.278 ml) was added and the reaction continued at rt for 5 h before the solvent was removed by evaporation. Purified by hplc to yield the title compound as a solid (22 mg, 29%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][S:9][C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[S:17]([C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1)(=[O:20])(=[O:19])[NH2:18]>>[S:17]([C:21]1[CH:28]=[CH:27][C:24]([CH:25]=[N:16][C:13]2[CH:14]=[CH:15][C:10]([S:9][S:8][C:5]3[CH:4]=[CH:3][C:2]([N:1]=[CH:25][C:24]4[CH:27]=[CH:28][C:21]([S:17](=[O:20])(=[O:19])[NH2:18])=[CH:22][CH:23]=4)=[CH:7][CH:6]=3)=[CH:11][CH:12]=2)=[CH:23][CH:22]=1)(=[O:20])(=[O:19])[NH2:18]
Reactant: NS(=O)(=O)c1ccc(C=O)cc1
Reactant: Nc1ccc(SSc2ccc(N)cc2)cc1
Product: NS(=O)(=O)c1ccc(C=Nc2ccc(SSc3ccc(N=Cc4ccc(S(N)(=O)=O)cc4)cc3)cc2)cc1

Procedure:
Following a procedure similar to that described in Example 1(i), but using bis(4-aminophenyl) disulfide [prepared as described in step (i) above] and 4-sulfamoylbenzaldehyde as starting materials, the title compound was obtained as a slightly yellow powder (yield 58%), melting at 200-230° C.
Reaction SMILES: [H-].[Na+].[CH:3]([C@H:5]1[C@H:12]([O:13][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:11][C@H:10]2[C@@H:6]1[CH2:7][C:8](=[O:22])[O:9]2)=O.[CH2:23]([CH2:26][O:27]C)OC>>[O:27]=[C:26]([CH:11]([CH3:10])[CH2:12][CH2:5][C:6]#[C:7][CH3:8])/[CH:23]=[CH:3]/[C@H:5]1[C@H:12]([O:13][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:11][C@H:10]2[C@@H:6]1[CH2:7][C:8](=[O:22])[O:9]2
Reactant: COCCOC
Reactant: O=C[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Product: CC#CCCC(C)C(=O)/C=C/[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 7.56 g of dimethyl-2-oxo-3 -methyl-6-octynylphosphate in 60 ml of dimethoxyethane is to a suspension of 1.33 g of sodium hydride (55% strength in oil) in 65 ml of dimethoxyethane at room temperature. Then the solution is agitated for 30 minutes at room temperature and cooled to -30° C. Subsequently, at -20° C., a solution of 7.66 g of (1S,5R,6R,7R)-6-formyl-7-benzoyloxy-2-oxabicyclo[3.3.0]octan-3-one in 84 ml of dimethoxyethane is added thereto and the mixture is stirred for another 2 hours at room temperature. The crude product is isolated analogously to Example (1a), thus obtaining 12.95 g of the title compound as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[C:13]([C:18]([OH:20])=[O:19])=[N:14][CH:15]=[CH:16][CH:17]=2)[N:4]=1.[CH3:21][C:22](=[N:24]O)[CH3:23].N1C=CC=CC=1.ClOP(=O)(OCl)N(C)C>CN(C)C=O.O>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([O:11][C:12]2[C:13]([C:18]([O:20][N:24]=[C:22]([CH3:23])[CH3:21])=[O:19])=[N:14][CH:15]=[CH:16][CH:17]=2)[N:6]=1
Reactant: COc1cc(OC)nc(Oc2cccnc2C(=O)O)n1
Reactant: CC(C)=NO
Agent: CN(C)P(=O)(OCl)OCl
Solvent: O
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: COc1cc(OC)nc(Oc2cccnc2C(=O)ON=C(C)C)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3.0 g of 3-(4,6-dimethoxypyrimidin-2-yl)oxypicolinic acid, 3.96 g of acetoxime and 1.71 g of pyridine were dissolved in 20 ml of N,N-dimethylformamide, and then, 3.51 g of dichloro-N,N-dimethylphosphoric acid amide was dropwise added thereto at 0° C. After the dropwise addition, the mixture was stirred at room temperature for 3 hours to complete the reaction. The reaction solution was poured into water. Precipitated crystals were separated by filtration, then washed with water and dried to obtain 2.20 g of the above identified compound as white crystals.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]2[O:14][N:15]=[C:16]([CH3:17])[C:3]=12.[CH2:18]([NH2:22])[CH2:19][CH2:20][CH3:21]>O>[CH2:18]([NH:22][C:2]1[C:3]2[C:16]([CH3:17])=[N:15][O:14][C:4]=2[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1)[CH2:19][CH2:20][CH3:21]
Reactant: CCCCN
Reactant: Cc1noc2nc(-c3ccccc3)cc(Cl)c12
Solvent: O
Product: CCCCNc1cc(-c2ccccc2)nc2onc(C)c12
Temperature: 25 °C

Procedure:
12.2 g. of 4-chloro-3methyl-6-phenylisoxazolo[5,4-b]-pyridine (0.05 mol.) are added to 150 ml. of n-butylamine. The reaction mixture is heated at 150°-160° for 3 hours in an autoclave and, after cooling to room temperature, is evaported in vacuo. The residue is treated with water, filtered off and dried. 14.1 g. (100%) of N-butyl-3-methyl-6-phenylisoxazolo[5,4-b]pyridin-4-amine are recrystallized from a mixture of ligroin and ethylacetate (3:1), m.p. 126°-127°.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]([S:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[C:4](=[O:20])[N:3]=1.[C:21](=O)([O-])[O-].[K+].[K+].CN(C)C=O.IC>CCOC(C)=O>[F:8][C:7]1[C:2](=[NH:1])[N:3]([CH3:21])[C:4](=[O:20])[N:5]([S:9]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)(=[O:10])=[O:11])[CH:6]=1
Reactant: COc1ccc(S(=O)(=O)n2cc(F)c(N)nc2=O)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(S(=O)(=O)n2cc(F)c(=N)n(C)c2=O)cc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 11.7 %

Procedure:
To an 8-mL screw capped vial were added 4-amino-5-fluoro-1-(4-methoxyphenylsulfonyl)pyrimidin-2(1H)-one (0.293 g, 0.979 mmol), anhydrous potassium carbonate (K2CO3; 0.271 g, 1.96 mmol), and N,N-dimethylformamide (DMF; 4 mL), followed by iodomethane (CH3I; 0.208 g, 1.47 mmol). The reaction vessel was sealed, and the reaction mixture was warmed to 60° C. and stirred for 4 h. The reaction mixture was cooled to room temperature, diluted with EtOAc (20 mL), and washed with water (H2O; 3×10 mL). The organic phase was dried over MgSO4, filtered, and the solvent was evaporated under reduced pressure. Purification by flash chromatography (silica gel (SiO2), EtOAc/Hexanes gradient) afforded the title compound as a pale yellow solid (36 milligrams (mg), 12%): mp 158-162° C.; 1H NMR (400 MHz, DMSO-d6) δ 8.01 (d, J=9.22 Hz, 2H), 7.74 (d, J=5.27 Hz, 1H), 7.04 (d, J=9.23 Hz, 2H), 3.90 (s, 3H), 3.31 (s, 3H); ESIMS m/z 314 ([M+H]+).
Reaction SMILES: [F:1][C:2]1[CH:22]=[N:21][CH:20]=[CH:19][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[C:10]([Cl:17])=[CH:9][C:8]=1[OH:18])=O.O1CCCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1>[Cl:17][C:10]1[C:11]([C:13]([F:16])([F:15])[F:14])=[CH:12][C:7]2[N:6]=[C:4]([C:3]3[CH:19]=[CH:20][N:21]=[CH:22][C:2]=3[F:1])[O:18][C:8]=2[CH:9]=1
Reactant: O=C(Nc1cc(C(F)(F)F)c(Cl)cc1O)c1ccncc1F
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Fc1cnccc1-c1nc2cc(C(F)(F)F)c(Cl)cc2o1
Reaction time: 1 h
Yield: 88.4 %

Procedure:
To a mixture of 2.08 g of 3-fluoro-N-[4-chloro-2-hydroxy-5-(trifluoromethyl)phenyl]isonicotinamide, 13 ml of tetrahydrofuran and 1.79 g of triphenylphosphine, 2.98 g of 40% toluene solution of diethyl azodicarboxylate was added dropwise at room temperature. The reaction mixture was stirred for one hour. The reaction mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 1.74 g of 6-chloro-2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 90”).
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[CH:5]1.CN(C)CCN(C)C.C([Li])CCC.[Cl:22][C:23]1[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:24]=1[C:25]([C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=1[Cl:34])=[O:26]>O1CCCC1>[Cl:22][C:23]1[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:24]=1[C:25]([C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=1[Cl:34])([C:5]1[N:4]([CH2:3][O:2][CH3:1])[CH:8]=[CH:7][N:6]=1)[OH:26]
Reactant: O=C(c1ccc(Cl)cc1Cl)c1ccc(Cl)cc1Cl
Reactant: COCn1ccnc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCn1ccnc1C(O)(c1ccc(Cl)cc1Cl)c1ccc(Cl)cc1Cl
Temperature: -60 °C
Reaction time: 1 h

Procedure:
To a solution of 7.6 g (0.0676 mol) of 1-(methoxymethyl)imidazole and 8.1 g (0.0676 mol) of N,N,N',N'-tetramethylethylenediamine in 150 ml of anhydrous tetrahydrofuran were added dropwise under a nitrogen atmosphere at -60° C., 43 ml. (0.070 mol) of n-butyl lithium solution (15% in n-hexane). The solution was stirred at -60° C. for one hour. Then 23 g (0.0676 mol) of 2,2',4,4'-tetrachlorobenzophenone (prepared as described by S. D. Wilson and Yuan Ying Cheng, J. Org. Chem. 5, 223-6 (1940)) in 150 ml. of anhydrous tetrahydrofuran were added dropwise. The solution was stirred another hour at -60° C. and one night at room temperature. The reaction mixture was decomposed with 100 ml. of water and extracted with diethyl ether. The organic phase was dried over sodium sulphate and concentrated and the residue was extracted with a mixture of 2N hydrochloric acid and diethyl ether on which a solid substance was formed, which was crystallised from a mixture of isopropyl alcohol and diethyl ether. The product appeared to be the hydrochloride of the desired compound, contaminated with the compound without methoxymethyl group. Ammonia and diethyl ether were added to liberate the free base. The ethereal phase was concentrated and the residue was four times crystallised from a mixture of isopropyl alcohol and petroleum ether (boiling range 60°-80° C.). α,α-Bis-(2,4-dichlorophenyl)-1-(methoxymethyl)imidazole-2-methanol was obtained. Melting point 145.5°-146° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([C:11]2[N:18]3[C:14]([S:15][CH:16]=[C:17]3[CH3:19])=[N:13][CH:12]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:20][Mg]Br.[NH4+].[Cl-]>C1COCC1>[CH3:20][C:9]([CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([C:11]1[N:18]2[C:14]([S:15][CH:16]=[C:17]2[CH3:19])=[N:13][CH:12]=1)[OH:10]
Reactant: C[Mg]Br
Reactant: Cc1csc2ncc(C(=O)CCc3ccccc3)n12
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1csc2ncc(C(C)(O)CCc3ccccc3)n12

Procedure:
A solution of (2-Phenylethyl)-3-methylimidazo[2,1-b]thiazol-5-yl methanone (Formula B-6) (0.40 g) in THF (6 mL) was treated with 3M ethereal methyl magnesium bromide (0.6 mL) and reacted for 18 hours. The suspension was treated with 5% NH4Cl solution and precipitated α,3-Dimethyl-α-(2-phenylethyl)imidazo[2,1-b]thiazole-5-methanol (Formula B-7) was extracted into ethyl acetate. The extract was dried and evaporated to a viscous residue which deposited α,3-Dimethyl-α-(2-phenylethyl)imidazo[2,1-b]thiazole-5-methanol (Formula B-7) (0.25 g) by ether trituration. Crystallization of the filter cake from ethyl acetate gave pure α,3-Dimethyl-α-(2-phenylethyl)imidazo[2,1-b]thiazole-5-methanol (Formula B-7) (0.13 g), m.p. 131-133°.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=2)[N:11]([CH2:22][C:23](O)=[O:24])[C:10](=[O:26])[CH:9]1[CH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)=O)(C)(C)C.[NH2:33][C:34]1[CH:35]=[C:36]2[C:49](=[CH:50][CH:51]=1)[CH2:48][C@:38]1([C:46]3[C:41](=[N:42][CH:43]=[CH:44][CH:45]=3)[NH:40][C:39]1=[O:47])[CH2:37]2.Cl.C(N=C=NCCCN(C)C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[F:20][C:18]1[CH:19]=[C:14]([CH:12]2[N:11]([CH2:22][C:23]([NH:33][C:34]3[CH:35]=[C:36]4[C:49](=[CH:50][CH:51]=3)[CH2:48][C@:38]3([C:46]5[C:41](=[N:42][CH:43]=[CH:44][CH:45]=5)[NH:40][C:39]3=[O:47])[CH2:37]4)=[O:24])[C:10](=[O:26])[CH:9]([CH:27]3[CH2:28][CH2:29][O:30][CH2:31][CH2:32]3)[NH:8][CH2:13]2)[CH:15]=[C:16]([F:21])[CH:17]=1
Reactant: Nc1ccc2c(c1)C[C@@]1(C2)C(=O)Nc2ncccc21
Reactant: CC(C)(C)OC(=O)N1CC(c2cc(F)cc(F)c2)N(CC(=O)O)C(=O)C1C1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(CN1C(=O)C(C2CCOCC2)NCC1c1cc(F)cc(F)c1)Nc1ccc2c(c1)C[C@@]1(C2)C(=O)Nc2ncccc21
Temperature: 50 °C
Reaction time: 1 h

Procedure:
0.10 g (0.22 mmol) 2-(4-(tert-butoxycarbonyl)-6-(3,5-difluorophenyl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)ethanoic acid (isomer mixture 1.1.1), 60 mg (0.24 mmol) (R)-5-amino-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one, 58 mg (0.30 mmol) 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide-hydrochloride, 41 mg (0.30 mmol) HOBT, 0.03 ml (0.24 mmol) TEA and 1.5 ml DMF were stirred overnight at RT. The reaction mixture was concentrated by rotary evaporation. The residue was stirred with 15 ml of a 1.25M methanolic hydrochloric acid solution for 1 h at 50° C. The mixture was concentrated by rotary evaporation and the residue was purified by HPLC. The product-containing fractions were combined and lyophilised. The product was obtained as an isomer mixture.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:10][C:11]2[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:12]=2[N:13]=1.[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=1[CH2:28]Br>>[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=1[CH2:28][N:13]1[C:12]2[CH:14]=[C:15]([CH3:19])[CH:16]=[C:17]([CH3:18])[C:11]=2[N:10]=[C:9]1[C:3]1[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=1[F:1]
Reactant: Fc1cccc(F)c1CBr
Reactant: Cc1cc(C)c2[nH]c(-c3c(F)cccc3F)nc2c1
Product: Cc1cc(C)c2nc(-c3c(F)cccc3F)n(Cc3c(F)cccc3F)c2c1
Yield: 91.2 %

Procedure:
To 2-(2,6-difluorophenyl)-4,6-dimethylbenzimidazole (Example 94) (0.50 g, 1.94 mmol) was added 2,6-difluoro-α-bromotoluene (0.52 g, 2.51 mmol, 130 M%). Flash chromatography of the crude product eluting with 2% methanol/CH2Cl2, and recrystallization from hexane gave white crystals of 1-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-4,6-dimethylbenzimidazole (0.68 g, 1.77 mmol, 91% yield). 1H NMR (200 MHz, CD2Cl2): δ7.51 (cm, 1H, H4), 7.23 (m, 1H, H4″), 7.11 (m, 1H, H5), 7.05 (cm, 2H, H3′,5′), 6.93 (m, 1H, H7), 6.80 (cm, 2H, H3″,5″), 5.29 (s, 2H, CH2PhF2), 2.58 (s, 3H, CH3), 2.44 (s, 3H, CH3).
Reaction SMILES: [CH3:1][CH2:2][C@H:3]1[O:18][C:16](=[O:17])[C@H:15]([CH3:19])[C@@H:14]([O:20][C@@H:21]2[O:26][C@@H:25]([CH3:27])[C@H:24]([OH:28])[C@@:23]([O:30][CH3:31])([CH3:29])[CH2:22]2)[C@H:13]([CH3:32])[C@@H:12]([O:33][C@@H:34]2[O:39][C@H:38]([CH3:40])[CH2:37][C@H:36]([N:41]([CH3:43])[CH3:42])[C@H:35]2[OH:44])[C@@:11]([OH:46])([CH3:45])[CH2:10][C@@H:9]([CH3:47])[C:7](=[O:8])[C@H:6]([CH3:48])[C@@H:5]([OH:49])[C@@:4]1([OH:51])[CH3:50].[BH4-].[Na+]>C1COCC1>[CH3:1][CH2:2][C@H:3]1[O:18][C:16](=[O:17])[C@H:15]([CH3:19])[C@@H:14]([O:20][C@@H:21]2[O:26][C@@H:25]([CH3:27])[C@H:24]([OH:28])[C@@:23]([O:30][CH3:31])([CH3:29])[CH2:22]2)[C@H:13]([CH3:32])[C@@H:12]([O:33][C@@H:34]2[O:39][C@H:38]([CH3:40])[CH2:37][C@H:36]([N:41]([CH3:42])[CH3:43])[C@H:35]2[OH:44])[C@@:11]([OH:46])([CH3:45])[CH2:10][C@@H:9]([CH3:47])[C@H:7]([OH:8])[C@H:6]([CH3:48])[C@@H:5]([OH:49])[C@@:4]1([OH:51])[CH3:50]
Reactant: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(O)C[C@@H](C)C(=O)[C@H](C)[C@@H](O)[C@]1(C)O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(O)C[C@@H](C)[C@H](O)[C@H](C)[C@@H](O)[C@]1(C)O
Temperature: 0 °C
Reaction time: 3 h
Yield: 58 %

Procedure:
To a solution of erythromycin A (22.0 g, 30 mmol) in THF (200 mL) cooled to −10° C. was added NaBH4 (2.27 g, 60 mmol) in small portions. The mixture was then allowed to stir at 0° C. for 3 h before the reaction was quenched with water. After evaporation of the majority of the solvent, dilute NaHCO3 solution was added, the mixture was extracted three times with EtOAc. The combined organic layers were washed with water and brine, dried over MgSO4. The crude product was purified by silica gel chromatography using 2:1 hexane-acetone with 1% Et3N to give pure product (12.8 g, 58% yield). m/z: 736.5 (MH); 13C-NMR (CDCl3): 177.00, 103.21, 96.32, 84.20, 83.10, 79.23, 77.72, 77.63, 74.99, 74.48, 72.66, 70.75, 70.69, 69.29, 66.09, 65.02, 49.32, 45.52, 41.73, 40.32 (2×), 36.91, 34.84, 34.23, 31.97, 28.81, 25.25, 21.68, 21.51, 21.18, 20.06, 18.12, 16.50, 15.06, 14.80, 10.81, 9.36.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([O-:13])=O)[S:10][C:3]=12.[Li+].S(Cl)(Cl)=O.C(Cl)Cl.[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:13])[S:10][C:3]=12
Reactant: O=C([O-])c1cc2nccc(Cl)c2s1
Reactant: C1CCNC1
Agent: [Li+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: O=C(c1cc2nccc(Cl)c2s1)N1CCCC1
Yield: 57.4 %

Procedure:
A solution of lithium 7-chloro-thieno[3,2-b]pyridine-2-carboxylate (0.50 g, 2.4 mmol), thionyl chloride (3.5 mmol, 1.8 ml), CH2Cl2 (20 ml), and DMF (0.2 ml) was heated to reflux. After 3 h the resulting yellow solution was concentrated under reduced pressure, and the residue was suspended in CH2Cl2 (20 mL). Pyrrolidine (2.35 mmol, 167 mg) was then added dropwise. After 12h the reaction mixture was concentrated onto silica gel (5 mL) and purified by flash chromatography on silica gel eluting with CH2Cl2/MeOH (97/3) to afford the title compound as a white solid (360 mg, 57%). MS: 266.9/268.9 (MH+); HPLC Rf: 4.51 min; HPLC purity: 98%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([CH3:27])([CH3:26])[C:12]([NH:14][NH:15][C:16](=[S:25])[NH:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[OH-].[Na+].Cl>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([C:12]2[N:17]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[C:16](=[S:25])[NH:15][N:14]=2)([CH3:27])[CH3:26])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C(C)(C)C(=O)NNC(=S)Nc2ccc(F)cc2)cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(C(C)(C)c2n[nH]c(=S)n2-c2ccc(F)cc2)cc1OC
Temperature: 25 °C
Yield: 64.8 %

Procedure:
A mixture of 2-(2-(3,4-dimethoxyphenyl)-2-methylpropanoyl)-N-(4-fluorophenyl)-hydrazinecarbothioamide (1.23 g, 3.14 mmol) and 2N NaOH (25 mL) was refluxed overnight. The reaction mixture was cooled to room temperature and acidified with 3N HCl to pH 5. The aqueous solution was extracted with DCM (30 mL×2). The combined organic layers were dried over MgSO4, filtered, and evaporated. The residue was purified by flash chromatography to give the title compound (760 mg, 65%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 12.52 (s, 1H), 6.94-6.90 (m, 2H), 6.70 (d, 1H), 6.60-6.57 (m, 2H), 6.50-6.46 (m, 2H), 3.89 (s, 3H), 3.77 (s, 3H), 1.57 (s, 6H).