Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:26]2[C:31]([CH3:32])=[CH:30][C:29]([OH:33])=[CH:28][C:27]=2[CH3:34])=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.Cl.Cl[CH2:37][C:38]1[CH:43]=[CH:42][N:41]=[C:40]([O:44][CH3:45])[CH:39]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:26]2[C:31]([CH3:32])=[CH:30][C:29]([O:33][CH2:37][C:38]3[CH:43]=[CH:42][N:41]=[C:40]([O:44][CH3:45])[CH:39]=3)=[CH:28][C:27]=2[CH3:34])=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2
Reactant: COc1cc(CCl)ccn1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(O)cc5C)ccc(F)c43)ccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(OCc6ccnc(OC)c6)cc5C)ccc(F)c43)ccc21
Temperature: 60 °C
Reaction time: 24 h

Procedure:
Methyl 2-((S)-6-((R)-7-fluoro-4-(4-hydroxy-2,6-dimethylphenyl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate (Intermediate 28-29) (46.3 mg) and 4-(chloromethyl)-2-methoxypyridine hydrochloride (58.2 mg) were suspended in dimethylformamide (1.8 mL) and potassium carbonate (62 mg) was added. The reaction mixture was shaken for 24 h at 60° C. and than directly chromatographed by HPLC on reversed phase. The product fractions are collected and lyophilized to give the title compound. Yield: 42 mg; LC (method 23): tR=2.21 min; Mass spectrum (ESI+): m/z=584 [M+H]+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([OH:12])=O)[CH:8]=2)[CH:3]=[N:2]1.[CH:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][C:23]1[NH:27][C:26]2[CH:28]=[CH:29][C:30]([NH2:32])=[CH:31][C:25]=2[N:24]=1)([CH3:15])[CH3:14].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[CH:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][C:23]1[NH:24][C:25]2[CH:31]=[C:30]([NH:32][C:10]([C:7]3[CH:8]=[C:9]4[C:4]([CH:3]=[N:2][NH:1]4)=[CH:5][CH:6]=3)=[O:12])[CH:29]=[CH:28][C:26]=2[N:27]=1)([CH3:15])[CH3:14]
Reactant: O=C(O)c1ccc2cn[nH]c2c1
Reactant: CC(C)c1ccccc1Nc1nc2cc(N)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CC(C)c1ccccc1Nc1nc2ccc(NC(=O)c3ccc4cn[nH]c4c3)cc2[nH]1

Procedure:
Methyl Indazole-6-carboxylate (4 mmol; Batt et al., J. Med. Chem. 2000, 43, 41-58) was hydrolyzed as in general procedure C to obtain 1H-Indazole-6-carboxylic acid. The carboxylic acid (0.5 mmol) was coupled with aforementioned N2-(2-isopropylphenyl)-1H-benzimidazole-2,5-diamine (0.5 mmol) using HBTU as described in general procedure D to yield 1H-indazole-6-carboxylic acid [2-(2-isopropylphenylamino)-3H-benzimidazol-5-yl]-amide as an off-white solid. MS: m/z 411 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[C:7]2[C:3]=1[CH:4]=[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[NH:6]2.C(O)(=O)C>[Fe].O>[NH2:11][C:8]1[CH:9]=[CH:10][C:2]([Cl:1])=[C:3]2[C:7]=1[NH:6][C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:4]2
Reactant: CCOC(=O)c1cc2c(Cl)ccc([N+](=O)[O-])c2[nH]1
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1cc2c(Cl)ccc(N)c2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 16.8 %

Procedure:
A stirred solution of 2.68 grams (0.01 mole) of 4-chloro-2-ethoxycarbonyl-7-nitroindole, 80 mL of acetic acid, and 15 mL of water was heated to 65° C., and 18.3 grams (0.048 mole) of iron powder was slowly added during a 20 minute period. Upon completion of addition, the reaction mixture was allowed to cool to 25° C. where it stirred for one hour. After this time, the reaction mixture was poured into water, and the resulting mixture was filtered through diatomaceous earth. The filter cake was washed thoroughly with ethyl acetate. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure a residue. The residue was purified by column chromatography, yielding 0.4 gram of title compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][CH:2]([S:4]([NH:7][CH:8]1[CH2:12][CH2:11][CH2:10][C:9]1=[O:13])(=[O:6])=[O:5])[CH3:3].[F:14][C:15]1[CH:20]=[CH:19][C:18]([Mg]Br)=[CH:17][CH:16]=1.[Cl-].[NH4+]>C1COCC1.O>[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:9]2([OH:13])[CH2:10][CH2:11][CH2:12][CH:8]2[NH:7][S:4]([CH:2]([CH3:1])[CH3:3])(=[O:6])=[O:5])=[CH:17][CH:16]=1
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: CC(C)S(=O)(=O)NC1CCCC1=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)S(=O)(=O)NC1CCCC1(O)c1ccc(F)cc1
Temperature: 25 °C

Procedure:
Scheme IA, step D: Into a flame dried 100 mL 3 neck flask that was fitted with a thermometer and condenser, 2-{[(methylethyl)sulfonyl]amino}cyclopentan-1-one (1.10 g, 5.36 mmol) in THF (25 mL) was added dropwise to 4-fluorophenylmagnesium bromide (3 mL, 2M solution in diethyl ether) while stirring at room temperature under a nitrogen atmosphere and keeping the temperature above 25° C. After the addition was complete, the reaction was refluxed for 2 hours and then stirred overnight at room temperature. In the morning, enough saturated ammonium chloride in water was added to precipitate the salts and the organic layer was decanted off. The remaining salts were washed two times with ether and the combined organic layers were concentrated under reduced vacuum. The resulting material was taken into ethyl acetate, washed once with water, dried over potassium carbonate, filtered, and concentrated under reduced vacuum to yield 930 mg of a dark oil. This isomeric mixture was purified via silica gel chromatography employing the Chromatotron® and using a 4000 micron rotor while eluting with a solvent of hexane/ethyl acetate 7:3 to provide the title compound (787 mg, 49%) as an oil. Ion Spray M.S. 300.1 (M*−1). Calculated for C14H20NO3SF—½H2O: Theory: C, 54.16; H, 6.82; N, 4.51. Found: C, 54.39; H, 6.61; N, 4.69.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]=[N:5][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:7][CH:8]=1.[NH:15]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:26]([O:25][C:23]([N:15]([CH2:2][C:3]1[N:4]=[N:5][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:7][CH:8]=1)[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:24])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)NC(=O)OC(C)(C)C
Reactant: BrCc1ccc(-c2ccccc2)nn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N(Cc1ccc(-c2ccccc2)nn1)C(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 2 h
Yield: 96.9 %

Procedure:
To a solution of 3-bromomethyl-6-phenylpyridazine (120 mg, 0.482 mmol) obtained in Reference Example 2-(a) in N,N-dimethylformamide (1.57 ml) were added di-tert-butyl iminodicarboxylate (127 mg, 0.585 mmol) and potassium carbonate (134 mg, 0.970 mmol), followed by stirring at 50° C. for 2 hours. After completion of the reaction, water was added to the reaction solution, followed by extraction with ethyl acetate. The separated organic layer was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (eluent; hexane:ethyl acetate=2:1→1:1 (UV)), and fractions containing the desired compound were concentrated under reduced pressure to afford the title compound (180 mg) as a slightly yellow solid. (Yield: 97%)
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:6]2[CH:17]=[CH:16][N:15]([C@@H:18]3[O:38][C@H:37]([CH2:39][O:40][CH2:41][C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[C@@H:28]([O:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C@@H:19]3[O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:7]=2[N:8]=[C:9](S(C)(=O)=O)[N:10]=1)[CH:2]=[CH2:3].[NH3:48]>>[NH2:48][C:9]1[N:10]=[C:5]([O:4][CH2:1][CH:2]=[CH2:3])[C:6]2[CH:17]=[CH:16][N:15]([C@@H:18]3[O:38][C@H:37]([CH2:39][O:40][CH2:41][C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[C@@H:28]([O:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C@@H:19]3[O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:7]=2[N:8]=1
Reactant: N
Reactant: C=CCOc1nc(S(C)(=O)=O)nc2c1ccn2[C@@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Product: C=CCOc1nc(N)nc2c1ccn2[C@@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Temperature: 100 °C

Procedure:
A mixture of 13.5 g of 4-allyloxy-2-methylsulfonyl-7-(2,3,5-tri-O-benzyl-β-D-arabinofuranosyl)-7H-pyrrolo-[2,3-d]pyrimidine and 250 ml of liquid ammonia is heated at 100° C. for 2 hours and allowed to evaporate in a stream of nitrogen. The residue is dissolved in ethyl acetate and chromatographed over silica gel with ethyl acetate to provide 9.3 g of pure 2-amino-4-allyloxy-7-(2,3,5-tri-O-benzyl-β-D-arabinofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([NH2:16])=[C:11]([NH2:17])[CH:10]=1.[O:18]1[C:22]2([CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[CH2:21][C:20]([CH:28]=O)=[N:19]1.O>CN(C=O)C>[CH3:15][C:13]1[C:12]2[NH:16][C:28]([C:20]3[CH2:21][C:22]4([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]4)[O:18][N:19]=3)=[N:17][C:11]=2[CH:10]=[C:9]([C:3]2[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=2[F:8])[CH:14]=1
Reactant: Cc1cc(-c2c(F)cccc2F)cc(N)c1N
Reactant: O=CC1=NOC2(CCCCC2)C1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(-c2c(F)cccc2F)cc2nc(C3=NOC4(CCCCC4)C3)[nH]c12
Temperature: 100 °C
Yield: 38 %

Procedure:
2′,6′-Difluoro-5-methyl-biphenyl-3,4-diamine (186 mg, 0.792 mmol, as prepared in the previous step) was placed in an 8 mL vial equipped with a stir bar, and dry DMF (2 mL) was added. 1-Oxa-2-aza-spiro[4.5]dec-2-ene-3-carbaldehyde (122 mg, 0.730 mmol, as prepared in step B of this Example) was added as a solution in DMF (2 mL). Solid Na2S2O5 (153 mg, 0.803 mmol) was added, and the mixture was heated to 100° C. for 4 h. The cooled mixture was poured into water (100 mL) and extracted three times with EtOAc (50 mL). The combined organic extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. The residue was purified by column chromatography using a 4-g SiO2 pre-packed column eluting with EtOAc/hexanes, 0:1 to 3:17, v/v over 30 min, yielding 105 mg (38%) of the title compound. 1H-NMR (400 MHz, d6-DMSO) δ: 7.43-7.55 (m, 2H), 7.15-7.30 (m, 3H), 3.35 (s, 2H), 2.61 (s, 3H), 1.63-1.83 (m, 6H), 1.34-1.57 (m, 4H). Mass Spectrum (LCMS, ESI pos.): Calcd. for C22H21F2N3O: 382.2 (M+H). found: 382.2.
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](F)=[CH:5][CH:4]=1)#[N:2].[C:14]1([N:20]2[C:24]3([CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[C:23](=[O:30])[NH:22][CH2:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[O:30]=[C:23]1[C:24]2([CH2:25][CH2:26][N:27]([C:6]3[C:7]4[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)[CH2:28][CH2:29]2)[N:20]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:21][NH:22]1
Reactant: N#Cc1ccc(F)c2ccccc12
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Product: N#Cc1ccc(N2CCC3(CC2)C(=O)NCN3c2ccccc2)c2ccccc12
Yield: 15.6 %

Procedure:
The title compound (7 mg, 16% yield) was prepared as described for 196MBT2-4 from 1-cyano-4-fluoronaphthalene (20 mg, 0.117 mmol) and 1-phenyl-1,3,8-triazaspiro-[4,5]decan-4-one (108 mg, 0.468 mmol).
Reaction SMILES: [CH2:1]([CH:3]([CH2:15][CH3:16])[CH2:4][NH:5][CH2:6][C:7]1[S:11][C:10](B(O)O)=[CH:9][CH:8]=1)[CH3:2].Br[C:18]1[CH:19]=[C:20]2[C:24](=[C:25]([C:27]([NH2:29])=[O:28])[CH:26]=1)[NH:23][CH:22]=[C:21]2[CH:30]1[CH2:35][CH2:34][N:33]([S:36]([CH2:39][CH3:40])(=[O:38])=[O:37])[CH2:32][CH2:31]1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([CH:3]([CH2:15][CH3:16])[CH2:4][NH:5][CH2:6][C:7]1[S:11][C:10]([C:18]2[CH:19]=[C:20]3[C:24](=[C:25]([C:27]([NH2:29])=[O:28])[CH:26]=2)[NH:23][CH:22]=[C:21]3[CH:30]2[CH2:31][CH2:32][N:33]([S:36]([CH2:39][CH3:40])(=[O:37])=[O:38])[CH2:34][CH2:35]2)=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCC(CC)CNCc1ccc(B(O)O)s1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCC(CC)CNCc1ccc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)s1
Temperature: 150 °C
Reaction time: 0.13 h

Procedure:
To a CEM microwave tube containing the crude (5-{[(2-ethylbutyl)amino]methyl}-2-thienyl)boronic acid (48 mg, 0.199 mmol) was added a solution of 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (65 mg, 0.157 mmol) in dioxane (1.75 mL), a solution of K2CO3 (130 mg, 0.942 mmol) in H2O (0.25 mL), and tetrakis(triphenylphosphine)palladium(0) (9 mg, 0.0079 mmol). The reaction was heated in a CEM microwave for 30 min at 150° C. The reaction mixture was filtered through a 2 g SCX cartridge (pre-equilibrated with 3 mL MeOH), eluting in sequence with MeOH (3 mL) and a 2 M solution of NH3/MeOH (9 mL). The NH3/MeOH fraction was dried under a stream of nitrogen at 50° C., and the crude product was taken up in dimethyl sulfoxide (1.1 mL) and purified on an Agilent MDAP (Zorbax Eclipse XDB-C18 column: 21.2×100 mm) eluting at 20 mL per min for 1 min with 10% CH3CN/H2O (0.1% TFA) then a linear gradient of 10% CH3CN/H2O (0.1% TFA) to 95% CH3CN/H2O (0.1% TFA) over 8 min and holding at the final concentration for 30 sec. The fractions containing product were filtered through a 2 g Pharmasil CHQAX column (polymer bound ammonium hydroxide; United Chemical Technologies) to remove TFA and concentrated under a stream of nitrogen at 50° C. to give impure title compound. The impure title compound was repurified on an Agilent MDAP and free based with the ammonium hydroxide column as shown above to give 8.5 mg of the title compound (10%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:4][C:5]([N:18]2[CH:22]=[N:21][N:20]=[N:19]2)=[C:6]([C:13](OCC)=[O:14])[C:7]=1[C:8](OCC)=[O:9].O.[NH2:30][NH2:31]>C(O)C>[NH2:1][C:2]1[C:7]2[C:8](=[O:9])[NH:31][NH:30][C:13](=[O:14])[C:6]=2[C:5]([N:18]2[CH:22]=[N:21][N:20]=[N:19]2)=[N:4][C:3]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NN
Reactant: CCOC(=O)c1c(-n2cnnn2)nc(-c2ccccc2)c(N)c1C(=O)OCC
Solvent: CCO
Solvent: O
Product: Nc1c(-c2ccccc2)nc(-n2cnnn2)c2c(=O)[nH][nH]c(=O)c12

Procedure:
In 2 ml of ethanol was dissolved 0.172 g of 3-amino-4,5-diethoxycarbonyl-2-phenyl-6-(tetrazol-1-yl)pyridine, whereto 1 ml of hydrazine monohydrate was added. The mixture was reacted at 90° C. for 2 hours. After 15 ml of ethanol was added, the mixture was cooled. The precipitate was collected by filtration and washed with ethanol. The thus-obtained precipitate was dissolved in 20 ml of hot water, and 0.7 ml of acetic acid was added. The mixture was cooled, and the resulting precipitate was collected by filtration, washed and dried, to give 0.11 g of the title compound as yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:10](=[CH:11][N:12]=1)[N:9]([CH3:13])[C:8](=[O:14])[CH2:7][CH2:6][N:5]2[CH2:15][C:16]1C(C)=NOC=1C.Cl.ClCC[N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.[H-].[Na+]>>[Cl:1][C:2]1[N:3]=[C:4]2[C:10]([N:9]([CH3:13])[C:8](=[O:14])[CH2:7][CH2:6][N:5]2[CH2:15][CH2:16][N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[CH:11][N:12]=1
Reactant: Cc1noc(C)c1CN1CCC(=O)N(C)c2cnc(Cl)nc21
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: CN1C(=O)CCN(CCN2CCOCC2)c2nc(Cl)ncc21

Procedure:
The title compound was prepared by an analogous method to the preparation of Intermediate 156, on a 0.3 mmol scale, utilising N-(2-chloroethyl)morpholine hydrochloride (Aldrich; 67 mg, 0.36 mmol) and Sodium Hydride (60% mineral oil dispersion; 36 mg, 0.75 mmol), as a solid (95 mg, 97%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([CH3:11])[CH:3]=1.[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1/[CH:17]=[CH:18]/[S:19]([NH2:22])(=[O:21])=[O:20].BrC1SC=CC=1.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1.CN(C)C=O>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:22][S:19](/[CH:18]=[CH:17]/[C:13]2[S:12][CH:16]=[CH:15][CH:14]=2)(=[O:21])=[O:20])=[O:8])=[C:4]([CH3:11])[CH:3]=1
Reactant: NS(=O)(=O)/C=C/c1cccs1
Reactant: Cc1cc(F)ccc1C(=O)O
Agent: Brc1cccs1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cc(F)ccc1C(=O)NS(=O)(=O)/C=C/c1cccs1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 4-fluoro-2-methyl-benzoic acid (197 mg, 1.27 mmol) and (E)-2-thiophen-2-yl-ethenesulfonic acid amide (155 mg, 0.82 mmol) (which was prepared analogously to example 1-1 steps i) to ii) starting from 2-bromo-thiophene) in dichloromethane (5 mL) and N,N-dimethylformamide (DMF) (2 mL) is added 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (EDCI) (277 mg, 1.45 mmol) and 4-(dimethylamino)-pyridine (DMAP) (172 mg, 1.41 mmol) at room temperature (RT). The mixture was stirred at RT for 24 h, and solvent removed under reduced pressure. The crude reaction mixture is partitioned between aq. 1M HCl (25 mL) and ethyl acetate (25 mL). The organic phase is separated and washed with aq. 1M HCl (2×25 mL), and then with sat. aq. K2CO3 solution (3×25 mL) and dried (sodium sulfate) and concentrated in vacuo. After flash chromatography (heptane/ethyl acetate 3:1 to 1:1) ((E)-2-Thiophen-2-yl-ethenesulfonic acid 4-fluoro-2-methyl-benzoylamide can be isolated as a white solid. Yield 65 mg (15%)
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:5]=[CH:6][C:7]([C:10]([O:12]C)=[O:11])=[N:8][CH:9]=1.O.O.[OH-].[Li+]>O1CCOCC1>[CH3:1][O:2][CH2:3][C:4]1[N:5]=[CH:6][C:7]([C:10]([OH:12])=[O:11])=[N:8][CH:9]=1
Reactant: COCc1cnc(C(=O)OC)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COCc1cnc(C(=O)O)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl 5-(methoxymethyl)pyrazine-2-carboxylate, 8-(1), (55 mg, crude) was dissolved in 1,4-dioxane (1 mL) and water (1 mL) was added followed by lithium hydroxide monohydrate (50 mg). After stirring at RT for 1 h, water (20 mL) was added and the mixture was extracted with ether (20 mL). The aqueous portion was acidified to pH 2 and extracted with EtOAc (2×25 mL). The combined EtOAc layers were dried over MgSO4 and evaporated to afford the title compound (19 mg). 1H NMR (400 MHz, CDCl3) δ ppm 3.58 (s, 3 H), 4.77 (s, 2 H), 8.80 (br. s., 1 H), 9.38 (br. s., 1 H)
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH2:10][C@@H:11]1[O:15]C(C)(C)[N:13]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[C@H:12]1[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([CH3:41])[N:36]=2)=[CH:31][CH:30]=1)=O)(C)(C)C.CO.Cl>C1COCC1>[NH2:8][C@@H:9]([CH2:42][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)[CH2:10][C@H:11]([OH:15])[C@@H:12]([NH:13][C:18](=[O:19])[O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH2:28][C:29]1[CH:30]=[CH:31][C:32]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([CH3:41])[N:36]=2)=[CH:33][CH:34]=1
Reactant: Cc1cccc(-c2ccc(C[C@H]3[C@H](C[C@H](Cc4ccccc4)NC(=O)OC(C)(C)C)OC(C)(C)N3C(=O)OCc3ccccc3)cc2)n1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cccc(-c2ccc(C[C@H](NC(=O)OCc3ccccc3)[C@@H](O)C[C@@H](N)Cc3ccccc3)cc2)n1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
A solution containing the product from Example 68B (0.07 g, 0.108 mmol) in a mixture of THF (0.5 mL), methanol (0.3 mL), and aqueous HCl (0.5 mL, 1 N) was stirred at 50° C. for 16 hours. The solvent was removed under reduced pressure to give the title compound as the hydrochloride salt, which was used without further purification.
Reaction SMILES: [OH:1][CH:2]([C:6](=[CH2:10])[CH2:7][CH2:8][CH3:9])[CH2:3][C:4]#[CH:5].N1C=CN=C1.[CH2:16]([Si:18]([CH2:22][CH3:23])([CH2:20][CH3:21])Cl)[CH3:17].O>CN(C)C=O>[CH2:10]=[C:6]([CH2:7][CH2:8][CH3:9])[CH:2]([O:1][Si:18]([CH2:22][CH3:23])([CH2:20][CH3:21])[CH2:16][CH3:17])[CH2:3][C:4]#[CH:5]
Reactant: CC[Si](Cl)(CC)CC
Reactant: C#CCC(O)C(=C)CCC
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: C#CCC(O[Si](CC)(CC)CC)C(=C)CCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 30.0 g. of 4-hydroxy-5-methylene-1-octyne and 31.02 g. of imidazole in 80 ml of dimethylformamide at 0° C., is added 40.9 g. of triethychlorosilane. The mixture is stirred at room temperature for 30 minutes, poured into cold water and extracted with petroleum ether. The petroleum ether is removed and the residue is distilled. The product is recovered in the fraction boiling at 103°-106° C. (1.5 mm.).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([Cl:15])[C:12]([OH:16])=[C:11]([Cl:17])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([Cl:17])[C:12]([O:16][CH2:19][CH2:20][CH2:21][O:22][C:23]2[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=2)=[C:13]([Cl:15])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1ccc(OCCCBr)cc1
Reactant: Oc1c(Cl)cc(OCc2ccccc2)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ccc(OCCCOc2c(Cl)cc(OCc3ccccc3)cc2Cl)cc1
Temperature: 25 °C
Yield: 79.9 %

Procedure:
To a mixture of 5.0 g of 4-benzyloxy-2,6-dichlorophenol, 4.7 g of 1-bromo-3-(4-chlorophenoxy)propane and 30 ml of N,N-dimethylformamide was added 2.7 g of potassium carbonate with stirring at room temperature. After stirring at room temperature for 12 hours, the reaction solution was poured into iced water and extracted twice with 200 ml of diethyl ether. The ether layers were combined, washed with water, dried over anhydrous magnesium sulfate and then concentrated to obtain a crude product. This crude product was subjected to silica gel chromatography to give 6.5 g of 4-benzyloxy-1-(3-(4-chlorophenoxy)propyloxy)-2,6-dichlorobenzene(yield: 85 %).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:7][CH:6]=1)=[O:4].[Br:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.CC(=O)OCC>C(#N)C>[Br:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([O:26][CH2:2][C:3]([C:5]2[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:7][CH:6]=2)=[O:4])=[O:25])=[CH:22][CH:21]=1
Reactant: O=C(O)c1ccc(Br)cc1
Reactant: CCCCCCCOc1ccc(C(=O)CBr)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCCCCCCOc1ccc(C(=O)COC(=O)c2ccc(Br)cc2)cc1
Reaction time: 8 h
Yield: 57 %

Procedure:
To a solution of 2-bromo-1-(4-(heptyloxy)phenyl)ethanone INT-4 (1.3 g, 4.2 mmol) and 4-bromobenzoic acid (0.70 g, 3.5 mmol) in ACN (30 mL) was added TEA (0.72 ml, 5.2 mmol). After stirring overnight, the mixture was poured onto aq. citric acid and EA then stirred for 10 min before the solid was collected by filtration. The cake was washed with water and iso-hexanes then dried to provide 905 mg (57%) of 2-(4-(heptyloxy)phenyl)-2-oxoethyl 4-bromobenzoate. LCMS-ESI (m/z) calculated for C22H25BrO4, 432.1. found 433.2 [M+H]+, tR=3.24 min (Method 8).