Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[N:21]=[C:20]4[N:22]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[C:23]([O:25][C@@H:26]5[CH2:30][O:29][C@@H:28]6[C@H:31]([O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[CH2:32][O:33][C@H:27]56)=[N:24][C:19]4=[CH:18][C:17]=3[Cl:50])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCCC1>[Si:35]([O:34][C@H:31]1[C@H:28]2[O:29][CH2:30][C@@H:26]([O:25][C:23]3[N:22]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[C:20]4=[N:21][C:16]([C:13]5[CH:14]=[CH:15][C:10]([C@H:7]6[CH2:8][CH2:9][C@H:4]([NH2:1])[CH2:5][CH2:6]6)=[CH:11][CH:12]=5)=[C:17]([Cl:50])[CH:18]=[C:19]4[N:24]=3)[C@H:27]2[O:33][CH2:32]1)([C:38]([CH3:40])([CH3:41])[CH3:39])([CH3:37])[CH3:36]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2cc(Cl)c(-c3ccc([C@H]4CC[C@H](N=[N+]=[N-])CC4)cc3)nc2n1COCC[Si](C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2cc(Cl)c(-c3ccc([C@H]4CC[C@H](N)CC4)cc3)nc2n1COCC[Si](C)(C)C
Temperature: 40 °C
Reaction time: 24 h

Procedure:
5-(4-((trans)-4-Azidocyclohexyl)phenyl)-2-((3R,3aR,6R,6aS)-6-(tert-butyldimethyl-silyloxy)hexahydrofuro[3,2-b]furan-3-yloxy)-6-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridine (130 mg) is dissolved in tetrahydrofurane (1 mL), treated with triphenylphosphine (57 mg) and stirred for 24 hours at 40° C. Then water (220 μL) is added and the mixture is stirred for 12 hours at 80° C. The mixture is partitioned between ethylacetate and saturated aqueous NH4Cl solution. The organic phase is dried (MgSO4) and concentrated. The residue is purified by HPLC on reversed phase to give the product, which is partitioned between 1 M aqueous NaOH solution and ethylacetate. The organic phase is washed with brine and dried (MgSO4). The residue is concentrated to give the title compound. LC (method 1): tR=1.24 min; Mass spectrum (ESI+): m/z=715 [M+H]+.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:21])=[C:11]([F:20])[C:12]=3[C:14]#[C:15][Si](C)(C)C)[C:7](=[O:22])[C:6]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:5]2)[CH2:3][CH2:2]1.[F-].[K+].C(Cl)(Cl)Cl.O>CN(C)C=O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:21])=[C:11]([F:20])[C:12]=3[C:14]#[CH:15])[C:7](=[O:22])[C:6]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(C#C[Si](C)(C)C)c(F)c(F)cc2c1=O
Agent: [F-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CN(C)C=O
Product: C#Cc1c(F)c(F)cc2c(=O)c(C(=O)OCC)cn(C3CC3)c12
Yield: 58.8 %

Procedure:
18.8 g of ethyl 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-(trimethylsilylethinyl)-4-oxo-3-quinolinecarboxylate and 9.7 g of potassium fluoride are stirred for 3 hours at room temperature in a mixture of 300 ml of dimethylformamide, 200 ml of chloroform and 15 ml of water. The mixture is then filtered, the filtrate is treated with 120 ml of water, and the mixture is acidified with dilute aqueous hydrochloric acid. After extraction by shaking with chloroform, the organic phase is dried over sodium sulphate and concentrated. The residue obtained is recrystallised from methanol. In this way, 9 g of ethyl 1-cyclopropyl-8-ethinyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate (59% of theory) are obtained.
Reaction SMILES: [CH2:1]([C:3]1[CH:10]=[C:9]([OH:11])[CH:8]=[C:7]([CH2:12][CH3:13])[C:4]=1[CH:5]=[O:6])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:20]([O:11][C:9]1[CH:8]=[C:7]([CH2:12][CH3:13])[C:4]([CH:5]=[O:6])=[C:3]([CH2:1][CH3:2])[CH:10]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCc1cc(O)cc(CC)c1C=O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCc1cc(OCc2ccccc2)cc(CC)c1C=O

Procedure:
4-Benzyloxy-2,6-diethyl-benzaldehyde was prepared from 2,6-diethyl-4-hydroxy-benzaldehyde, cesium carbonate and benzyl bromide in analogy to Example 213b): yellow oil; 1H-NMR (CDCl3): 1.25 (6H, t, 2×CH3), 2.98 (4H, q, 2×CH2), 5.12 (2H, s, OCH2), 6.72 (2H, s, 2×ArH), 7.33-7.45 (5H, m, Ph), 10.47 (1H, s, CH═O).
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[CH:7]([NH:14][S:15]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[CH:20][CH:19]=1)(=[O:17])=[O:16])CCCC(=O)C)([CH3:4])([CH3:3])[CH3:2].[CH3:34][C:35](C)([O-:37])[CH3:36].[K+].Cl.[CH2:41]1COC[CH2:42]1>O>[C:1]([O:5][C:6]([CH:7]1[C:35]([OH:37])([CH3:36])[CH2:34][CH2:42][CH2:41][N:14]1[S:15]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)=[CH:20][CH:19]=1)(=[O:16])=[O:17])=[O:33])([CH3:2])([CH3:3])[CH3:4]
Reactant: C1CCOC1
Reactant: CC(C)(C)[O-]
Reactant: CC(=O)CCCC(NS(=O)(=O)c1ccc(OCc2ccc(F)cc2)cc1)C(=O)OC(C)(C)C
Agent: Cl
Agent: [K+]
Solvent: O
Product: CC(C)(C)OC(=O)C1N(S(=O)(=O)c2ccc(OCc3ccc(F)cc3)cc2)CCCC1(C)O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 2-[4-(4-fluoro-benzyloxy)-benzenesulfonylamino]6-oxo-heptanoic acid tert-butyl ester (0.70 g, 1.5 mmol) in 6 mL of THF was added potassium tert-butoxide (0.7 mL of a 1M solution in THF, 0.70 mmol). After stirring for 24 h at room temperature, the mixture was diluted with water, acidified with 1M HCl and extracted 3× into ethyl acetate. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. Filtration of the residue through a pad of silica gel eluting with 1:1 ethyl acetate-hexane afforded 1-[4-(4-fluoro-benzyloxy)-benzenesulfonyl]-3-hydroxy-3-methyl-piperidine-2-carboxylic acid tert-butyl ester as a mixture of diastereomers. Separation of the diastereomers by radial chromatography (1-4% acetone-CH2Cl2, 4 mm plate) afforded 0.12 g of each diastereomer as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([OH:13])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl[S:17]([N:20]=C=O)(=[O:19])=[O:18]>C1(C)C=CC=CC=1>[F:1][C:2]([F:14])([F:15])[C:3]1[CH:4]=[C:5]([O:13][S:17](=[O:19])(=[O:18])[NH2:20])[CH:6]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:8]=1
Reactant: Oc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: Cc1ccccc1
Product: NS(=O)(=O)Oc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 48.1 %

Procedure:
This compound was prepared using the procedure of Example 84 from a mixture of 9.8 g (0.043 mole) of 3,5-bis(trifluoromethyl)phenol and 3.9 ml (0.095 mole) of chlorosulfonyl isocyanate in 50 ml of toluene. The solid product was recrystallized from benzene to yield 6.4 g (48%) of a pale yellow solid; mp 118°-120° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:14]=[N:13][C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[N:6]=1.C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24].C(Cl)(Cl)Cl>C(Cl)Cl>[CH3:22][S:23]([O:1][CH2:2][CH2:3][O:4][C:5]1[CH:14]=[N:13][C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[N:6]=1)(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: OCCOc1cnc2c(n1)CCCC2
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)OCCOc1cnc2c(n1)CCCC2
Yield: 99.9 %

Procedure:
291 mg (1.5 mmol) of 2-(2-hydroxyethoxy)-5,6,7,8-tetrahydroquinoxaline was dissolved in 15 ml of methylene chloride. To the resultant solution was added 0.25 ml (1.8 mmol) of triethylamine and then, 0.13 ml (1.65 mmol) of methanesulfonyl chloride was added dropwise thereto. The resultant mixture was stirred at room temperature for 2.5 hours to effect a reaction. To the resultant reaction mixture was added chloroform to obtain a mixture. The mixture was extracted with an aqueous potassium carbonate solution to thereby obtain an organic layer and an aqueous layer. The aqueous layer was subjected to extraction with chloroform to obtain an additional organic layer. The two organic layers were combined, dried over sodium sulfate, and subjected to filtration, followed by concentration, to thereby obtain 408 mg of 2-(2-methanesulfonyloxyethoxy) -5,6,7,8-tetrahydroquinoxaline. The thus obtained 2-(2-methanesulfonyloxyethoxy)-5,6,7,8-tetrahydroquinoxaline was dissolved in 10 ml of acetonitrile. To the resultant solution were added 0.31 g (2.25 mmol) of potassium carbonate and 294 mg (1.8 mmol) of 1-(2-pyridyl)piperazine, and the resultant mixture was heated under reflux for 24 hours. Then, the mixture was subjected to filtration to filter off insoluble substances, which were then washed with acetonitrile, to thereby obtain a filtrate. The solvent of the filtrate was distilled off in vacuo to thereby obtain a residue. The obtained residue was purified by silica gel column chromatography. That is, the residue was charged in a column of 20 g of silica gel (Art7734, manufactured and sold by E. Merck, Darmstadt) and eluted with chloroform-methanol (100:1), to thereby obtain 522 mg of 2-[2-{4-(2-pyridyl)-1-piperazinyl}ethoxy]-5,6,7,8-tetrahydroquinoxaline (compound 517) (yield: 100%).
Reaction SMILES: [O:1]([CH2:8][C:9]1[S:15][CH:14]2[CH:11]([C:12](=[O:33])[N:13]2[C:16](=C(O)C)[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)=[O:18])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(Cl)(=O)=O.O(CC1S[CH:52]2[CH:49](C(=O)[N:51]2[C:54](=C(OS(C)(=O)=O)C)[C:55]([O:57][CH2:58][C:59]2C=CC([N+]([O-])=O)=CC=2)=O)N=1)C1C=CC=CC=1.N1CCOCC1>O1CCCC1.C(N(CC)CC)C>[O:1]([CH2:8][C:9]1[S:15][CH:14]2[CH:11]([C:12](=[O:33])[N:13]2[C:16](=[C:52]([N:51]2[CH2:54][CH2:55][O:57][CH2:58][CH2:59]2)[CH3:49])[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)=[O:18])[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(O)=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C2N=C(COc3ccccc3)SC21
Reactant: CC(OS(C)(=O)=O)=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C2N=C(COc3ccccc3)SC21
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1COCCN1
Solvent: C1CCOC1
Product: CC(=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C2N=C(COc3ccccc3)SC21)N1CCOCC1
Reaction time: 1.5 h

Procedure:
One dissolves p-nitrobenzyl α-[3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-hydroxyethylidene)acetate (940 mg) in tetrahydrofuran (14 ml), adds triethylamine (0.61 ml) and methanesulfonyl chloride (0.172 ml), and stirs for 1 hour at -15° to -20° C. To the produced solution of p-nitrobenzyl α-[3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-methanesulfonyloxyethylidene)-acetate, one adds morpholine (0.209 ml), stirs for 1.5 hours at -15° to -20° C., and for 2 hours at 0° C., to give a solution of p-nitrobenzyl α-[3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-morpholinoethylidene)acetate, cools to -15° C., adds pyridine (0.174 ml) followed by after 5 minutes a solution of bromine in carbon tetrachloride (1 mole/liter: 2.1 ml), stirs for 15 minutes at the same temperature, pours into water (50 ml), and extracts with ethyl acetate (50 ml). The extract solution is washed with water, dried over magnesium sulfate, and evaporated to give residue (1.7 g). Purification of the residue by chromatography over silica gel containing 10% water gives from the fractions eluted with a mixture of benzene and ethyl acetate (2:1) p-nitrobenzyl α-[3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]-hept-2-en-6-yl]-α-(2-bromo-1-morpholinoethylidene)acetate (1.109 g; Yield: 89.7%) and p-nitrobenzyl α-[3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(2-bromo-1-morpholinoethyl)-α-methanesulfonylacetate (85 mg; Yield: 7.7%).
Reaction SMILES: [Si]([O:8][C@@H:9]([C@H:11]1[C:32](=[O:33])[N:13]2[C:14]([C:26]([O:28][CH2:29][CH:30]=[CH2:31])=[O:27])=[C:15]([C:18]3[N:25]4[C:21]([S:22][CH:23]=[CH:24]4)=[CH:20][N:19]=3)[C@H:16]([CH3:17])[C@H:12]12)[CH3:10])(C(C)(C)C)(C)C.C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.C(OCC)(=O)C>[OH:8][C@@H:9]([C@H:11]1[C:32](=[O:33])[N:13]2[C:14]([C:26]([O:28][CH2:29][CH:30]=[CH2:31])=[O:27])=[C:15]([C:18]3[N:25]4[C:21]([S:22][CH:23]=[CH:24]4)=[CH:20][N:19]=3)[C@H:16]([CH3:17])[C@H:12]12)[CH3:10]
Reactant: C=CCOC(=O)C1=C(c2ncc3sccn23)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)C(=O)N12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CCOC(=O)C1=C(c2ncc3sccn23)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Temperature: 25 °C
Reaction time: 36 h
Yield: 59.7 %

Procedure:
To a solution of 0.35 g of allyl (1S,5R,6S)-6-((1R)-1-t-butyldimethylsilyloxyethyl)-2-(imidazo[5,1-b]thiazole-5-yl)-1-methyl-1-carbapen-2-em-3-carboxylate in 12 ml of THF was added under ice-cooling 0.66 ml of acetic acid and 2.9 ml of a 1 M solution of tetra-n-butyl-ammonium fluoride in THF, and the mixture was stirred at room temperature for 36 hours. The reaction mixture was diluted with 50 ml of ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and saturated aqueous saline in this sequence, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue thus obtained was purified by column chromatography on silica gel (ethyl acetate) to give 0.16 g of allyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-5-yl)-1-methyl-1-carbapen-2-em-3-carboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([C:12]([OH:14])=O)[CH:11]=1)[NH:8][C:7](=[O:15])[CH2:6]2.O1CCCC1.[C:21]1([Li])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([C:12](=[O:14])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:11]=1)[NH:8][C:7](=[O:15])[CH2:6]2
Reactant: COc1cc2c(c(C(=O)O)c1)NC(=O)C2
Reactant: [Li]c1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: COc1cc2c(c(C(=O)c3ccccc3)c1)NC(=O)C2
Reaction time: 2 h

Procedure:
A suspension of 1.0 g. (4.9 mmole) of 5-methoxy-7-carboxyindolin-2-one in 20 ml. of tetrahydrofuran was treated dropwise with 12 ml. of commercially prepared phenyllithium solution (2.3 molar ether: benzene; 0.28 moles). After stirring for 2 hours the reaction mixture was poured into water and extracted several times with ethyl ether and benzene. The combined extracts were washed with water, dried over sodium sulfate and concentrated using a rotary evaporator to a solid residue which on recrystallization from acetone-water gave 259 mg. (21%) of a yellow powder which melted at 154° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[C:4]([CH:12]=[CH2:13])[CH:3]=1.[Cl:14][C:15]1[CH:20]=[C:19](Cl)[C:18]([CH2:22]Cl)=[CH:17][N:16]=1.C(N1C2C=CC=CC=2C=CC2N=C(Cl)C(F)=CC=2C1)(=O)C>>[C:9]([N:8]1[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[CH:12]=[CH:13][C:19]2[CH:20]=[C:15]([Cl:14])[N:16]=[CH:17][C:18]=2[CH2:22]1)(=[O:11])[CH3:10]
Reactant: C=Cc1cc(Cl)ccc1NC(C)=O
Reactant: ClCc1cnc(Cl)cc1Cl
Agent: CC(=O)N1Cc2cc(F)c(Cl)nc2C=Cc2ccccc21
Product: CC(=O)N1Cc2cnc(Cl)cc2C=Cc2cc(Cl)ccc21
Yield: 51.7 %

Procedure:
The title compound (67.6 mg, 52%) was prepared from 9B (80 mg, 0.41 mmol) and 41B (80 mg, 0.41 mmol) in two steps by a route analogous to that used for the preparation of 1D. HPLC Rt=2.886 min; LCMS Found: (M+H)+=319.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[F:13][C:14]1[N:19]=[CH:18][C:17]([CH2:20][N:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)=[CH:16][CH:15]=1.[Li+].CC([N-]C(C)C)C.[B:42](OC(C)C)([O:47]C(C)C)[O:43]C(C)C>C1COCC1>[C:30]([O:29][C:27]([N:24]1[CH2:23][CH2:22][N:21]([CH2:20][C:17]2[CH:16]=[C:15]([B:42]([OH:47])[OH:43])[C:14]([F:13])=[N:19][CH:18]=2)[CH2:26][CH2:25]1)=[O:28])([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(F)nc2)CC1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)N1CCN(Cc2cnc(F)c(B(O)O)c2)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 86.3 %

Procedure:
n-Butyllithium (2.5 M in hexanes, 36.1 mL, 90 mmol) was added to a stirred solution of diisopropylamine (12.8 mL, 90 mmol) in tetrahydrofuran (150 mL, 75 mmol) at −40° C. and the slightly yellow solution was stirred at the same temperature for 1 h, and then cooled to −78° C. A solution of tert-butyl 4-((6-fluoropyridin-3-yl)methyl)piperazine-1-carboxylate (22.22 g, 75 mmol) in THF (100 mL) was cannulated slowly into the LDA solution over 30 min. The brown mixture was stirred at the same temperature for 1.5 h and then a solution of triisopropyl borate (25.9 mL, 113 mmol) in THF (50 mL) was added slowly. The resulting mixture was stirred at the same temperature for 30 min and then the cooling bath was removed. After the reaction mixture had warmed up to room temperature, the yellow heterogeneous mixture was quenched with 1.0 M NaOH(aq) (50 mL) and stirred for an additional 30 min. The separated aqueous layer was carefully acidified with 5 N aqueous HCl until acidic (pH 4 to about 5) and the resulting cloudy mixture was diluted with EtOAc (150 mL). The separated aqueous layer was extracted with EtOAc (2×150 mL) and the combined organic phases were dried (Na2SO4), filtered, and concentrated to give 5-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)-2-fluoropyridin-3-ylboronic acid (21.93 g, 64.7 mmol, 86% yield) as a pale yellow solid. LCMS (API-ES) m/z 340 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:20][CH3:21])[CH2:4][NH:5][S:6]([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:19])[CH:15]=2)[CH:10]=1)(=[O:8])=[O:7].[H-].[Na+].Br[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>CN(C=O)C.O1CCCC1>[CH2:29]([O:28][C:26](=[O:27])[CH2:25][N:5]([CH2:4][CH:3]([O:2][CH3:1])[O:20][CH3:21])[S:6]([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:19])[CH:15]=2)[CH:10]=1)(=[O:8])=[O:7])[CH3:30]
Reactant: CCOC(=O)CBr
Reactant: COC(CNS(=O)(=O)c1ccc2cc(Cl)ccc2c1)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)CN(CC(OC)OC)S(=O)(=O)c1ccc2cc(Cl)ccc2c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
N-(2,2-Dimethoxyethyl)-6-chloro-2-naphthalenesulfonamide was dissolved in DMF (100 ml) and combined with sodium hydride (1.16 g, in oil), cooled to 0° C., treated dropwise with a solution of ethyl bromoacetate (4.843 g) in tetrahydrofuran (15 ml) and then stirred at room temperature for 3 hours. The reaction mixture was concentrated and the residue was dissolved in ethyl acetate, washed with water, aqueous sodium bicarbonate and brine, dried and concentrated to obtain N-(2,2-dimethoxyethyl)-N-(6-chloro-2-naphthalenesulfonyl)glycine ethyl ester as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:18]2[CH:19]=[N:20][N:21]([CH:23]3[CH2:28][CH2:27][N:26]([C:29](=[O:31])[CH3:30])[CH2:25][CH2:24]3)[CH:22]=2)=[C:6]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=3)[O:8][C:7]=12.C(=O)([O-])[O-].[K+].[K+].Br[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=1>CC(C)=O>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:18]2[CH:19]=[N:20][N:21]([CH:23]3[CH2:24][CH2:25][N:26]([C:29](=[O:31])[CH3:30])[CH2:27][CH2:28]3)[CH:22]=2)=[C:6]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:39][C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=4)[CH:12]=3)[O:8][C:7]=12
Reactant: CC(=O)N1CCC(n2cc(-c3cnc(N)c4oc(-c5cccc(O)c5)cc34)cn2)CC1
Reactant: BrCc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)N1CCC(n2cc(-c3cnc(N)c4oc(-c5cccc(OCc6ccccn6)c5)cc34)cn2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.1 %

Procedure:
1-(4-{4-[7-Amino-2-(3-hydroxy-phenyl)-furo[2,3-c]pyridin-4-yl]-pyrazol-1-yl}-piperidin-1-yl)-ethanone (50 mg, 0.12 mmol) was dissolved in acetone (10 mL) and potassium carbonate (50 mg, 0.36 mmol) and 2-bromomethyl-pyridine (24 mg, 0.14 mmol) was added. The solution was stirred at RT overnight. After filtration the filtrate was concentrated and the residue was purified by preparative TLC (10% MeOH:DCM) to afford 8 mg (13%) of the title compound. 1H NMR (400 MHz, CD3OD): δ 8.56-8.57 (d, J=4 Hz, 1H), 8.17 (s, 1H), 7.85-7.93 (m, 3H), 7.74 (s, 1H), 7.66-7.68 (d, J=7.2 Hz, 2H), 7.54 (s, 1H), 7.39-7.43 (m, 2H), 7.10-7.12 (d, J=8 Hz, 1H), 5.29 (s, 2H), 4.65-4.72 (m, 1H), 4.49-4.60 (m, 1H), 4.06-4.14 (m, 1H), 3.33-3.35 (m, 1H), 2.80-2.88 (m, 1H), 2.20-2.27 (m, 2H), 2.16 (s, 3H), 1.95-2.11 (m, 2H); MS (ESI): 509.11 [M+H]+; HPLC tR=2.18 min (ZQ3: polar—4 min).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][C@@H:10]2[OH:18])[CH:5]=[N:4][CH:3]=1.C[O-].[Na+].[C:22]([O-])(O)=[O:23].[Na+]>CO.CCOC(C)=O>[CH3:22][O:23][C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][C@@H:10]2[OH:18])[CH:5]=[N:4][CH:3]=1
Reactant: O=C([O-])O
Reactant: O[C@H]1Cc2ccccc2[C@H]1Nc1cncc(Cl)n1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cncc(N[C@@H]2c3ccccc3C[C@@H]2O)n1
Temperature: 25 °C
Yield: 71 %

Procedure:
To a solution of (1R,2S)-1-[(6-chloropyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol (2 g, 7.6 mmol) in MeOH (26 mL) was added a solution of NaOMe (1.3 g, 23 mmol) in MeOH (40 mL). The mixture was heated at reflux for 24 hr. Additional NaOMe (1.3 g) was added. Continue heating at reflux for 24 hr, and then add additional NaOMe (1.3 g). Continue heating at reflux for 24 hr and cool to rt. Dilute with EtOAc and was with sat. aq. NaHCO3. The solids were removed by filtration. Separate phases and wash organic extract with additional sat. aq. NaHCO3. Dry organic extracts over MgSO4, filter and concentrate. Purify by biotage MPLC (90 g column, 25% ethyl acetate/hexanes) to afford 1.4 g (71%) of (1R,2S)-1-[(6-methoxypyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol as an oil: 1H NMR (CDCl3) δ 3.04–3.08, 3.23–3.29, 3.91, 4.75–4.78, 5.18, 5.42–5.45, 7.25–7.34, 7.57–7.61; MS (ESI+) for C14H15N3O2 m/z 258 (M+H)+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[C:5]([C:18]1[CH:23]=[CH:22][C:21]([O:24]CC2C=CC=CC=2)=[CH:20][CH:19]=1)[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][N:15]([CH3:17])[CH3:16])=[CH:8][CH:7]=1>C(O)C.C(OCC)(=O)C.C(N(CC)CC)C>[Cl:1][CH2:2][CH2:3]/[C:4](/[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)=[C:5](\[C:18]1[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=1)/[C:6]1[CH:7]=[CH:8][C:9]([O:12][CH2:13][CH2:14][N:15]([CH3:17])[CH3:16])=[CH:10][CH:11]=1
Reactant: CN(C)CCOc1ccc(C(=C(CCCl)c2ccccc2)c2ccc(OCc3ccccc3)cc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CCO
Product: CN(C)CCOc1ccc(/C(=C(/CCCl)c2ccccc2)c2ccc(O)cc2)cc1

Procedure:
8.4 g of 4-chloro-1-(4-benzyloxyphenyl)-1-[4-[2-(N,N-dimethylamino )-ethoxy]phenyl]-2-phenyl-1-butene is hydrogenated in 340 ml of ethanol-ethyl acetate (1: 1) containing 11 drops of triethylamine using 5%Pd--C as a catalyst. The catalyst is filtered off and the solvent is evaporated. The residue is treated with ethanol and the product is filtered. The yield is 4.9 g (71%).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:31]=[CH:30][C:29](C(O)=O)=[CH:28][CH:27]=1.[NH2:35][CH2:36][CH:37]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[OH:38]>>[OH:38][CH:37]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:36][NH:35][C:16]([C@@H:9]1[CH2:10][C:11](=[N:13][O:14][CH3:15])[CH2:12][N:8]1[C:6]([C:29]1[CH:28]=[CH:27][C:26]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH3:19])=[CH:31][CH:30]=1)=[O:7])=[O:18]
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: NCC(O)c1ccccc1
Reactant: Cc1ccccc1-c1ccc(C(=O)O)cc1
Product: CON=C1C[C@@H](C(=O)NCC(O)c2ccccc2)N(C(=O)c2ccc(-c3ccccc3C)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 2′-methyl[1,1′-biphenyl]-4-carboxylic acid, and (1RS)-2-amino-1-phenylethanol, the title compound was obtained in 96.4% purity by HPLC. MS(ESI+): m/z=472.