Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(CC)CC.F[B-](F)(F)F.[N:13]1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=[N:14]1.[C:30]([O:34][C:35]([N:37]1[CH2:44][CH2:43][C@:42]2([CH3:47])[C@H:45]([CH3:46])[C@H:38]1[CH2:39][C:40]1[CH:51]=[CH:50][C:49]([C:52](O)=[O:53])=[CH:48][C:41]=12)=[O:36])([CH3:33])([CH3:32])[CH3:31].O.NN>CN(C)C=O.O>[C:30]([O:34][C:35]([N:37]1[CH2:44][CH2:43][C@:42]2([CH3:47])[C@H:45]([CH3:46])[C@H:38]1[CH2:39][C:40]1[CH:51]=[CH:50][C:49]([C:52]([NH:13][NH2:14])=[O:53])=[CH:48][C:41]=12)=[O:36])([CH3:32])([CH3:31])[CH3:33]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: C[C@@H]1[C@H]2Cc3ccc(C(=O)O)cc3[C@]1(C)CCN2C(=O)OC(C)(C)C
Agent: F[B-](F)(F)F
Agent: NN
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@@H]1[C@H]2Cc3ccc(C(=O)NN)cc3[C@]1(C)CCN2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
NEt3 (1.7 mL) and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (3.9 g) are added in turn to a solution of (2R,6R,11S)-6,11-dimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3,8-dicarboxylic acid 3-tertbutyl ester (4.2 g) in dimethylformamide (10 mL). The resulting solution is stirred at ambient temperature for 30 min, before hydrazine hydrate (3 mL) is added. The solution is stirred further at room temperature for 1 h and then water (30 mL) is added. The resulting mixture is extracted with ethyl acetate and the combined organic extracts are washed with 1 M aqueous NaOH solution, water, and brine. After drying (MgSO4), the solvent is evaporated and the residue is purified by chromatography on silica gel (cyclohexane/EtOAc 1:4->0:1) to give the title compound.
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([O:14][C:15]1[CH:16]=[C:17]([CH:34]=[C:35]([CH3:37])[CH:36]=1)[O:18][CH2:19][CH2:20][CH2:21][O:22][N:23]1C(=O)C2=CC=CC=C2C1=O)(=[O:13])=[O:12].Cl.[OH-].[Na+]>CC(O)C.O>[CH3:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([O:14][C:15]1[CH:16]=[C:17]([CH:34]=[C:35]([CH3:37])[CH:36]=1)[O:18][CH2:19][CH2:20][CH2:21][O:22][NH2:23])(=[O:13])=[O:12]
Reactant: COc1ccccc1S(=O)(=O)Oc1cc(C)cc(OCCCON2C(=O)c3ccccc3C2=O)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: COc1ccccc1S(=O)(=O)Oc1cc(C)cc(OCCCON)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
A mixture of sodium borohydride (45 mg, 1.1 mmol) and N-[3-[3-(2-methoxyphenylsulfonyloxy)-5-methylphenoxy]propoxy]phthalimide (113 mg, 0.23 numol, prepared in the preceding step) in 2-propanol (12 mL) and water (2 mL) was stirred overnight at ambient temperature. The reaction mixture was adjusted to pH 1 aqueous HCl (3.5 mL, 2N), and the solution was stirred at 50° C. for 2 h. The solution was cooled to 0° C. and adjusted to pH 12 with 2N NaOH. The solution was stirred at ambient temperature for 2 h, then 2-propanol was removed by rotary evaporation. The resulting mixture was extracted with ethyl acetate (2×30 mL). The combined organic extracts were washed with brine (40 mL), dried over Na2SO4, filtered, and evaporated to give the title compound (79 mg, 95%) as a colorless oil. 1 H-NMR (300 MHz, CDCl3) (7.82 (dd, 1H, J=7.9,1.7 Hz), 7.61 (ddd, 1H, J=8.4, 7.5, 1.8 Hz), 7.08 (dd, 1H, J=8.4, 0.8 Hz), 7.00 (ddd, 1H, J=8, 7.5, 1 Hz), 6.58 (br s, 1H), 6.50 (br s, 1H), 6.45 (t, 1H, J=2.1 Hz), 5.38 (br s, 2H), 4.02 (s, 3H), 3.92 (t, 2H, J=6.3 Hz), 3.79 (t, 2H, J=6.2 Hz), 2.23 (s, 3H), 2.00 (pentet, 2H, J=6.2 Hz). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. for C17H21NO6S: 390.1 (M+Na). Found: 390.1.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]O)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[C:46]([N:54]1[C:59](=[O:60])[CH:58]=[CH:57][NH:56][C:55]1=[O:61])(=[O:53])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.CCCCCC.CCOC(C)=O>[C:46]([N:54]1[C:59](=[O:60])[CH:58]=[CH:57][N:56]([CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][O:39][C:20]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:55]1=[O:61])(=[O:53])[C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1
Reactant: O=C(c1ccccc1)n1c(=O)cc[nH]c1=O
Reactant: OCCCCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(c1ccccc1)n1c(=O)ccn(CCCCCOC(c2ccccc2)(c2ccccc2)c2ccccc2)c1=O
Temperature: 25 °C
Yield: 53 %

Procedure:
Polymer supported triphenyl phosphine (2.5 eq, 3 mmol/g loading) was swelled in dry THF for 15 minutes then the alcohol 14 (1 eq, 300 mg) and the N3-benzoyluracil (1.5 eq) were added into the suspension, which was shaken at room temperature under atmosphere of nitrogen. A solution of DIAD (2 eq) in THF was added slowly into the suspension. The reaction was shaken overnight until the disappearance of the alcohol was observed by TLC. The resin was then filtered off and washed with THF (5 ml). The solvent was removed under reduced pressure to afford a residue which was taken in a mixture of Hexane/EtOAc (50:50). The formed white precipitate was removed and the solution was concentrated to an orange oil and purified by flash chromatography using a mixture of Hexane/EtOAc (40:60) as eluent which gave the title compound (250 mg, 53%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][CH:7]=[CH:8][CH:9]=1)=[O:4].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30](=[O:33])[CH2:31]Br)=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:31][C:30]([C:27]2[CH:28]=[CH:29][C:24]([O:23][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:25][CH:26]=2)=[O:33])[CH:7]=[CH:8][CH:9]=1)=[O:4]
Reactant: O=C(CBr)c1ccc(OCc2ccccc2)cc1
Reactant: COC(=O)c1ccc[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccn1CC(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 50 °C

Procedure:
A suspension of 200 mg (1.60 mmol) 1H-pyrrole-2-carboxylic acid methyl ester and 1.56 g (4.79 mmol) cesium carbonate in 3 ml DMF is heated to 50° C. under stirring. Then a solution of 488 mg (1.60 mmol) 1-(4-benzyloxy-phenyl)-2-bromo-ethanone in 1 ml DMF is added within 3 minutes. The reaction mixture is stirred for 18 hours at 50° C. The reaction mixture is filtered with suction and the filtrate is evaporated. The residue is crystallized from diethyl ether to give 1-[2-(4-benzyloxy-phenyl)-2-oxo-ethyl]-1H-pyrrole-2-carboxylic acid methyl ester as beige crystals; HPLC/MS 2.51 min (A), [M+H] 350.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].[F:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=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.C(=O)([O-])[O-].[Na+].[Na+]>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:2]2[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[C:4]([CH:5]=[O:6])[CH:3]=2)=[CH:15][CH:14]=1
Reactant: COc1ccc(C=O)cc1Br
Reactant: OB(O)c1ccc(F)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: [Na+]
Product: COc1ccc(C=O)cc1-c1ccc(F)cc1
Yield: 79.4 %

Procedure:
By the reaction in the same manner as in Example 5-(ii) using 3-bromo-p-anisaldehyde (14.0 g), 4-fluorophenylboronic acid (14.6 g), 2M aqueous sodium carbonate solution (260 ml) and tetrakis(triphenylphosphine)palladium(0) (3.76 g), the title compound (11.9 g) was obtained as white needle crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][C@@H:13]([CH3:16])[C@H:12]([CH2:17]OS(C)(=O)=O)[CH2:11]2)=[CH:4][CH:3]=1.[N-:23]=[N+:24]=[N-:25].[Na+]>CN(C)C=O>[N:23]([CH2:17][C@H:12]1[C@H:13]([CH3:16])[CH2:14][CH2:15][N:10]([CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:11]1)=[N+:24]=[N-:25]
Reactant: [N-]=[N+]=[N-]
Reactant: C[C@@H]1CCN(CCc2ccc(F)cc2)C[C@H]1COS(C)(=O)=O
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H]1CCN(CCc2ccc(F)cc2)C[C@H]1CN=[N+]=[N-]
Temperature: 50 °C
Reaction time: 28 h

Procedure:
A mixture of methanesulfonic acid trans-{l-[2-(4-fluorophenyl)ethyl]-4-methylpiperidin-3-ylmethyl} ester (the crude material from Part D, about 1.0 mmol) and sodium azide (195 mg, 3 mmol) in N,N-dimethylformamide (4 mL) was stirred at 50° C. for 28 hours. The mixture was cooled to room temperature, filtered, and the solid was rinsed with ethyl acetate. The combined filtrates were diluted with ethyl acetate, and the resulting solution was washed twice with water, dried over sodium sulfate, and concentrated under vacuum. The residue was an orange oil (252 mg, 91%) which was used without further purification. 1H NMR (300 MHz, CDCl3) δ7.17 (m, 2H), 6.98 (t, J=9 Hz, 2H), 3.50 (dd, J=12, 3 Hz, 1H), 3.25 (dd, J=12, 8 Hz, 1H), 3.08 (dm, J=10 Hz, 1H), 3.00 (dm, J=11 Hz, 1H), 2.83 (m, 2H), 2.60 (m, 2H), 2.04 (m, 1H), 1.88 (t, J=11 Hz, 1H), 1.71 (m, 1H), 1.60 (m, 1H), 1.5-1.3 (m, 2H), 1.00 (d, J=7 Hz, 3H).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([N:7]=[N:8][C:9]2[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=2)=[CH:5][CH:6]=1.IC.[C:18](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:18][O:15][C:12]1[CH:11]=[CH:10][C:9]([N:8]=[N:7][C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=2)=[CH:14][CH:13]=1
Reactant: Oc1ccc(N=Nc2ccccc2)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1ccc(N=Nc2ccccc2)cc1

Procedure:
A mixture of 4-phenylazophenol (9.9 g; 50 mmol), iodomethane (7.1 g; 50 mmol), potassium carbonate (6.9 g; 50 mmol), and acetone (100 ml) was refluxed 48 h. After evaporating off the solvent, the residue was dissolved in water (25 ml), diethyl ether (50 ml) and THF (30 ml). The aqueous layer was extracted with ether (3×20 ml) and the combined organic solutions were washed with saturated NaCl solution (1×20 ml) and dried (MgSO4). After filtration and evaporation, the residue was recrystallized from 96% ethanol to give 8.7 g (82%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH:25]=[C:24]([CH:26]=[CH2:27])[CH:23]=[C:22]4[C:28]4[NH:32][N:31]=[N:30][N:29]=4)=[CH:17][CH:16]=3)[C:9]([CH2:11][CH2:12][CH3:13])=[N:10][C:3]=12>[Pd].CO>[CH2:26]([C:24]1[CH:23]=[C:22]([C:28]2[NH:32][N:31]=[N:30][N:29]=2)[N:21]([C:18]2[CH:19]=[CH:20][C:15]([CH2:14][N:8]3[C:4]4=[N:5][CH:6]=[CH:7][C:2]([CH3:1])=[C:3]4[N:10]=[C:9]3[CH2:11][CH2:12][CH3:13])=[CH:16][CH:17]=2)[CH:25]=1)[CH3:27]
Reactant: C=Cc1cc(-c2nnn[nH]2)n(-c2ccc(Cn3c(CCC)nc4c(C)ccnc43)cc2)c1
Agent: [Pd]
Solvent: CO
Product: CCCc1nc2c(C)ccnc2n1Cc1ccc(-n2cc(CC)cc2-c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 7-methyl-2-propyl-3-[4-[2-(1H-tetrazol-5-yl)4-vinyl-1-pyrrolyl]benzyl]-3H-imidazo[4,5-b]pyridine (40 mg), 10% palladium on carbon (10 mg) and methanol (5 ml) was stirred at room temperature for 4 hours under hydrogen atmosphere (3 atm). After filtration, the filtrate was evaporated in vacuo. The residue was purified by preparative thin layer chromatography (dichloromethane:methanol=5:1) to give 3-[4-[4-ethyl-2-(1H-tetrazol-5-yl)-1-pyrrolyl]benzyl]-7-methyl-2-propyl-3H-imidazo[4,5-b]pyridine (20 ml).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]([OH:14])=O)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[F:15][C:16]([F:29])([F:28])[C:17]1[CH:18]=[C:19]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[NH2:20]>>[F:15][C:16]([F:28])([F:29])[C:17]1[CH:18]=[C:19]([NH:20][C:12]([C:3]2[C:2]([OH:1])=[N:11][C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[N:4]=2)=[O:14])[CH:21]=[C:22]([C:24]([F:25])([F:27])[F:26])[CH:23]=1
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C(O)c1nc2ccccc2nc1O
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nc2ccccc2nc1O
Yield: 2.7 %

Procedure:
Using 3-hydroxyquinoxaline-2-carboxylic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:11][C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[C:4]21[CH2:19][C:18]1[C:13](=[CH:14][CH:15]=[C:16]([NH:20][C:21]3[N:26]=[CH:25][N:24]=[C:23]([C:27](O)=[O:28])[CH:22]=3)[CH:17]=1)[CH2:12]2.[F:30][C:31]1[CH:32]=[C:33]([C@@H:38]2[CH2:43][CH2:42][C:41]([CH3:45])([CH3:44])[CH2:40][NH:39]2)[CH:34]=[C:35]([F:37])[CH:36]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:37][C:35]1[CH:34]=[C:33]([C@@H:38]2[CH2:43][CH2:42][C:41]([CH3:45])([CH3:44])[CH2:40][N:39]2[C:27]([C:23]2[N:24]=[CH:25][N:26]=[C:21]([NH:20][C:16]3[CH:17]=[C:18]4[C:13](=[CH:14][CH:15]=3)[CH2:12][C:4]3([C:5]5[C:6](=[N:7][CH:8]=[CH:9][CH:10]=5)[NH:11][C:3]3=[O:2])[CH2:19]4)[CH:22]=2)=[O:28])[CH:32]=[C:31]([F:30])[CH:36]=1
Reactant: O=C(O)c1cc(Nc2ccc3c(c2)CC2(C3)C(=O)Nc3ncccc32)ncn1
Reactant: CC1(C)CC[C@@H](c2cc(F)cc(F)c2)NC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1(C)CC[C@@H](c2cc(F)cc(F)c2)N(C(=O)c2cc(Nc3ccc4c(c3)CC3(C4)C(=O)Nc4ncccc43)ncn2)C1

Procedure:
64 mg (0.17 mmol) 6-(2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-ylamino)pyrimidine-4-carboxylic acid hydrochloride, 70 mg (0.16 mmol) (S)-2-(3,5-difluorophenyl)-5,5-dimethylpiperidine, 40 μL (0.23 mmol) DIPEA and 65 mg (0.17 mmol) HATU in 0.80 mL DMF were stirred overnight at RT. The purification was carried out by preparative HPLC-MS. The product-containing fractions were combined and lyophilised.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[C:9]1([N:15]2[C:27]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:21]3[C:16]2=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CN(C=O)C>[Br:8][C:24]1[CH:25]=[CH:26][C:27]2[N:15]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:16]3[C:21]([C:22]=2[CH:23]=1)=[CH:20][CH:19]=[CH:18][CH:17]=3
Reactant: O=C1CCC(=O)N1Br
Reactant: c1ccc(-n2c3ccccc3c3ccccc32)cc1
Solvent: CN(C)C=O
Product: Brc1ccc2c(c1)c1ccccc1n2-c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 97.2 %

Procedure:
NBS (19.31 g, 109 mmol) in DMF was added to 9-phenyl-9H-carbazole (24 g, 99 mmol) in 200 mL at 0° C. dropwise. The reaction was monitored by HPLC. The reaction was quenched by adding 500 mL of water after 2 h. After stirring at room temperature for 24 h, the clear solution was decanted and solid residue was dissolved in dichloromethane and washed with water and LiCl solution. The solution was dried with MgSO4 and the solvent was evaporated. The residue was used for the next step without further purification. The product contains starting material, monobromo, and dibromo. 31 g of product was obtained.
Reaction SMILES: C([O:3][C:4](=O)/[C:5](/[C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:20])=[O:19])=[CH:14][CH:13]=1)=[CH:6]/[CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)C.CC(C[AlH]CC(C)C)C.C1(C)C=CC=CC=1>>[CH2:25]([O:24][CH2:23][CH2:22][CH2:21][S:18]([C:15]1[CH:14]=[CH:13][C:12](/[C:5](=[CH:6]\[CH:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)/[CH2:4][OH:3])=[CH:17][CH:16]=1)(=[O:20])=[O:19])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)/C(=C/C1CCCC1)c1ccc(S(=O)(=O)CCCOCc2ccccc2)cc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Product: O=S(=O)(CCCOCc1ccccc1)c1ccc(/C(=C\C2CCCC2)CO)cc1
Yield: 77.9 %

Procedure:
Following the method of example 54e, reaction of (E)-2-[4-(3-benzyloxy-propane-1-sulfonyl)-phenyl]-3-cyclopentyl-acrylic acid ethyl ester (2.05 g, 4.49 mmol) with DIBAL in toluene (9.43 mL, 11.2 mmol) and 1 h at ambient temperature gives the title compound as an oil (1.45 g). MS (m/e): 415 (M+H).
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:10]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[F:19])=[CH:9][C:8]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]([O:32]C)=[O:31])=[CH:24][CH:23]=2)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[OH-].[Li+]>C1COCC1.CCO>[CH3:4][C:2]([C:5]1[C:10]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[F:19])=[CH:9][C:8]([CH2:20][O:21][C:22]2[CH:23]=[CH:24][C:25]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[CH:26][CH:27]=2)=[CH:7][CH:6]=1)([CH3:1])[CH3:3]
Reactant: COC(=O)CCc1ccc(OCc2ccc(C(C)(C)C)c(-c3cc(OC)ccc3F)c2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2cc(COc3ccc(CCC(=O)O)cc3)ccc2C(C)(C)C)c1
Reaction time: 16 h
Yield: 83.4 %

Procedure:
To a stirred solution of 2.2 (0.0421 g, 0.0934 mmol) in THF (2.00 mL) and EtOH (2.00 mL) at 23° C. was added 1N lithium hydroxide (2.00 mL, 2.00 mmol). Stirring continued for 16 hours. The reaction mixture was concentrated in vacuo. 1N HCl was added to reach pH 1, and the resulting mixture was extracted with EtOAc (3×10 mL), dried over MgSO4 and concentrated in vacuo. The residue was then purified by flash chromatography (SiO2 gel 60, eluted with 0%-20% EtOAc in hexanes) to give a clear oil (0.034 g, 82% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.59 (1H, d, J=8.2 Hz), 7.41 (1H, dd, J=8.6, 2.2 Hz), 7.22 (1H, dd, J=9.0, 7.4 Hz), 7.11 (1H, d, J=2.2 Hz), 7.00 (1H, t, J=8.6 Hz), 6.88-6.79 (5H, m), 5.01 (2H, s), 3.79 (3H, s), 2.94 (2H, t, J=7.8 Hz), 2.68 (2H, t, J=7.8 Hz), 1.24 (9H, s). MS ESI (neg.) m/e: 871.3 (2M−H)+, 435.1 (M−H)+.
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5]([O:17][CH2:18][O:19][CH3:20])=[C:6]([O:15][CH3:16])[CH:7]=[C:8]2[CH:13]=[O:14])[CH3:2].[Cl-].[NH4+].O1CCC[CH2:24]1>C[Li].ClCCl.[O-2].[O-2].[Mn+4]>[CH2:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5]([O:17][CH2:18][O:19][CH3:20])=[C:6]([O:15][CH3:16])[CH:7]=[C:8]2[C:13](=[O:14])[CH3:24])[CH3:2]
Reactant: CCc1cccc2c(C=O)cc(OC)c(OCOC)c12
Reactant: C1CCOC1
Agent: [Mn+4]
Agent: [Cl-]
Agent: [Li]C
Solvent: ClCCl
Product: CCc1cccc2c(C(C)=O)cc(OC)c(OCOC)c12
Reaction time: 0.5 h

Procedure:
2 g of 5-ethyl-3-methoxy-4-methoxymethoxy-1-naphthalenecarbaldehyde was dissolved in 20 ml of absolute tetrahydrofuran, to which 11.5 ml of an ethyl solution of 1.12M methyl lithium was added at -78° C. After 30 minutes, an ammonium chloride aqueous solution was added to the solution and extracted with ethyl acetate. The resultant organic phase was dried with anhydrous magnesium sulfate and the solvent was distilled off to obtain 2.1 g of a brown oily substance. This substance was dissolved in 20 ml of dichloromethane without isolation and purification, to which 30 g of manganese dioxide was added, followed by agitation at room temperature for 20 hours. The insoluble matters were removed by filtration and the filtrate was concentrated, followed by purification by silica gel column chromatography (10% ethyl acetate/hexane) to obtain 1.3 g of the captioned compound as a yellow oily substance.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:8][S:9][C:10](SC)=[CH:11][N+:12]([O-:14])=[O:13]>>[CH3:8][S:9][C:10]([NH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)=[CH:11][N+:12]([O-:14])=[O:13]
Reactant: Nc1cccnc1
Reactant: CSC(=C[N+](=O)[O-])SC
Product: CSC(=C[N+](=O)[O-])Nc1cccnc1

Procedure:
3-Aminopyridine and 1,1-bis(methylthio)-2-nitroethylene were processed as in Example 54B to provide the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:7]([OH:9])=O)[O:5][CH:6]=1.O=S(Cl)[Cl:12]>>[Br:1][C:2]1[CH:3]=[C:4]([C:7]([Cl:12])=[O:9])[O:5][CH:6]=1
Reactant: O=C(O)c1cc(Br)co1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1cc(Br)co1
Temperature: 25 °C

Procedure:
The crude 4-bromo-furan-2-carboxylic acid (30 g, 157 mmol) was placed in a 500 mL round bottom flask equipped with a magnetic stirring bar and a reflux condenser, and the flask was alternately evacuated and filled with nitrogen several times. The solids were suspended in benzene (400 mL), treated with SOCl2 (60 mL, 823 mmol) and the mixture was heated to reflux in a heating mantle. Dark tarry materials form on the walls of the reaction flask during the course of the reaction. After ˜135 minutes at reflux a sample of the reaction was concentrated under reduced pressure and analyzed by 13C NMR. The NMR was quite clean and showed the reaction to be complete. [13C-NMR (400 MHz, CDCl3): δ 154.9, 147.6, 146.3, 126.0, 102.5] After ˜3 hours at reflux the reaction mixture was allowed to cool to ambient temperature. The pale brown supernatant solution of the acid chloride was decanted from the dark solids, and the solids were rinsed with additional benzene. The benzene solutions were combined and concentrated under reduced pressure to afford 4-bromofuran-2-carbonyl chloride as a pale brown oil. This crude material was carried on to the amide formation without purification.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[C:3]=1[C:4]([O-])=[O:5].[CH3:12][NH2:13].C1COCC1>>[OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[C:3]=1[C:4]([NH:13][CH3:12])=[O:5]
Reactant: O=C([O-])c1c(O)cccc1O
Reactant: CN
Solvent: C1CCOC1
Product: CNC(=O)c1c(O)cccc1O
Temperature: 100 °C

Procedure:
The mixture of 2,6-dihydroxybenzoate (168 mg, 1.0 mmol) and 2 M methylamine in THF (3 mL, 6.0 mmol) in a sealed tube was heated to 100° C. overnight. The reaction mixture was then concentrated under reduced pressure and purified on silica gel eluting with hexane/ethyl acetate (1:1) to provide titled compound (67 mg). MS (ESI(+)) m/e 168 (M+H)+; 1H NMR (300 MHz, DMSO-d6) 12.57(bs, 2H), 8.82 (bs, 1H), 7.14 (t, 1H), 6.35 (d, 2H), 2.85(d, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:34][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[O:21][CH:22]3[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23]3)[C:7]=2[C:6]=1[CH3:35])=[O:4].Cl>CO.O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1[S:34][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[O:21][CH:22]3[CH2:26][CH2:25][NH:24][CH2:23]3)[C:7]=2[C:6]=1[CH3:35])=[O:4]
Reactant: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3OC3CCN(C(=O)OC(C)(C)C)C3)c2c1C
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3OC3CCNC3)c2c1C
Reaction time: 8 h

Procedure:
To a stirred suspension of 4-[2-(1-tert-Butoxycarbonyl-pyrrolidin-3-yloxy)-4-fluoro-phenylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester (1.2 g) in MeOH (4.0 ml) was added HCl in dioxane (4N; 4.0 ml) dropwise. The reaction mixture was stirred for 8 h. The solvent was removed under reduced pressure. The residue was purified by chromatography.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C@@H:18]3[CH:23]4[CH2:24][CH2:25][N:20]([CH2:21][CH2:22]4)[CH2:19]3)=[O:17])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[CH3:26][N:27]=[C:28]=[O:29]>C1COCC1.CN(C=O)C>[CH3:26][NH:27][C:28](=[O:29])[O:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16]([C@@H:18]3[CH:23]4[CH2:24][CH2:25][N:20]([CH2:21][CH2:22]4)[CH2:19]3)=[O:17])=[CH:13][CH:14]=2)=[CH:5][CH:4]=1
Reactant: CN=C=O
Reactant: O=C(Nc1ccc(-c2ccc(CO)cc2)cc1)[C@H]1CN2CCC1CC2
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CNC(=O)OCc1ccc(-c2ccc(NC(=O)[C@H]3CN4CCC3CC4)cc2)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
35 mg (0.10 mmol) of (3R)-N-[4′-(hydroxymethyl)-1,1′-biphenyl-4-yl]-1-azabicyclo-[2.2.2]octane-3-carboxamide are dissolved in 1 ml of a 1:1 THF/DMF mixture. 12 mg (0.21 mmol) of methyl isocyanate are added, and the mixture is stirred at 60° C. overnight. The solvent is removed under reduced pressure, and the crude product is purified by preparative HPLC. 20 mg (49% of theory) of the title compound are obtained.