Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:6]([O:13][N:14]1[C:19](=[O:20])[C:18]2[CH:21]=[C:22]([F:26])[C:23](Cl)=[N:24][C:17]=2[N:16]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[C:15]1=[O:34])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>C(#N)C>[CH2:6]([O:13][N:14]1[C:19](=[O:20])[C:18]2[CH:21]=[C:22]([F:26])[C:23]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[N:24][C:17]=2[N:16]([C:27]2[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=2)[C:15]1=[O:34])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C1CCNC1
Reactant: O=c1c2cc(F)c(Cl)nc2n(-c2ccc(F)cc2)c(=O)n1OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=c1c2cc(F)c(N3CCCC3)nc2n(-c2ccc(F)cc2)c(=O)n1OCc1ccccc1
Yield: 79.3 %

Procedure:
Pyrrolidine (0.04 mL, 0.52 mmol) was added to a solution of 3-benzyloxy-7-chloro-6-fluoro-1-(4-fluorophenyl)-1H-pyrido[2,3-d]pyrimidine-2,4-dione (Example Q-2, 0.17 g, 0.42 mmol) and triethylamine (0.36 mL, 2.6 mmol) in 20 mL of acetonitrile. The solution was warmed to reflux for 17 hours, cooled, and concentrated to a solid. The solid was dissolved in chloroform, washed with 1N HCl, saturated NaHCO3, brine, and dried over magnesium sulfate. The solution was concentrated to give 0.15 g of the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.[CH3:27][S:28]([C:31]1[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=1)(=[O:30])=[O:29]>ClC1C=CC=CC=1Cl.Cl.COC(C)(C)C>[Cl:1][C:2]1[C:3]([NH:35][C:34]2[CH:33]=[CH:32][C:31]([S:28]([CH3:27])(=[O:30])=[O:29])=[CH:37][CH:36]=2)=[C:4]2[NH:10][C:9]([C:11]3[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH2:19][N:20]4[CH2:21][CH2:22][O:23][CH2:24][CH2:25]4)=[CH:15][CH:16]=3)=[N:8][C:5]2=[N:6][CH:7]=1
Reactant: Clc1cnc2[nH]c(-c3ccc(OCCN4CCOCC4)cc3)nc2c1Cl
Reactant: CS(=O)(=O)c1ccc(N)cc1
Agent: Cl
Solvent: Clc1ccccc1Cl
Solvent: COC(C)(C)C
Product: CS(=O)(=O)c1ccc(Nc2c(Cl)cnc3nc(-c4ccc(OCCN5CCOCC5)cc4)[nH]c23)cc1
Temperature: 180 °C
Yield: 26.5 %

Procedure:
6,7-Dichloro-2-[4-(2-morpholin-4-ylethoxy)phenyl]-3H-imidazo[4,5-b]pyridine (Example 206) (0.02 g, 0.05 mmol) and 4-(methylsulfonyl)aniline (0.1 g) were dissolved in o-dichlorobenzene (0.7 ml) and 4 drops of concentrated HCl were added and the reaction mixture was heated in a microwave oven at 180° C. for 10 min. The reaction mixture was diluted with tert-butyl methyl ether (5 ml) and extracted with 2M HCl (10 ml). The aqueous phase was basified with 10M NaOH and extracted with EtOAc. The organic phase was evaporated in vacuo and the residue was dissolved in CH3CN (2 ml) and purified by HPLC-C is, giving the title product (7 mg, 26%).
Reaction SMILES: B(Br)(Br)Br.[C:5]([NH:13][C@@:14]1([C:26]([O:28]C)=[O:27])[CH2:23][CH2:22][C:21]2[C:16](=[C:17]([O:24]C)[CH:18]=[CH:19][CH:20]=2)[CH2:15]1)(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Cl-].[NH4+].C(OCC)(=O)C>ClCCl>[C:5]([NH:13][C@@:14]1([C:26]([OH:28])=[O:27])[CH2:23][CH2:22][C:21]2[C:16](=[C:17]([OH:24])[CH:18]=[CH:19][CH:20]=2)[CH2:15]1)(=[O:12])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: COC(=O)[C@]1(NC(=O)c2ccccc2)CCc2cccc(OC)c2C1
Agent: BrB(Br)Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(N[C@@]1(C(=O)O)CCc2cccc(O)c2C1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.8 %

Procedure:
28.7 ml of boron tribromide solution (1M in dichloromethane) were added dropwise under argon and while cooling with ice to a solution of 1.95 g (5.75 mmol) of methyl (S)-2-benzamido-8-methoxy-1,2,3,4-tetrahydro-naphthalene-2-carboxylate in 15 ml of dichloromethane. The reaction mixture was stirred at 0° for 30 minutes and at room temperature for 3 hours and then poured into a mixture of ice, saturated ammonium chloride solution and ethyl acetate. The organic phase was separated, extracted with saturated sodium chloride solution, dried over MgSO4 and concentrated. The residue was dried in a high vacuum, suspended in diethyl ether/hexane (1:4) and filtered off. The filter residue was dried, there being obtained 1.75 g (97.8%) of (S)-2-benzamido-8-hydroxy-1,2,3,4-tetrahydro-naphthalene-2-carboxylic acid. [α]D =+84.3° (c=0.3, methanol). IR (KBr): 3362m(br.), 3064w, 3022w, 2976w, 2938w, 2620w, 1718s, 1644s, 1588m, 1523s, 1487m, 1467s, 1330m, 1278s, 1082w, 716m.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11](F)[C:12]=3[F:14])[C:7](=[O:16])[CH:6]([C:17]([OH:19])=[O:18])[CH2:5]2)[CH2:3][CH2:2]1.[CH:20]12[CH2:27][NH:26][CH2:25][CH:24]1[CH2:23][CH2:22][NH:21]2>CS(C)=O>[CH:20]12[CH2:27][N:26]([C:11]3[C:12]([F:14])=[C:13]4[C:8]([C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5][N:4]4[CH:1]4[CH2:3][CH2:2]4)=[CH:9][CH:10]=3)[CH2:25][CH:24]1[CH2:23][CH2:22][NH:21]2
Reactant: C1CC2CNCC2N1
Reactant: O=C(O)C1CN(C2CC2)c2c(ccc(F)c2F)C1=O
Solvent: CS(C)=O
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3CC4CCNC4C3)ccc2c1=O

Procedure:
620 mg (2.3 mmol) of 1-cyclopropyl-7,8-difluoro-1,3-dihydro-4-oxo-3-quinolinecarboxylic acid together with 315 mg (2.8 mmol) of 2,7-diazabicyclo[3.3.0]octane and 0.51 g (4.6 mmol) of 1,4-diazabicyclo[2.2.21]octane are heated for two hours at 120° C. in 23 ml of dimethyl sulphoxide. All volatile components are removed under a high vacuum, and the residue is stirred thoroughly with acetonitrile and dried at approximately 100° C.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([CH2:8][CH2:9][C:10]([NH:12][CH3:13])=[O:11])=[O:7])=[CH:4][CH:3]=1.[CH2:16]([CH:18]1[O:20][CH2:19]1)Cl.N1CCCCC1.[OH-].[Na+]>ClCCl>[O:20]1[CH2:19][CH:18]1[CH2:16][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([CH2:8][CH2:9][C:10]([NH:12][CH3:13])=[O:11])=[O:7])=[CH:14][CH:15]=1
Reactant: ClCC1CO1
Reactant: CNC(=O)CCC(=O)c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCNCC1
Solvent: ClCCl
Product: CNC(=O)CCC(=O)c1ccc(OCC2CO2)cc1
Yield: 81.1 %

Procedure:
A mixture of finely ground 3-(4-hydroxybenzoyl)-N-methylpropionamide (20.7 g, 0.1 mole), epichlorohydrin (77 g, 0.83 mole), and piperidine (0.5 ml) was heated on a steam bath for 90 minutes. Evaporation under reduced pressure gave a viscous oil which was dissolved in dichloromethane (500 ml) and shaken with dilute sodium hydroxide (100 ml). The organic phase was washed with water, dried and evaporated to a slurry. Addition of ether gave the required 3-[4-(2,3-epoxypropoxy)benzoyl]-N-methylpropionamide (21.36g.,81%) which was recrystallised from chloroform/ether, m.p. 133°-140° C.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[C:8]([C:11]([O:13]C)=[O:12])[N:7]=[CH:6][C:5]=2[CH:4]=[CH:3]1.[OH-].[Na+]>CO.[Cl-].[Na+].O>[CH3:1][N:2]1[C:10]2[CH:9]=[C:8]([C:11]([OH:13])=[O:12])[N:7]=[CH:6][C:5]=2[CH:4]=[CH:3]1
Reactant: COC(=O)c1cc2c(ccn2C)cn1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cn1ccc2cnc(C(=O)O)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 79.9 %

Procedure:
In a 500 mL pear flask was added methyl 1-methyl-1H-pyrrolo[3,2-c]pyridine-6-carboxylate (1B, 14 g, 71 mmol) in methanol (71.0 ml). At 0° C. was added 1N sodium hydroxide solution (140 ml, 140 mmol). This was then stirred at 0° C. for 1 h, when the reaction was complete. Brine (25 ml) was added and methanol was removed in vacuo. The aqueous mixture was washed twice with EtOAc. The aqueous layer was then acidified to pH 4; the resulting precipitate was collected on a fritted glass funnel and dried overnight under a stream of nitrogen to give the desired product 1-methyl-1H -pyrrolo[3,2-c]pyridine-6-carboxylic acid (1C, 10 g, 83% yield) as an off white powder. This was used in next step without further purification.
Reaction SMILES: [Cl:1]C(OC(Cl)C)=O.C([N:15]1[CH2:41][CH2:40][CH2:39][C:17]2([O:21][CH2:20][C:19]([C:22]3[CH:27]=[C:26]([N:28]4[C:32]([C:33]([F:36])([F:35])[F:34])=[N:31][N:30]=[N:29]4)[CH:25]=[CH:24][C:23]=3[O:37][CH3:38])=[CH:18]2)[CH2:16]1)C1C=CC=CC=1>ClCCl>[ClH:1].[CH3:38][O:37][C:23]1[CH:24]=[CH:25][C:26]([N:28]2[C:32]([C:33]([F:35])([F:36])[F:34])=[N:31][N:30]=[N:29]2)=[CH:27][C:22]=1[C:19]1[CH2:20][O:21][C:17]2([CH2:39][CH2:40][CH2:41][NH:15][CH2:16]2)[CH:18]=1
Reactant: COc1ccc(-n2nnnc2C(F)(F)F)cc1C1=CC2(CCCN(Cc3ccccc3)C2)OC1
Reactant: CC(Cl)OC(=O)Cl
Solvent: ClCCl
Product: COc1ccc(-n2nnnc2C(F)(F)F)cc1C1=CC2(CCCNC2)OC1
Product: Cl
Temperature: -4 °C
Reaction time: 0.5 h

Procedure:
1-Chloroethyl chloroformate (1.9 ml, 17.6 mmol) was added dropwise at 4° C. to a solution of 7-benzyl-3-(2-methoxy-5-(5-trifluoromethyl-1H-tetrazol-1-yl)phenyl)-1-oxa-7-azaspiro[4,5]dec-3-ene (free base of Ex. 2; 6.16 g, 13.07 mmol) in dichloromethane (60 ml). The reaction mixture was stirred at -4° C. for 30 minutes, allowed to warm to room temperature over 30 minutes and stirred at room temperature for 15 minutes. The reaction mixture was concentrated in vacuo, the residual red oil dissolved in methanol (60 ml) and heated at reflux for 40 minutes. The mixture was allowed to cool, concentrated in vacuo and the residue triturated with ether to give a title compound in two crops (3.54 g, 65%), m.p. 203°-205° C.; (Found: C, 48.33; H, 4.44; N, 16.31. C17H19ClF3N5O2. 0.25H2O requires C, 48.35; H, 4.65; N, 16.58%); δH (360MHz, DMSO-d6) 1.72-1.96 (4H, m), 2.85 (1H, m), 3.11 (3H, m), 4.00 (3H, s, ArOCH3), 4.99 (2H, m, 2-CH2, 6.64 (1H, br s, 4-CH=), 7.38 (1H, d, J 8.9Hz, 3'-H), 7.65 (1H, d, J 2.5Hz, 6'-H), 7.76 (1H, dd, J 8.9, 2.5Hz, 4'-H); m/z (ES+) 382 ([M+H]+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([OH:8])[CH:7]=1.[H-].[Na+].[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:25]([C:27]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[N:29]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:28]=2Cl)=[O:26])[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]>CN1C(=O)CCC1>[C:12]([O:16][C:17]([N:19]1[CH2:20][CH2:21][N:22]([C:25]([C:27]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[N:29]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:28]=2[O:8][C:6]2[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[CH3:9])=[O:26])[CH2:23][CH2:24]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2c(Cl)n(-c3ccccc3)c3ccccc23)CC1
Reactant: Cc1ccc(F)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: Cc1ccc(F)cc1Oc1c(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c2ccccc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 38.1 %

Procedure:
To a solution of 5-fluoro-2-methylphenol (43.0 mg, 341 μmol) in NMP (1.5 ml) was added sodium hydride (15.0 mg, 375 μmol; 60% dispersion in mineral oil), and the suspension was stirred at room temperature under an argon atmosphere for 20 min. After addition of 50.0 mg (114 μmol) of the compound of step 1, the reaction mixture was stirred for 2 h at 150° C. in a microwave reactor. The mixture was filtered and purified by preparative HPLC. The eluate was lyophilized overnight to give 23 mg of the title compound.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[C:6]([NH:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:5]=1.C([O:21][CH2:22][C:23]1[CH:27]=[CH:26][O:25][C:24]=1[C:28](=[O:31])[CH2:29]Br)(=O)C.O>CN(C=O)C>[NH2:9][C:8]1[C:7]2[C:6](=[CH:5][C:4]([Cl:3])=[CH:11][CH:10]=2)[N:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:29]=1[C:28]([C:24]1[O:25][CH:26]=[CH:27][C:23]=1[CH2:22][OH:21])=[O:31]
Reactant: CCOC(=O)Nc1cc(Cl)ccc1C#N
Reactant: CC(=O)OCc1ccoc1C(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)n1c(C(=O)c2occc2CO)c(N)c2ccc(Cl)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 15.8 %

Procedure:
To a suspension of sodium hydride (60% w/w dispersion in mineral oil, 390 mg, 8.8 mmol) in DMF (20 ml) was added a solution of 4-chloro-2-(ethoxycarbonylamino)benzonitrile (step 1, 2 g, 8.8 mmol) in DMF (5 ml) at 0° C. After stirring for 1 h at 0° C., 3-acetoxymethyl-2-(bromoacetyl)furan (step 1, 2.3 g, 8.8 mmol) was added and the resulting mixture was stirred at room temperature for an additional 6 h. The mixture was poured into water (100 ml), and extracted with ethyl acetate (300 ml). The organic extract was washed with saturated aqueous sodium bicarbonate (100 ml), brine (100 ml), and then dried (MgSO4) and concentrated. The residue was diluted with a mixture of ethanol (20 ml) and water (10 ml), and then potassium carbonate (ca. 2 g) was added. After stirring for 6 h, the mixture was poured into a saturated aqueous ammonium chloride (100 ml) and the mixture extracted with ethyl acetate (300 ml). The organic extract was washed with brine (100 ml), dried (MgSO4) and concentrated. The residue was purified by flash column chromatography eluting with ethyl acetate/hexane (2/1) to give 505 mg (16%) of the titled compound as yellow solids. Mass; M+=362
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[C:4](=[N:8]O)[C:5](=[O:7])[CH3:6].[C:11](O)(=[O:13])[CH3:12]>C(OC(=O)C)(=O)C.[Pd]>[CH3:1][O:2][C:3](=[O:10])[CH:4]([NH:8][C:11](=[O:13])[CH3:12])[C:5](=[O:7])[CH3:6]
Reactant: CC(=O)O
Reactant: COC(=O)C(=NO)C(C)=O
Agent: [Pd]
Solvent: CC(=O)OC(C)=O
Product: COC(=O)C(NC(C)=O)C(C)=O
Reaction time: 20 h
Yield: 60 %

Procedure:
Part B: Crude 2-hydroxyimino-3-oxo-butyric acid methyl ester (24 gram, ˜0.15 mol) dissolved in a magnetically stirred mixture of acetic acid (293 ml), acetic acid anhydride (110 ml) and Pd/C (4 gram) was hydrogenated for 20 hours at room temperature at 1 atmosphere H2 pressure. After filtration over hyflo, the acetic acid and acetic acid anhydride were removed by concentration in vacuo. The resulting crude mixture was purified by flash chromatography (dichloromethane/methanol=95/5 (v/v)) to give 2-acetylamino-3-oxo-butyric acid methyl ester (16.7 gram, 60% yield) as a white solid. Rf (dichloromethane/methanol=95/5 (v/v))=0.4. 1H-NMR (400 MHz, CDCl3): 2.08 (s, 3H), 2.40 (s, 3H), 3.83 (s, 3H), 5.29 (d, J˜7, 1H), 6.71 (br s, 1H).
Reaction SMILES: [Br:1][CH:2](Br)[C:3]([C:5]1C=CC=[CH:7][CH:6]=1)=O.[CH2:12]([NH:19][CH2:20][CH2:21][C:22]#[N:23])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(C(C)C)CC)(C)C.[CH3:33][C:34]([CH3:36])=[O:35]>>[CH2:12]([N:19]([CH2:33][C:34]([C:36]1[CH:7]=[CH:6][CH:5]=[CH:3][C:2]=1[Br:1])=[O:35])[CH2:20][CH2:21][C:22]#[N:23])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N#CCCNCc1ccccc1
Reactant: CC(C)=O
Reactant: O=C(c1ccccc1)C(Br)Br
Solvent: CCN(C(C)C)C(C)C
Product: N#CCCN(CC(=O)c1ccccc1Br)Cc1ccccc1
Reaction time: 12 h

Procedure:
A solution of 97.5 g of 2-bromo-α-bromoacetophenone in 200 ml of acetone is poured dropwise, at ambient temperature, into a solution of 61.7 g de N-benzyl-2-cyanoethylamine and 67 ml of diisopropylethylamine in 200 ml of acetone. After stirring for 12 hours, the reaction mixture is evaporated, taken up in ether, washed twice with 500 ml of water each time and dried. After evaporating under reduced pressure, 131.9 g of expected product are obtained.
Reaction SMILES: C(CO[C:6]1[CH:7]=[C:8](/[C:13](=[CH:46]\[CH:47]=[C:48]2\[N:49]([CH2:71][CH2:72][CH2:73][S:74]([O-:77])(=[O:76])=[O:75])[C:50]3[CH:51]=[CH:52][C:53]4[C:62](S([O-])(=O)=O)=[CH:61][C:60](S([O-])(=O)=O)=[CH:59][C:54]=4[C:55]=3[C:56]\2([CH3:58])[CH3:57])/[CH:14]=[CH:15]/[C:16]2[C:24]([CH3:26])([CH3:25])[C:23]3[C:22]4[CH:27]=[C:28](S([O-])(=O)=O)[CH:29]=[C:30](S([O-])(=O)=O)[C:21]=4[CH:20]=[CH:19][C:18]=3[N+:17]=2[CH2:39][CH2:40][CH2:41][S:42]([O-:45])(=[O:44])=[O:43])[CH:9]=[C:10](F)[CH:11]=1)(O)=O.[Na+:78].[Na+].[Na+].[Na+].[Na+].Br/C(=C\C=C1\N(CCCS([O-])(=O)=O)C2C=CC3C=CC=CC=3C=2C\1(C)C)/C=C/C1C(C)(C)C2C3C=CC=CC=3C=CC=2[N+]=1CCCS([O-])(=O)=O.[Na+].[OH:134][CH2:135][CH2:136][CH2:137][CH2:138][O:139]C1C=C(B(O)O)C=CC=1>>[CH3:58][C:56]1([CH3:57])[C:55]2[C:54]3[CH:59]=[CH:60][CH:61]=[CH:62][C:53]=3[CH:52]=[CH:51][C:50]=2[N:49]([CH2:71][CH2:72][CH2:73][S:74]([O-:77])(=[O:75])=[O:76])/[C:48]/1=[CH:47]/[CH:46]=[C:13](\[C:8]1[CH:7]=[CH:6][CH:11]=[C:10]([O:134][CH2:135][CH2:136][CH2:137][CH2:138][OH:139])[CH:9]=1)/[CH:14]=[CH:15]/[C:16]1[C:24]([CH3:25])([CH3:26])[C:23]2[C:22]3[CH:27]=[CH:28][CH:29]=[CH:30][C:21]=3[CH:20]=[CH:19][C:18]=2[N+:17]=1[CH2:39][CH2:40][CH2:41][S:42]([O-:45])(=[O:43])=[O:44].[Na+:78]
Reactant: CC1(C)C(/C=C/C(=C/C=C2/N(CCCS(=O)(=O)[O-])c3ccc4c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc4c3C2(C)C)c2cc(F)cc(OCC(=O)O)c2)=[N+](CCCS(=O)(=O)[O-])c2ccc3c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc3c21
Reactant: OCCCCOc1cccc(B(O)O)c1
Agent: CC1(C)C(/C=C/C(Br)=C/C=C2/N(CCCS(=O)(=O)[O-])c3ccc4ccccc4c3C2(C)C)=[N+](CCCS(=O)(=O)[O-])c2ccc3ccccc3c21
Agent: [Na+]
Product: CC1(C)C(/C=C/C(=C/C=C2/N(CCCS(=O)(=O)[O-])c3ccc4ccccc4c3C2(C)C)c2cccc(OCCCCO)c2)=[N+](CCCS(=O)(=O)[O-])c2ccc3ccccc3c21

Procedure:
Compound 40 is prepared analogously to compounds 16 and 29, except with sodium 3-(2-((1E,3Z,5E)-3-bromo-5-(1,1-dimethyl-3-(3-sulfonatopropyl)-1H-benzo[e]indol-2(3H)-ylidene)penta-1,3-dienyl)-1,1-dimethyl-1H-benzo[e]indolium-3-yl)propane-1-sulfonate and 3-(4-hydroxybutoxy)phenylboronic acid as starting materials.
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[CH2:10][C@H:9](N)[CH2:8][CH2:7][C@@H:6]1[N:12]1[CH2:16][CH2:15][C@H:14]([NH:17][C:18](=[O:27])[O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:13]1=[O:28])(=[O:3])[CH3:2].C(C1C(=O)C(=[O:43])C=C(C(C)(C)C)C=1)(C)(C)C>CO.CCOC(C)=O>[C:1]([NH:4][C@@H:5]1[CH2:10][C:9](=[O:43])[CH2:8][CH2:7][C@@H:6]1[N:12]1[CH2:16][CH2:15][C@H:14]([NH:17][C:18](=[O:27])[O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:13]1=[O:28])(=[O:3])[CH3:2]
Reactant: CC(C)(C)C1=CC(=O)C(=O)C(C(C)(C)C)=C1
Reactant: CC(=O)N[C@@H]1C[C@H](N)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(=O)N[C@@H]1CC(=O)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of benzyl (S)-1-((1S,2R,4R)-2-acetamido-4-aminocyclohexyl)-2-oxopyrrolidin-3-ylcarbamate (13.3 g, 34 mmol) and 3,5-di-tert-butylcyclohexa-3,5-diene-1,2-dione (7.54 g, 34 mmol) in methanol (160 ml) was stirred at room temperature for 2 h. The solution was concentrated and diluted with acetone (132 ml) and water (33 ml), followed by addition of Dowex-50WX8-200 (33 g). The reaction was stirred at room temperature for 2 h. Dowex-50WX8-200 was removed by filtration and washed with dichloromethane (300 ml). The filtrate was concentrated under vacuum to remove most of acetone. The residue was diluted with dichloromethane (200 ml) and washed with aqueous NaHCO3 solution (200 ml) and brine (200 ml). The combined aqueous layers were extracted with dichloromethane (2×100 ml). The combined organic extracts were dried over Na2SO4 and concentrated. The product benzyl (S)-1-((1S,2R)-2-acetamido-4-oxocyclohexyl)-2-oxopyrrolidin-3-ylcarbamate was obtained as a solid (12 g, 90% yield) by crystallization in EtOAc (100 ml) and Hexane (200 ml). 1H-NMR (500 MHz, DMSO-d6) δ ppm 7.99 (d, J=9.35 Hz, 1H), 7.44 (d, J=8.80 Hz, 1H), 7.28-7.39 (m, 5H), 5.03 (s, 2H), 4.50 (s, 1H), 4.31 (d, J=12.10 Hz, 1H), 4.18 (q, J=8.98 Hz, 1H), 3.27 (m, 2H), 2.82 (dd, J=15.12, 5.22 Hz, 1H), 2.52-2.65 (m, 1H), 2.40 (dd, J=12.92, 4.67 Hz, 1H), 2.15-2.31 (m, 2H), 2.09 (d, J=15.40 Hz, 1H), 1.90 (m, 1H), 1.81 (s, 3H), 1.68 (m, 1H). m/z: 388.46 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:13][CH:12]([CH3:14])[C:11](=[O:15])[N:10]([C@@H:16]([CH2:24][CH3:25])[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@@H:9]2[C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:33](Br)[CH:34]=C.[Li+].[CH3:38][Si]([N-][Si](C)(C)C)(C)C.[NH4+].[Cl-]>C1COCC1>[CH2:14]([C:12]1([CH3:38])[CH2:13][C@H:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C@@H:9]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[N:10]([C@@H:16]([CH2:24][CH3:25])[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:11]1=[O:15])[CH:33]=[CH2:34]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC[C@@H](C(=O)OC(C)(C)C)N1C(=O)C(C)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reactant: C=CCBr
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CCC1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)C(=O)OC(C)(C)C)C1=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 10.2 g (21.4 mmol) of (2S)-tert-butyl 2-((2S,3R)-3-(3-chlorophenyl)-2-(4-chlorophenyl)-5-methyl-6-oxopiperidin-1-yl)butanoate (Example 66, Step B, mixture of diastereomers) and allyl bromide (7.24 mL, 86 mmol) in THF (210 mL) was added LHMDS, (1.0M solution in THF; 64.2 mL, 64.2 mmol) at R.T. Let it stir at R.T. for 5 min. Then the reaction mixture was heated at 50° C. for 3 h. Sat. aq. NH4Cl solution was added and the mixture was extracted with CH2Cl2. The combined organic layers were washed with water and sat. aq. NaCl solution, dried over MgSO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography, eluting with a gradient of 0% to 20% EtOAc in hexane, to provide the title compound as a mixture of stereoisomers at C-3.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH:11]1[C:24]2[C:23]3([CH2:26][N:27]4[CH2:32][CH2:31][CH:30]([CH2:33][OH:34])[CH2:29][CH2:28]4)[CH2:25][CH:16]([C:17]4[C:22]3=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:15]=2[CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C.[OH-].[Na+]>ClCCl>[CH:21]1[C:22]2[C:23]3([CH2:26][N:27]4[CH2:32][CH2:31][CH:30]([CH:33]=[O:34])[CH2:29][CH2:28]4)[CH2:25][CH:16]([C:15]4[C:24]3=[CH:11][CH:12]=[CH:13][CH:14]=4)[C:17]=2[CH:18]=[CH:19][CH:20]=1
Reactant: OCC1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=CC1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Temperature: -60 °C
Reaction time: 0.25 h
Yield: 79.3 %

Procedure:
A solution of oxalyl chloride (3.86 g, 30.4 mmol) in dichloromethane (100 mL) was cooled to -60° C. and treated dropwise with dimethylsulfoxide (2.49 g, 31.89 mmol), resulting in vigorous gas evolution. The resulting mixture was stirred at -60° C. for 15 min, then was treated dropwise with a solution of 1-(9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)4- piperidinemethanol (6.47 g, 20.25 mmol) in dichloromethane (30 mL). This mixture was stirred at -60° C. for 1 h, then was treated with triethylamine (6.15 g, 60.75 mmol). The reaction was allowed to warm to room temperature, then was poured into 10% aqueous sodium hydroxide (50 mL) and extracted with chloroform (3×75 mL). The organic extracts were washed sequentially with 1N aqueous sodium hydroxide (50 mL) and brine (50 mL), combined, dried (K2CO3), filtered and evaporated to leave a tan solid. Trituration with hexane (50 mL) followed by filtration gave the title compound (5.09 g, 16.05 mmol, 79%) as a tan solid. 1H NMR (d6-DMSO): δ9.57 (s, 1H, CHO), 7.28 (m, 2H), 7.17 (m, 2H), 6.91 (m, 4H), 4.30 (s, 1H, H--C(10)), 3.34 (s, 2H, CH2N), 2.86 (m, 2H, eq-H--C(2')), 2.45 (s, 2H, H--C(11)), 2.29 (m, 3H, ax-H--C(2'), H--C(4')), 1.76 (m, 2H, eq-H--C(3')), 1.45 (m, 2H, ax-H--C(3')).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[F:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[C:13]2[CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.Cl[CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[O:40][CH3:41])[CH2:30][CH2:29]1>C(#N)C.O>[F:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[C:13]2[CH:19]1[CH2:24][CH2:23][N:22]([CH2:26][CH2:27][N:28]2[CH2:29][CH2:30][N:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[O:40][CH3:41])[CH2:32][CH2:33]2)[CH2:21][CH2:20]1
Reactant: Fc1ccc2[nH]cc(C3CCNCC3)c2c1
Reactant: COc1ccccc1N1CCN(CCCl)CC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COc1ccccc1N1CCN(CCN2CCC(c3c[nH]c4ccc(F)cc34)CC2)CC1
Yield: 82.7 %

Procedure:
Pulverized potassium carbonate (0.35 g, 2.5 mmole) and potassium iodide (0.44 g, 2.5 mmole) was added to a mixture of 4-(5-fluoro-1H-indol-3-yl)piperidine (0.5 g, 2.3 mmole) and 1-(2-chloroethyl)-4-(2-methoxyphenyl)piperazine (0.58 g, 2.3 mmole) in 20 ml of acetonitrile. The resulting mixture was heated to reflux under nitrogen for 3 hours. After cooling, it was diluted with water (150 ml) and the product extracted into ethyl acetate (50 ml). The organic layer was washed with water (50 ml), brine (50 ml), and after drying over sodium sulfate, filtration and concentration in vacuo afforded the required product as a white solid (0.83 g, 83 %). Treatment with an excess of 1M etheral hydrochloric acid gave the acid addition salt, which was recrystallized from methanol.