Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:12]([C:13]2[C:21]3[C:20]([NH2:22])=[N:19][CH:18]=[N:17][C:16]=3[N:15]([CH3:23])[CH:14]=2)=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH2:7][NH:8]2.[F:24][C:25]([F:37])([F:36])[C:26]1[N:31]=[C:30]([CH2:32][C:33](O)=[O:34])[CH:29]=[CH:28][CH:27]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C)C=O.O>[Cl:3][C:4]1[C:12]([C:13]2[C:21]3[C:20]([NH2:22])=[N:19][CH:18]=[N:17][C:16]=3[N:15]([CH3:23])[CH:14]=2)=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH2:7][N:8]2[C:33](=[O:34])[CH2:32][C:30]1[CH:29]=[CH:28][CH:27]=[C:26]([C:25]([F:24])([F:37])[F:36])[N:31]=1
Reactant: Cn1cc(-c2ccc3c(c2Cl)CCN3)c2c(N)ncnc21
Reactant: O=C(O)Cc1cccc(C(F)(F)F)n1
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: O
Solvent: CN(C)C=O
Product: Cn1cc(-c2ccc3c(c2Cl)CCN3C(=O)Cc2cccc(C(F)(F)F)n2)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.2 %

Procedure:
To a solution of 5-(4-chloro-2,3-dihydro-1H-indol-5-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine 2HCl (300 mg, 0.805 mmol), [6-(trifluoromethyl)-2-pyridinyl]acetic acid (90 wt %) (183 mg, 0.805 mmol), HATU (306 mg, 0.805 mmol), in N,N-Dimethylformamide (DMF) (50 mL) under nitrogen at 0° C. was added DIEA (0.562 mL, 3.22 mmol). The reaction was stirred overnight at room temperature, then poured into water and stirred for one hour. A brown precipitate formed which was collected by filtration and washed with water. The solid was dissolved in ca. 25 mL chloroform, and purified by flash chromatography (0-100% EtOAc in chloroform→0-10% MeOH in EtOAc, 24-g column) to afford 5-(4-chloro-1-{[6-(trifluoromethyl)-2-pyridinyl]acetyl}-2,3-dihydro-1H-indol-5-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (161.5 mg) as an off-white solid. LC-MS (ES) m/z=487 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.22-3.30 (m, 2H), 3.74 (s, 3H), 4.22 (s, 2H), 4.37 (t, J=8.34 Hz, 2H), 5.72-6.02 (m, 2H), 7.18-7.25 (m, 2H), 7.71 (d, J=7.83 Hz, 1H), 7.83 (d, J=7.58 Hz, 1H), 8.01 (d, J=8.34 Hz, 1H), 8.10 (t, J=7.96 Hz, 1H), 8.13 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[NH:10][C:8](=[O:9])[C:7]2=[CH:13][CH:14]=1)([O-:3])=[O:2].[CH:15]1([CH2:18]Br)[CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:15]1([CH2:18][N:10]2[C:11](=[O:12])[C:6]3=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:14][CH:13]=[C:7]3[C:8]2=[O:9])[CH2:17][CH2:16]1
Reactant: O=C1NC(=O)c2cc([N+](=O)[O-])ccc21
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1c2ccc([N+](=O)[O-])cc2C(=O)N1CC1CC1
Temperature: 100 °C
Yield: 82.4 %

Procedure:
4-Nitrophthalimide (6.15 g, 32.0 mmol) was dissolved in DMF (60 mL). Cyclopropylmethyl bromide (9.3 mL, 96 mmol) and potassium carbonate (8.85 g, 64.0 mmol) were added and the mixture was heated to 100° C. for 4 hours. The mixture was allowed to cool to room temperature, and then partitioned between water (500 mL) and ethyl acetate (400 mL). The organic phase was collected, dried with Na2SO4, filtered and taken to dryness using rotary evaporation. The residue was dried overnight in a vacuum oven to afford 6.49 g (82%) of pure N-cyclopropylmethyl-4-nitrophthalimide as a powder.
Reaction SMILES: C(OC([N:8]1[CH2:26][CH2:25][C@@H:11]2[N:12]([CH3:24])[C:13]3[C:14]([C:20]([F:23])([F:22])[F:21])=[CH:15][C:16](Br)=[CH:17][C:18]=3[C@@H:10]2[CH2:9]1)=O)(C)(C)C.[NH2:27][C:28]1[C:29]([O:34][CH3:35])=[N:30][CH:31]=[CH:32][CH:33]=1.CC([O-])(C)C.[Na+]>>[CH3:35][O:34][C:29]1[C:28]([NH:27][C:16]2[CH:15]=[C:14]([C:20]([F:21])([F:22])[F:23])[C:13]3[N:12]([CH3:24])[C@H:11]4[CH2:25][CH2:26][NH:8][CH2:9][C@H:10]4[C:18]=3[CH:17]=2)=[CH:33][CH:32]=[CH:31][N:30]=1
Reactant: CN1c2c(cc(Br)cc2C(F)(F)F)[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]21
Reactant: COc1ncccc1N
Agent: CC(C)(C)[O-]
Agent: [Na+]
Product: COc1ncccc1Nc1cc2c(c(C(F)(F)F)c1)N(C)[C@H]1CCNC[C@@H]21

Procedure:
The title compound was prepared by following the general Method A as a yellow solid (25 mg, 13%) from (4aS,9bR)-8-bromo-5-methyl-6-trifluoromethyl-1,3,4,4a,5,9b-hexahydro-pyrido[4,3-b]indole-2-carboxylic acid tert-butyl ester (Example 45, 217 mg, 0.5 mmol), 3-amino-2-methoxy-pyridine (186 mg, 1.5 mmol) and NaOt-Bu (144 mg, 1.5 mmol). MS (ESI): 379 (base, M+H).
Reaction SMILES: [C:1]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:6]=[CH:5][C:4]([C:7]2[N:12]=[C:11]3[N:13]=[C:14]([S:24]([CH3:27])(=O)=O)[N:15](COCC[Si](C)(C)C)[C:10]3=[CH:9][C:8]=2[Cl:28])=[CH:3][CH:2]=1.C1(C2[O:46][C@H:45]3[CH2:47][C@@H](S)[CH2:49][O:50][C@@H:44]3[CH2:43][O:42]2)C=CC=CC=1.[H-].[Na+].C(=O)(O)[O-].[Na+].[OH-].[Na+].Cl>CN(C=O)C>[C:1]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:2]=[CH:3][C:4]([C:7]2[N:12]=[C:11]3[N:13]=[C:14]([S:24][C@H:27]4[CH2:49][O:50][C@H:44]([CH2:43][OH:42])[C@@H:45]([OH:46])[CH2:47]4)[NH:15][C:10]3=[CH:9][C:8]=2[Cl:28])=[CH:5][CH:6]=1
Reactant: C[Si](C)(C)CCOCn1c(S(C)(=O)=O)nc2nc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc21
Reactant: S[C@H]1CO[C@@H]2COC(c3ccccc3)O[C@H]2C1
Agent: Cl
Agent: O=C([O-])O
Agent: [H-]
Solvent: CN(C)C=O
Product: OC[C@H]1OC[C@H](Sc2nc3nc(-c4ccc(-c5ccccc5)cc4)c(Cl)cc3[nH]2)C[C@@H]1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 5-([1,1′-biphenyl]-4-yl)-6-chloro-2-(methylsulfonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridine (35 mg, 0.066 mmol) and (4aR,7R,8aS)-2-phenylhexahydropyrano[3,2-d][1,3]dioxine-7-thiol (21 mg, 0.082 mmol) under nitrogen in anhydrous DMF (0.7 mL) at room temperature was added NaH (4 mg, 0.102 mmol) in one portion. After stirring at room temperature for 1 hour, the mixture was poured into saturated aqueous sodium bicarbonate (30 mL) and extracted with EtOAc (60 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The resultant orange oil was dissolved in formic acid (1.0 mL). Then saturated aqueous potassium hydrogen sulfate (0.2 mL) was added and the mixture was stirred at 50° C. After 1.5 hours, the mixture was poured into saturated aqueous sodium bicarbonate (60 mL) and extracted with EtOAc (2×60 mL). The combined organic layers were concentrated under reduced pressure. The resultant white film was dissolved in methanol (3 mL). Then 5N aqueous NaOH (0.5 mL, 2.5 mmol) was added and the mixture was allowed to stir at room temperature. After 15 minutes, the mixture was neutralized with 1N aqueous HCl (2.5 mL, 2.5 mmol), poured into saturated aqueous sodium bicarbonate (30 mL) and extracted with EtOAc (60 mL). The organic layer was separated, dried over sodium sulfate and concentrated under reduced pressure. The resultant white film was chromatographed using a Biotage™ 20 g (2×10 g in series) silica gel cartridge eluted with 0-10% methanol in DCM over 20 column volumes. The combined product fractions were concentrated under reduced pressure, dissolved in MeCN and water, frozen at −78° C., and lyophilized to dryness to provide the title compound as a white solid. LC-MS: calculated for C24H22ClN3O3S 467.11, observed m/e: 468.10 (M+H)+ (Rt 2.03/4 min). 1H NMR δ (ppm)(CD3OD): 7.97 (s, 1H), 7.75-7.68 (m, 5H), 7.46 (t, J=7.5 Hz, 2H), 7.36 (t, J=7.5 Hz, 1H), 4.28 (dd, J=11.0, 4.5 Hz, 1H), 4.03 (m, 1H), 3.87 (dd, J=11.5, 0.8 Hz, 1H), 3.66-3.57 (m, 2H), 3.37 (t, J=11.0 Hz, 1H), 3.15 (m, 1H), 2.54 (m, 1H), 1.60 (q, J=12.0 Hz, 1H)
Reaction SMILES: O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+].[C:28]([O:32][C:33]([NH:35][C@:36]([CH:70]1[CH2:75][CH2:74][CH2:73][CH2:72][CH2:71]1)([C:38]([N:40]1[CH2:69][CH2:68][CH2:67][C@H:41]1[C:42]([NH:44][CH2:45][C:46]1[CH:51]=[C:50]([Cl:52])[CH:49]=[CH:48][C:47]=1[CH2:53][CH:54]([NH:58]C1C=CC(OC)=CC=1)[CH:55]([F:57])[F:56])=[O:43])=[O:39])N)=[O:34])([CH3:31])([CH3:30])[CH3:29]>O.CC#N>[NH2:58][CH:54]([CH:55]([F:57])[F:56])[CH2:53][C:47]1[CH:48]=[CH:49][C:50]([Cl:52])=[CH:51][C:46]=1[CH2:45][NH:44][C:42](=[O:43])[C@@H:41]1[CH2:67][CH2:68][CH2:69][N:40]1[C:38](=[O:39])[C@H:36]([NH:35][C:33]([O:32][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:34])[CH:70]1[CH2:71][CH2:72][CH2:73][CH2:74][CH2:75]1
Reactant: COc1ccc(NC(Cc2ccc(Cl)cc2CNC(=O)[C@@H]2CCCN2C(=O)[C@](N)(NC(=O)OC(C)(C)C)C2CCCCC2)C(F)F)cc1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)N1CCC[C@H]1C(=O)NCc1cc(Cl)ccc1CC(N)C(F)F)C1CCCCC1
Temperature: 25 °C
Yield: 56.1 %

Procedure:
A solution of CAN (0.274 g, 0.50 mmol) in water (2.0 mL) was added to a stirred solution of 1-{(2R)-2-[(tert-butoxycarbonyl)amino]-2-cyclohexylglycyl}-N-(5-chloro-2-{3,3-difluoro-2-[(4-methoxyphenyl)amino]propyl}benzyl)-L-prolinamide (0.168 g, 0.25 mmol) in CH3CN (3.0 mL) at 0° C. and the resulting solution was warmed to ambient temperature. After 18 h the solution was partitioned between EtOAc(20 mL) and 10% aqueous NH4OH (10 mL). The resulting two phase suspension was filtered and the organic layer was washed with 10% sodium sulfite and brine, dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (eluting with 5% methylene chloride, 70% ethyl acetate/hexanes followed by ammonium hydroxide/methanol/chloroform, 1:9:90) to give N-[2-(2-amino-3,3-difluoropropyl)-5-chlorobenzyl]-1-{(2R)-2-[(tert-butoxycarbonyl)amino]2-cyclohexylethanoyl}-L-prolinamide (0.0801 g) as an oil; MS m/z=571.4.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH:8]([CH:9]=[C:10]([O:15][CH3:16])[C:11]([F:14])([F:13])[F:12])[C:7]1([CH3:18])[CH3:17])=[O:5])C.[OH-].[Na+]>C(O)C.O>[CH3:17][C:7]1([CH3:18])[CH:8]([CH:9]=[C:10]([O:15][CH3:16])[C:11]([F:14])([F:13])[F:12])[CH:6]1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)C1C(C=C(OC)C(F)(F)F)C1(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COC(=CC1C(C(=O)O)C1(C)C)C(F)(F)F
Yield: 60.5 %

Procedure:
16.6 g (0.0624 mol) of 2,2-dimethyl-3-(3,3,3-trifluoro-2-methoxy-prop-1-enyl)-cyclopropanecarboxylic acid ethyl ester were dissolved in 100 ml of ethanol, a solution of 2.9 g (0.073 mol) of sodium hydroxide in 75 ml of water was then added and the mixture was heated to the reflux temperature for 4 hours, while stirring. The ethanol was then distilled off under a waterpump vacuum, the residue was taken up in 300 ml of water and the aqueous mixture was extracted once with 300 ml of methylene chloride. The aqueous phase was separated off, acidified with concentrated hydrochloric acid and then extracted twice with 300 ml of methylene chloride. The organic phase was then separated off over magnesium sulphate, dried and the solvent was distilled off under a waterpump vacuum. Last residues of solvent were removed by brief incipient distillation at a bath temperature of 50° C. under 2 mbar. 9 g (60.6% of theory) of 2,2-dimethyl-3-(3,3,3-trifluoro-2-methoxy-prop-1-enyl)-cyclopropanecarboxylic acid were then obtained as a yellow viscous oil.
Reaction SMILES: [OH-].[K+].[NH2:3][C:4]1[C:5]2[C:10]([N:11]=[C:12]3[C:17]=1[C:16](=[O:18])[CH2:15][CH2:14][CH2:13]3)=[CH:9][CH:8]=[CH:7][CH:6]=2.[F:19][C:20]([F:30])([F:29])[C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24]Br>C1(C)C=CC=CC=1.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[F:19][C:20]([F:29])([F:30])[C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24][NH:3][C:4]1[C:5]2[C:10]([N:11]=[C:12]3[C:17]=1[C:16](=[O:18])[CH2:15][CH2:14][CH2:13]3)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: Nc1c2c(nc3ccccc13)CCCC2=O
Reactant: FC(F)(F)c1cccc(CBr)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C1CCCc2nc3ccccc3c(NCc3cccc(C(F)(F)F)c3)c21
Reaction time: 1 h
Yield: 42 %

Procedure:
In 150 ml of toluene and 700 ml of 30% potassium hydroxide were combined 3.00 g of 9-amino-3,4-dihydroacridin-1(2H)-one and 0.72 g of tetrabutylammonium hydrogen sulfate. The reaction was mechanically stirred and heated with a steam bath. To it was added dropwise a solution of 13.5 g 3-trifluoromethylbenzyl bromide in 30 ml of toluene over 1 hour. After the addition, heating was continued 1 hour during which the reaction went to completion. The organic phase was separated, washed with ice-cold saturated NaCl solution, dried over anhydrous magnesium sulfate, filtered and evaporated to an oil. The oil was diluted with 10 ml of ethyl acetate and purified by preparative HPLC (ethyl acetate). The product-containing fractions were evaporated and recrystallized from DCM/hexane to yield 2.20 g of solid, mp 147°-149° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N+:5]([O-:9])[CH:6]=[CH:7][CH:8]=1.OS(O)(=O)=O.[N+:15]([O-])([OH:17])=[O:16].[OH-].[Na+]>>[CH3:1][O:2][C:3]1[CH:4]=[N+:5]([O-:9])[CH:6]=[CH:7][C:8]=1[N+:15]([O-:17])=[O:16]
Reactant: COc1ccc[n+]([O-])c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: COc1c[n+]([O-])ccc1[N+](=O)[O-]
Temperature: 75 °C
Yield: 41 %

Procedure:
A solution of 3-methoxypyridine-N-oxide (24 g, 0.19 mol) and con. H2SO4 (45 ml)was carefully prepared by adding the acid slowly to the solid N-oxide using an ice bath for cooling. After solution is effected, it is rapidly stirred and fuming nitric acid (45 ml) is added over 15 min. The reaction mixture was warmed to 75° C. for 2.5 hours. The contents were poured onto ice and neutralized to pH 9 with cooling using 50% NaOH. The mixture was extracted three times with CH2Cl2, dried, (Na2SO4) and solvent evaporated under reduced pressure to produce an oil. The crude product was chromatographed on silica gel using CH2Cl2 /MeOH (99:1) as the eluent to give 17.5 g (41%) of the pure product as a crystalline solid, m.p. 125°-127° C. The structural assignment is supported by the proton NMR spectrum.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:23])([F:22])[F:21])[CH:14]=1)[C:7]([C:24](O)=[O:25])=[CH:6]2)#[N:2].[OH:27][CH2:28][C@H:29]1[CH2:34][CH2:33][CH2:32][CH2:31][C@H:30]1[NH2:35]>>[OH:27][CH2:28][C@H:29]1[CH2:34][CH2:33][CH2:32][CH2:31][C@H:30]1[NH:35][C:24]([C:7]1[N:8]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:22])([F:23])[F:21])[CH:14]=2)[C:9]2[C:5]([CH:6]=1)=[CH:4][C:3]([C:1]#[N:2])=[CH:11][CH:10]=2)=[O:25]
Reactant: N[C@@H]1CCCC[C@@H]1CO
Reactant: N#Cc1ccc2c(c1)cc(C(=O)O)n2Cc1cccc(OC(F)(F)F)c1
Product: N#Cc1ccc2c(c1)cc(C(=O)N[C@@H]1CCCC[C@@H]1CO)n2Cc1cccc(OC(F)(F)F)c1

Procedure:
The title compound was prepared using 5-cyano-1-(3-trifluoromethoxy-benzyl)-1H-indole-2-carboxylic acid [prepared from 3-(trifluoromethoxy)benzyl bromide and ethyl 5-cyanoindole-2-carboxylate] and cis-2-hydroxymethyl-1-cyclohexylamine in a manner similar to that described in Example 11.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[O:50]=[C:51]1[C:60]2[C:55](=[CH:56][CH:57]=[C:58]([C:61]3[CH:62]=[C:63]([NH2:67])[CH:64]=[CH:65][CH:66]=3)[CH:59]=2)[O:54][CH:53]=[CH:52]1>CN(C=O)C>[O:50]=[C:51]1[C:60]2[C:55](=[CH:56][CH:57]=[C:58]([C:61]3[CH:62]=[C:63]([NH:67][C:23]([C:18]4[C:19](=[O:22])[O:20][C:21]5[C:16]([CH:17]=4)=[CH:15][CH:14]=[CH:13][C:12]=5[O:11][CH3:10])=[O:25])[CH:64]=[CH:65][CH:66]=3)[CH:59]=2)[O:54][CH:53]=[CH:52]1
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Reactant: Nc1cccc(-c2ccc3occc(=O)c3c2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc2cc(C(=O)Nc3cccc(-c4ccc5occc(=O)c5c4)c3)c(=O)oc12
Temperature: 25 °C
Yield: 98 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.014 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(4-oxo-4H-chromen-6-yl)-phenylamine (0.015 g, 0.065 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.028 g of product in 100% yield: LCMS (ESI) m/z 440 (MH+).
Reaction SMILES: C[O:2][C:3](=[O:32])[C:4]([CH3:31])([CH3:30])[CH2:5][C:6]1[N:7]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[C:8]2[C:13]([C:14]=1[S:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:12][C:11]([O:20][CH3:21])=[CH:10][CH:9]=2.C1COCC1.[Li+].[OH-]>CO>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([CH2:22][N:7]2[C:8]3[C:13](=[CH:12][C:11]([O:20][CH3:21])=[CH:10][CH:9]=3)[C:14]([S:15][C:16]([CH3:19])([CH3:17])[CH3:18])=[C:6]2[CH2:5][C:4]([CH3:31])([CH3:30])[C:3]([OH:32])=[O:2])=[CH:24][CH:25]=1
Reactant: COC(=O)C(C)(C)Cc1c(SC(C)(C)C)c2cc(OC)ccc2n1Cc1ccc(Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc2c(c1)c(SC(C)(C)C)c(CC(C)(C)C(=O)O)n2Cc1ccc(Cl)cc1
Temperature: 80 °C

Procedure:
The compound from Step A was hydrolysed using 325 mL of THF, 600 mL of MeOH and 325 mL of 1.0M LiOH. The solution was heated to 80° C. for 3 h. The solution was acidified with 1N HC1 and extracted with 3×200 mL of EtOAc. The organic phase was washed with water (2×150 mL) and dried over MgSO4. The solution was evaporated to dryness to provide the title compound. m.p. 190°-191° C. Anal C, H, N: Calc. C 65.27; H 6.57; N 3.04, Found C 65.28; H 6.58; N 3.04
Reaction SMILES: Cl[CH2:2][O:3][C:4](=[O:6])[CH3:5].[C:7]([NH:10][C:11]1[C:12]([I:27])=[C:13]([N:22]([C:24](=[O:26])[CH3:25])[CH3:23])[C:14]([I:21])=[C:15]([C:18]([O-:20])=[O:19])[C:16]=1[I:17])(=[O:9])[CH3:8].[Cs+].[I-].[Na+]>CN(C=O)C>[C:7]([NH:10][C:11]1[C:12]([I:27])=[C:13]([N:22]([C:24](=[O:26])[CH3:25])[CH3:23])[C:14]([I:21])=[C:15]([C:18]([O:20][CH2:2][O:3][C:4](=[O:6])[CH3:5])=[O:19])[C:16]=1[I:17])(=[O:9])[CH3:8]
Reactant: CC(=O)Nc1c(I)c(C(=O)[O-])c(I)c(N(C)C(C)=O)c1I
Reactant: CC(=O)OCCl
Agent: [Cs+]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1c(I)c(C(=O)OCOC(C)=O)c(I)c(N(C)C(C)=O)c1I
Reaction time: 21 h

Procedure:
Chloromethylacetate (Neuenschwander, Markus et. al., Helv. Chim. Acta, 61 (1978) 2047) (2.30 g, 21.2 mmol) in dry DMF (100 ml) is added dropwise at 50° C. to a solution of cesium 5-(N-acetylamino)-3-(N-acetyl-N-methylamino)-2,4,6-triiodobenzenecarboxylate (13.4 g, 17.7 mmol) and sodium iodide (133 mg, 0.89 mmol) in dry DMF (210 ml). The precipitate is removed by filtration after stirring for 21 hours and the solvent is removed at reduced pressure. The residue is dissolved in chloroform (200 ml) and washed four times with a saturated sodium hydrogen carbonate solution. After drying with magnesium sulfate the solvent is removed at reduced pressure to give the title compound:
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)S[C:6]=1[C:17]([O:19][CH3:20])=[O:18])(=[O:3])[CH3:2]>[Ni]>[CH3:20][O:19][C:17](=[O:18])[CH2:6][CH:5]([CH2:9][CH2:8][C:10]1[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=1)[NH:4][C:1](=[O:3])[CH3:2]
Reactant: COC(=O)c1sc(-c2ccc(C)cc2)cc1NC(C)=O
Agent: [Ni]
Product: COC(=O)CC(CCc1ccc(C)cc1)NC(C)=O
Yield: 99 %

Procedure:
Methyl 3-acetamido-5-(4-methylphenyl)thiophene-2-carboxylate (1.4905 g, 5.15 mmol) was reductively desulfurized using Raney nickel to yield the title compound as a white gum (1.3434 g, 5.10 mmol, 99.1%); mp: 50-51° C.; TLC: Rf=0.63 (Solvent I), 0.85 (Solvent L); IR (cm−1): 3288 (NH), 2906 (CH aliphatic), 1731 (ester C═O), 1639 (amide C═O), 807 (═CH); 1H nmr (CDCl3): δ 7.07 (s, 4H), 6.08 (br d, 1H, J=8.8 Hz), 4.28 (sextet, 1H, J=5.3 Hz), 3.67 (s, 3H), 2.63 (d, 2H, J=8.2 Hz), 2.55 (m, 2H), 2.30 (s, 3H), 1.96 (s, 3H), 1.84 (quintet, 2H, J=7.9 Hz).
Reaction SMILES: O[CH2:2][C:3]1[O:7][C:6]([C:8]#[N:9])=[CH:5][CH:4]=1.[Cl:10][C:11]1[CH:12]=[CH:13][C:14](=[O:48])[N:15]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][C:24]3[N:25]=[CH:26][N:27](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:28]=3)=[CH:19][N:18]=2)[CH:16]=1.C(N(C(C)C)CC)(C)C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>ClCCl>[Cl:10][C:11]1[CH:12]=[CH:13][C:14](=[O:48])[N:15]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][C:24]3[N:25]([CH2:2][C:3]4[O:7][C:6]([C:8]#[N:9])=[CH:5][CH:4]=4)[CH:26]=[N:27][CH:28]=3)=[CH:19][N:18]=2)[CH:16]=1
Reactant: O=c1ccc(Cl)cn1-c1ccc(Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cn1
Reactant: N#Cc1ccc(CO)o1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: N#Cc1ccc(Cn2cncc2Cc2ccc(-n3cc(Cl)ccc3=O)nc2)o1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of the alcohol from step 2 (0.017 g, 0.137 mmol), 5-chloro-5'-(1-triphenylmethyl-1H-imidazol-4-ylmethyl)-[1,2']bipyridinyl-2-one from Example 23, Step 5 (0.0758 g, 0.143 mmol) and diisopropylethylamine (0.047 mL, 1.49 mmol) in dichloromethane (1.3 mL) at -78° C. was added trifluoromethanesulfonic anhydride (0.023 mL, 0.136 mmol) and the mixture stirred at -78° C. for 1 hour. The mixture was allowed to warm to 0° C. and stirred for 2 hours. The solvent was evaporated in vacuo. The residue was dissolved in methanol (1 mL), heated at reflux for 2 hour, and the solvent evaporated in vacuo. The residue was partitioned between CH2Cl2 and sat. aq. NaHCO3 solution. The organic layer was dried, (Na2SO4) and the solvent evaporated in vacuo. The residue was chromatographed (Silica gel, 1:99 to 3:97 MeOH:CH2Cl2) to afford the title compound as a white solid.
Reaction SMILES: [C:1]([C:4]([CH:17]1[CH2:21][CH2:20][NH:19][CH2:18]1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2].Br[CH2:23][CH2:24][C:25]1[CH:34]=[CH:33][C:28]2[O:29][CH2:30][CH2:31][O:32][C:27]=2[CH:26]=1.C(=O)([O-])[O-].[K+].[K+].C(#N)C>O>[C:1]([C:4]([CH:17]1[CH2:21][CH2:20][N:19]([CH2:23][CH2:24][C:25]2[CH:34]=[CH:33][C:28]3[O:29][CH2:30][CH2:31][O:32][C:27]=3[CH:26]=2)[CH2:18]1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2]
Reactant: NC(=O)C(c1ccccc1)(c1ccccc1)C1CCNC1
Reactant: BrCCc1ccc2c(c1)OCCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: NC(=O)C(c1ccccc1)(c1ccccc1)C1CCN(CCc2ccc3c(c2)OCCO3)C1
Temperature: 25 °C

Procedure:
A mixture containing 3-(R,S)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine (0.3 g--see Preparation 8), 6-(2-bromoethyl)-1,4-benzodioxan (0.26 g--see Preparation 21), anhydrous potassium carbonate (0.4 g) and acetonitrile (10 ml) was heated under reflux for 3 hours. On cooling to room temperature, water (40 ml) was added and the mixture was extracted with dichloromethane (3×30 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give a foam which was purified by column chromatography on silica eluting with dichloromethane containing methanol (0% up to 10%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a colourless foam, yield, 0.21 g.
Reaction SMILES: [CH2:1]([N:8]([CH3:19])[C:9]1[CH:14]=[C:13]([N+:15]([O-])=O)[CH:12]=[CH:11][C:10]=1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.Cl>[CH2:1]([N:8]([CH3:19])[C:9]1[CH:14]=[C:13]([NH2:15])[CH:12]=[CH:11][C:10]=1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1N(C)Cc1ccccc1
Agent: Cl
Solvent: CO
Product: Cc1ccc(N)cc1N(C)Cc1ccccc1

Procedure:
SnCl2-dihydrate (1117 mg, 4.95 mmol) is added to a solution of N-Benzyl-N,2-dimethyl-5-nitro-aniline (247 mg, 0.96 mmol) in methanol (10 mL) and conc. HCl (1 mL). After boiling under reflux for 2.5 h, volatiles are evaporated under reduced pressure and the residue is partitioned between EtOAc and water, the pH being adjusted to approx. 10 by the addition of 2N NaOH. The organic layer is washed with sat. brine, dried (Na2SO4), and evaporated. Chromatography of the residue (silica gel, hexanes/EtOAc 3:2) yields N3-benzyl-N3,4-dimethyl-benzene-1,3-diamine