Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1([OH:14])[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH2:3]1.[CH:15](N(C(C)C)CCCC)([CH3:17])[CH3:16].[CH:26]([Si:29](Cl)([CH:33]([CH3:35])[CH3:34])[CH:30]([CH3:32])[CH3:31])([CH3:28])[CH3:27]>CN(C)C=O>[CH2:17]([O:14][C:2]1([O:1][Si:29]([CH:33]([CH3:35])[CH3:34])([CH:30]([CH3:32])[CH3:31])[CH:26]([CH3:28])[CH3:27])[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][N:9]2[CH2:10][CH2:11][CH2:12][CH2:13]2)[CH2:3]1)[C:15]#[CH:16]
Reactant: CCCCN(C(C)C)C(C)C
Reactant: OC1(O)C=CC=C(CN2CCCC2)C1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C#CCOC1(O[Si](C(C)C)(C(C)C)C(C)C)C=CC=C(CN2CCCC2)C1
Temperature: 0 °C

Procedure:
To a solution of 3-hydroxy-1-(pyrrolidin-1-yl)methyl-3-hydroxybenzene (0.95 g) in dry dimethylformamide (5 ml) was added by syringe, with stirring, diisopropylbutylamine (1.1 ml) followed by triisopropylsilyl chloride (0.97 ml). The reaction mixture was stirred at ambient temperature for 1 hr, ice (10 g) was added and after stirring for 10 mins, the mixture was poured into ice/water and extracted with ethyl acetate. The extract was washed with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was flash column chromatographed (silica gel) eluting with dichloromethane, 1%, 2% and 5% methanol/dichloromethane. The appropriate fractions were collected and concentrated to give 0.65 g of product. Additional fractions were collected, concentrated and chromatographed over silica gel. Concentration of the appropriate fractions gave 0.15 g of product. Total yield 0.80 g (50%).
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]1[N:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([CH2:18][OH:19])[C:12]=2[Cl:20])[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30].O>ClCCl>[C:1]([NH:4][CH2:5][C:6]1[N:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([CH2:18][O:19][S:29]([CH3:28])(=[O:31])=[O:30])[C:12]=2[Cl:20])[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NCc1cccn1-c1ccc(Cl)c(CO)c1Cl
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)NCc1cccn1-c1ccc(Cl)c(COS(C)(=O)=O)c1Cl
Reaction time: 2 h
Yield: 100.4 %

Procedure:
To a mixture of 2-acetamidomethyl-1-(2,4-dichloro-3-hydroxymethylphenyl)pyrrole (51 mg) and triethylamine (19.8 mg) in dichloromethane (2 ml) was added methanesulfonyl chloride (20.5 mg) under nitrogen atmosphere in ice-methanol bath, and the mixture was stirred for 2 hours at the same temperature. The reaction mixture was poured into water and extracted with chloroform. The extract was washed with water, saturated sodium bicarbonate solution and brine, dried over magensium sulfate and evaporated in vacuo to give 2-acetamidomethyl-1-[2,4-dichloro-3-(methanesulfonyloxymethyl)phenyl]pyrrole (64 mg) as oil.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[S:27][C:28]([CH:31]([OH:33])[CH3:32])=[CH:29][N:30]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[Cl:34]N1C(=O)CCC1=O>O1CCCC1.C(OCC)(=O)C>[Cl:34][C:23]1[CH:22]=[C:21]([CH:13]([C:10]2[CH:11]=[CH:12][C:7]([S:4]([CH:1]3[CH2:3][CH2:2]3)(=[O:5])=[O:6])=[CH:8][CH:9]=2)[CH2:14][CH:15]2[CH2:16][CH2:17][O:18][CH2:19][CH2:20]2)[NH:25][C:24]=1[C:26]1[S:27][C:28]([CH:31]([OH:33])[CH3:32])=[CH:29][N:30]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(O)c1cnc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)s1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(O)c1cnc(-c2[nH]c(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)cc2Cl)s1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution (5 mL) of 1-[2-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)-1,3-thiazol-5-yl]ethanol (300 mg) in tetrahydrofuran was added N-chlorosuccinimide (82.3 mg) at 0° C., and the mixture was stirred at 50° C. overnight. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, and washed with saturated aqueous sodium hydrogen carbonate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to preparative HPLC to give a mixture of the title compound and a positional isomer thereof (210 mg). The mixture of the obtained positional isomers was dissolved in hexane-2-propanol (700:300, volume ratio, 18.8 mL), and the solution was subjected to HPLC using CHIRALPAK AD (50 mmID×500 mL, manufactured by DAICEL CHEMICAL INDUSTRY LTD.). Using hexane-2-propanol (700:300, volume ratio) as a mobile phase, the solution was eluted at flow rate 60 mL/min and at 30° C., and the both fractions were separated at retention times 41.0 min and 55.0 min, and concentrated. The obtained solid was dissolved in ethyl acetate, and the insoluble material was filtered off. The filtration was concentrated to give the title compound (93.2 mg, yield 29%) as a colorless amorphous solid. MS: 521 (MH+).
Reaction SMILES: CC(C)([O-])C.[K+].O1CCCC1.[Cl:12][C:13]1[CH:22]=[C:21]([O:23][C@H:24]2[CH2:41][O:40][C@@H:26]([CH2:27][O:28]C(=O)C3C=CC([N+]([O-])=O)=CC=3)[CH2:25]2)[C:20]([Cl:42])=[C:19]2[C:14]=1[CH2:15][CH2:16][NH:17][C:18]2=[O:43].[CH2:44]([O:51][C:52]1[C:57]([CH2:58]Cl)=[C:56]([CH3:60])[CH:55]=[C:54]([CH3:61])[N:53]=1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>CN(C)C=O.C(OCC)(=O)C>[CH2:44]([O:51][C:52]1[C:57]([CH2:58][N:17]2[CH2:16][CH2:15][C:14]3[C:19](=[C:20]([Cl:42])[C:21]([O:23][C@@H:24]4[CH2:25][C@H:26]([CH2:27][OH:28])[O:40][CH2:41]4)=[CH:22][C:13]=3[Cl:12])[C:18]2=[O:43])=[C:56]([CH3:60])[CH:55]=[C:54]([CH3:61])[N:53]=1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: O=C(OC[C@H]1C[C@@H](Oc2cc(Cl)c3c(c2Cl)C(=O)NCC3)CO1)c1ccc([N+](=O)[O-])cc1
Reactant: Cc1cc(C)c(CCl)c(OCc2ccccc2)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1cc(C)c(CN2CCc3c(Cl)cc(O[C@H]4CO[C@@H](CO)C4)c(Cl)c3C2=O)c(OCc2ccccc2)n1
Reaction time: 0.5 h
Yield: 25.9 %

Procedure:
Potassium tert-butoxide solution in tetrahydrofuran (1.0 M, 645 μL, 0.645 mmol) was added dropwise to a cooled (0° C.) solution of 2,5-anhydro-3-deoxy-4-O-(5,8-dichloro-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)-1-O-(4-nitrobenzoyl)-L-threo-pentitol (296n, 120 mg, 0.249 mmol) in anhydrous N,N-dimethylformamide (4 mL). After stirring for 30 minutes, a solution of 2-(benzyloxy)-3-(chloromethyl)-4,6-dimethylpyridine (compound Z, 71 mg, 0.273 mmol) in anhydrous N,N-dimethylformamide (1 mL) was added and stirring continued at 0° C. for 30 more minutes. The reaction mixture was diluted with ethyl acetate (50 mL), washed with water (2×50 mL) and brine (50 mL), dried over sodium sulfate, concentrated to dryness, and purified by silica gel chromatography (eluting with a gradient of 0-100% ethyl acetate in heptane), affording 1,4-anhydro-2-O-(2-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-5,8-dichloro-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-deoxy-L-threo-pentitol (296o, 36 mg, 26% yield) as a solid. 1H NMR (400 MHz, CDCl3) δ 7.45 (d, J=7.21 Hz, 2H), 7.29-7.40 (m, 3H), 6.94 (s, 1H), 6.62 (s, 1H), 5.43 (s, 2H), 4.92 (br. s., 1H), 4.87 (s, 2H), 4.15-4.26 (m, 2H), 3.91 (dd, J=10.39, 3.91 Hz, 1H), 3.75-3.84 (m, 1H), 3.66-3.75 (m, 1H), 3.25 (t, J=6.05 Hz, 2H), 2.69 (t, J=6.05 Hz, 2H), 2.42 (s, 3H), 2.34-2.40 (m, 1H), 2.32 (s, 3H), 2.03-2.16 (m, 2H). MS: 557 [M+1].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.C1(C)C=CC=CC=1.[CH2:32]([N:34]([CH2:37]C)[CH2:35]C)[CH3:33].ClC(Cl)([O:42][C:43](=O)[O:44]C(Cl)(Cl)Cl)Cl.CN(C)CCO>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:43](=[O:42])[O:44][CH2:33][CH2:32][N:34]([CH3:37])[CH3:35])=[C:18]([CH3:24])[CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Reactant: CCN(CC)CC
Agent: CN(C)CCO
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3cc(C)c(NC(=O)OCCN(C)C)cc3C)c2cc1OC
Temperature: 25 °C
Yield: 22 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (85 mg) was added to toluene/triethylamine=10/1 (9 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (115 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 2-dimethylaminoethanol (33 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (28 mg, yield 22%).
Reaction SMILES: ClC1C=C(C([N:11]2[CH2:16][CH2:15][O:14][C@@H:13]([CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:12]2)C)C=CC=1Cl.Br[CH:27]([C:29]1[CH:34]=[CH:33][C:32]([F:35])=[C:31]([F:36])[CH:30]=1)[CH3:28]>>[C:21]([O:20][C:19](=[O:25])[NH:18][CH2:17][C@@H:13]1[O:14][CH2:15][CH2:16][N:11]([CH:27]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[C:31]([F:36])[CH:30]=2)[CH3:28])[CH2:12]1)([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(Br)c1ccc(F)c(F)c1
Reactant: CC(c1ccc(Cl)c(Cl)c1)N1CCO[C@@H](CNC(=O)OC(C)(C)C)C1
Product: CC(c1ccc(F)c(F)c1)N1CCO[C@@H](CNC(=O)OC(C)(C)C)C1

Procedure:
Prepared in similar fashion to tert-Butyl {(2S)-4-[1-(3,4-dichlorophenyl)ethyl]morpholin-2-yl}methylcarbamate (as described in WO 02/026723) using (+)-4-(1-bromoethyl)-1,2-difluorobenzene.
Reaction SMILES: [CH3:1][CH:2]([NH:12][C:13](=[O:24])[CH:14]=[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[CH:18]=1)[CH3:16])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[C:25]1(=[O:32])[O:31][C:29](=[O:30])[CH2:28][CH2:27][CH2:26]1>C1(C)C=CC=CC=1>[CH3:1][CH:2]([NH:12][C:13](=[O:24])[CH:14]=[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:25](=[O:32])[CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])[CH:18]=1)[CH3:16])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: O=C1CCCC(=O)O1
Reactant: CCCCCCCCCC(C)NC(=O)C=C(C)c1cccc(N)c1
Solvent: Cc1ccccc1
Product: CCCCCCCCCC(C)NC(=O)C=C(C)c1cccc(NC(=O)CCCC(=O)O)c1
Reaction time: 0.08 h

Procedure:
A stirred solution of 0.61 g. of N-(1-methyldecyl)-3-(3-aminophenyl)-2-butenamide, prepared in a manner analogous to Preparation 27, in 25 ml. of toluene, was heated on a steam bath and then 0.23 g. of glutaric anhydride was added in one portion. After 5 minutes, the reaction mixture was cooled and the solvent was removed by evaporation in vacuo. The residue was recrystallized twice from acetonitrile, to give 370 mg. of the title compound, m.p. 136°-140° C. This latter material was recrystallized from isopropanol/water to give 196 mg. of material having a melting point of 140°-141.5° C. The IR spectrum (KBr disc) showed absorptions at 3390, 2895, 1724, 1681, 1613 and 1575 cm-1. The NMR spectrum (DMSO-d6) showed absorptions at 0.90 (m, 3H), 1.08 (m, 3H), 1.26 (s, 16H), 1.89 (m, 2H), 2.40 (m, 7H, under DMSO-d6), 3.80 (m, 1H), 6.19 (s, 1H), 7.51 (m, 6H) and 9.90 (s, 1H) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]/[N:9]=[CH:10]/[C:11]2[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:18])=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:20]>C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][N:9]=[C:10]([Cl:20])[C:11]2[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:18])=[CH:6][CH:7]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: Fc1cccc(Cl)c1/C=N/Nc1ccc(Br)cc1
Solvent: c1ccccc1
Product: Fc1cccc(Cl)c1C(Cl)=NNc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 23 %

Procedure:
To a solution of (2E)-1-(4-bromophenyl)-2-(2-chloro-6-fluorobenzylidene) hydrazine (0.300 g, 1.32 mmol) in benzene (10 mL) was added PCl5 (0.330 g, 1.58 mmol). The reaction mixture was stirred at RT for 18 h. The reaction mass was quenched in water, neutralized with NaHCO3 and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate and concentrated to afford 0.110 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 7.17 (d, J=8.7 Hz, 2H), 7.41 (d, J=8.7 Hz, 3H), 7.45-7.61 (m, 2H), 10.26 (s, 1H). MS (m/z): 361.34 (M−H)−.
Reaction SMILES: Br[C:2]1[C:3]([CH3:15])=[C:4]([CH3:14])[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]=2[C:12]=1[CH3:13].[F:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1>>[F:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]2[CH2:28][CH2:27][N:26]([C:2]3[C:3]([CH3:15])=[C:4]([CH3:14])[C:5]4[O:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]=4[C:12]=3[CH3:13])[CH2:25][CH2:24]2)=[CH:21][CH:22]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: Cc1c(C)c2c(c(C)c1Br)CC(C)(C)O2
Product: Cc1c(C)c(N2CCN(c3ccc(F)cc3)CC2)c(C)c2c1OC(C)(C)C2
Yield: 27.2 %

Procedure:
By using 5-bromo-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran (269 mg, 0.999 mmol) synthesized in Reference example 4 and 1-(4-fluorophenyl)piperazine (541 mg, 3.00 mmol), the reaction was carried out in the same manner as Example 21 to synthesize the title compound 100 mg (yield 27%). Melting point was 175 to 177° C. (hexane).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([S:9][CH3:10])=[C:4]([Cl:11])[N:3]=1.CC(CC)=O.[CH2:17]([NH2:19])[CH3:18].[OH-].[Na+]>O>[CH2:17]([NH:19][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([S:9][CH3:10])=[C:4]([Cl:11])[N:3]=1)[CH3:18]
Reactant: CCN
Reactant: CSc1c(Cl)nc(Cl)nc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCC(C)=O
Product: CCNc1nc(Cl)c(SC)c(Cl)n1
Temperature: 5 °C

Procedure:
45.9 Grams of 2,4,6-trichloro-5-methylthio-pyrimidine, 150 g of methylethylketone and 130 g of water are introduced into a 250 ml reactor provided with a stirrer. To this mixture maintained at 5° C. are added in a period of 30 minutes 9.44 g of ethylamine in 32.5% aqueous solution. The temperature of 5° C. is maintained for one and one half hours. Then 8.08 g of caustic soda in 30% aqueous solution are added. The mixture is maintained at 20° C. for 4 hours and over night in a refrigerator at about 0° C. A precipitate appears which is isolated by filtration, washed with 16 ml of methylethylketone and recrystallized twice from 180 ml of ethanol. 10.5 G of 2-ethylamino-4,6-dichloro-5-methylthio-pyrimidine are thus obtained, which melts at 147° C. and which is identified by its infra-red spectrum (IR) and it nuclear magnetic resonance spectrum (NMR).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][CH:6]=1)[OH:4].O.NN>C(O)C.O1CCCC1.[Pd]>[NH2:11][C:8]1[CH:9]=[CH:10][C:5]([CH:3]([OH:4])[C:2]([F:1])([F:14])[F:15])=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(C(O)C(F)(F)F)cc1
Agent: [Pd]
Agent: NN
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccc(C(O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 2,2,2-trifluoro-1-(4-nitro-phenyl)-ethanol (2.0 g, 9 mmol) in ethanol (100 ml) and tetrahydrofuran (37 ml) was treated under argon with Pd/C (250 mg) and hydrazine hydrate (80% in water, 6.15 ml, 127 mmol, 14 equiv.) The mixture was stirred at room temperature for 30 min, then the black solid was filtered and the solvent evaporated. 1-(4-Amino-phenyl)-2,2,2-trifluoro-ethanol was obtained as a light yellow deliquescent solid, 1.8 g (100%). δH (300 MHz; CDCl3) 7.24 (2H, d), 6.67 (2H, d), 4.87 (1H, m), 3.72 (2H, bs), 3.32 (1H, bs).
Reaction SMILES: CN(C)/[CH:3]=[C:4]1/[C:5](=O)[CH:6]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:7][CH2:8][CH2:9]/1.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[CH3:26][O:27][C:28]1[CH:29]=[C:30]([NH:40][C:41]([NH2:43])=[NH:42])[CH:31]=[CH:32][C:33]=1[N:34]1[CH:38]=[C:37]([CH3:39])[N:36]=[CH:35]1>>[CH:10]1([CH:6]2[C:5]3[N:43]=[C:41]([NH:40][C:30]4[CH:31]=[CH:32][C:33]([N:34]5[CH:38]=[C:37]([CH3:39])[N:36]=[CH:35]5)=[C:28]([O:27][CH3:26])[CH:29]=4)[N:42]=[CH:3][C:4]=3[CH2:9][CH2:8][CH2:7]2)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: CN(C)/C=C1\CCCC(C2CCCCC2)C1=O
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Solvent: O=[N+]([O-])O
Product: COc1cc(Nc2ncc3c(n2)C(C2CCCCC2)CCC3)ccc1-n1cnc(C)c1

Procedure:
The title compound was prepared from crude 3-[1-dimethylamino-meth-(E)-ylidene]-bicyclohexyl-2-one (84 mg, 0.36 mmol) and N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-guanidine dinitrate (111 mg, 0.30 mmol) using in analogous manner the procedure described in example 45b). Obtained as yellow crystals (61 mg, 49%). MS ISP (m/e): 418.3 (100) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=9.57 (s, 1H), 8.21 (s, 1H), 7.90 (s, 1H), 7.65 (s, 1H), 7.39 (d, 1H), 7.21 (d, 1H), 7.03 (s, 1H), 3.82 (s, 3H), 2.51-2.65 (m, 2H), 2.14 (s, 3H), 1.72-1.94 (m, 3H), 1.52-1.70 (m, 5H), 1.02-1.35 (m, 7H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:10]=[N:11][C:12]2[NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[C:18]([CH:40]=3)[CH2:19][CH2:20][C:21]3[CH:29]=[C:25]([NH:26][C:27]=1[N:28]=2)[CH:24]=[CH:23][C:22]=3[O:30][CH2:31][C:32](=[O:39])[N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.C(N(CC)C(C)C)(C)C.[C:50](Cl)(=[O:52])[CH3:51]>CN(C)C=O>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:50]([N:36]1[CH2:37][CH2:38][N:33]([C:32](=[O:39])[CH2:31][O:30][C:22]2[CH:23]=[CH:24][C:25]3[NH:26][C:27]4[N:28]=[C:12]([NH:13][C:14]5[CH:15]=[CH:16][CH:17]=[C:18]([CH:40]=5)[CH2:19][CH2:20][C:21]=2[CH:29]=3)[N:11]=[CH:10][C:9]=4[Cl:8])[CH2:34][CH2:35]1)(=[O:52])[CH3:51]
Reactant: O=C(COc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2)N1CCNCC1
Reactant: CC(=O)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)N1CCN(C(=O)COc2ccc3cc2CCc2cccc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 46 %

Procedure:
6-Chloro-12-(2-oxo-2-piperazin-1-ylethoxy)-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene trifluoroacetate (11.1 mg, 0.019 mmol) was stirred in N,N-dimethylformamide (1.0 mL) with N,N-diisopropylethylamine (17 μL, 0.096 mmol), and acetyl chloride (1.5 μL, 0.021 mmol) was added. Purification by preparative LCMS (pH 2) gave the desired compound (46%). LCMS for C26H28ClN6O3 (M+H)+: m/z=507.2.
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[CH2:7][CH:8]([CH2:12][CH2:13][P:14]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C:9]([OH:11])=O)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[C:42]1([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[CH:47]=[CH:46][C:45]([CH2:48][CH2:49][NH2:50])=[CH:44][CH:43]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl>CN(C=O)C>[C:1]([O:5][C:6](=[O:32])[CH2:7][CH:8]([C:9](=[O:11])[NH:50][CH2:49][CH2:48][C:45]1[CH:46]=[CH:47][C:42]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)=[CH:43][CH:44]=1)[CH2:12][CH2:13][P:14]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])([CH3:3])([CH3:2])[CH3:4]
Reactant: NCCc1ccc(-c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)CC(CCP(=O)(OCc1ccccc1)OCc1ccccc1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CC(CCP(=O)(OCc1ccccc1)OCc1ccccc1)C(=O)NCCc1ccc(-c2ccccc2)cc1

Procedure:
A solution of the compound of Example 77 (770 mg, 1.67 mmol) in anhydrous DMF (2 mL) was treated with DIEA (1.5 mL), 4-biphenylethyl amine (672 mg, 3.34 mmol), and TBTU (775 mg, 2.34 mmol). The reaction mixture was stirred for 24 h at room temperature after which HCl (1M, excess) was added. The mixture was extracted several times with ethyl acetate. The recombined organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was flashed with 50% ethyl acetate in hexanes and the desired product was obtained as a white solid. 1H NMR (CDCl3, 400 MHz: 1.41(s, 9H); 1.61-1.87(m, 4H); 2.15, 2.59(2dd, J1=16.4 Hz. J2=4.2 Hz, 2H); 2.67(m, 1H); 2.80(m, 2H); 3.49(m, 2H); 4.96(m, 4H); 6.35(t, J=5.6 Hz); 7.32(m, 13H); 7.42(m, 2H); 7.55(m, 4H); 31P NMR(CDCl3, 400 MHz): 33.05.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][S:5]([C:8]1[S:9][C:10]2[CH:17]=[CH:16][C:15]([C:18]3[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=3)=[CH:14][C:11]=2[C:12]=1[CH3:13])(=[O:7])=[O:6].[Si:28](Cl)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29].N1C=CN=C1>CN(C=O)C.CCOCC>[Si:28]([O:1][CH2:2][CH2:3][NH:4][S:5]([C:8]1[S:9][C:10]2[CH:17]=[CH:16][C:15]([C:18]3[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=3)=[CH:14][C:11]=2[C:12]=1[CH3:13])(=[O:7])=[O:6])([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29]
Reactant: COC(=O)c1ccc(-c2ccc3sc(S(=O)(=O)NCCO)c(C)c3c2)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2ccc3sc(S(=O)(=O)NCCO[Si](C)(C)C(C)(C)C)c(C)c3c2)cc1

Procedure:
A solution of Example 398B (200 mg, 0.5 mmol), tert-butyldimethylsilyl chloride (85 mg, 0.55 mmol) and imidazole (36 mg, 0.6 mmol) in DMF (5 mL) at room temperature was stirred for 24 hours, diluted with ether, filtered through a pad of silica gel, and concentrated to provide the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.Br[CH2:10][C:11](=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13].C(=O)(O)[O-].[Na+]>CC(C)=O>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]2[N:3]([CH:10]=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:1]=2)[CH:4]=1
Reactant: CCOC(=O)C(=O)CBr
Reactant: Nc1ccc(Cl)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: CCOC(=O)c1cn2cc(Cl)ccc2n1
Temperature: 60 °C
Yield: 72.3 %

Procedure:
A solution of 2-amino-5-chloropyridine (2.0 g, 16 mmol) [Matrix Scientific, 021118] in acetone (39 mL) was treated with ethyl bromopyruvate (2.2 mL, 16 mmol) and heated at 60° C. for 45 min. The reaction mixture was cooled to 20° C. and the suspension was filtered. The solid that was collected was washed with a small amount of cold acetone and dried in vacuo. The solid was diluted with ethanol (12 mL) and water (19 mL), heated at 65° C., and treated with sodium bicarbonate (1.6 g, 19 mmol) portionwise. The reaction mixture was cooled to 20° C. and the suspension was filtered. The solid that was collected was washed with water (4×80 mL) and dried in vacuo to give the desired product (2.6 g, 74%). LCMS for C10H10ClN2O2 (M+H)+: m/z=225.1.
Reaction SMILES: [CH3:1][O:2][NH2:3].C([O-])([O-])=O.[K+].[K+].[F:10][C:11]1[CH:18]=[C:17]([N:19]2[CH2:23][CH2:22][N:21]([C:24]3[CH:25]=[N:26][CH:27]=[CH:28][C:29]=3[CH3:30])[C:20]2=[O:31])[CH:16]=[CH:15][C:12]=1[CH:13]=O.CO>C(COC)OC.C(Cl)(Cl)Cl>[CH3:1][O:2][N:3]=[CH:13][C:12]1[CH:15]=[CH:16][C:17]([N:19]2[CH2:23][CH2:22][N:21]([C:24]3[CH:25]=[N:26][CH:27]=[CH:28][C:29]=3[CH3:30])[C:20]2=[O:31])=[CH:18][C:11]=1[F:10]
Reactant: CON
Reactant: Cc1ccncc1N1CCN(c2ccc(C=O)c(F)c2)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CON=Cc1ccc(N2CCN(c3cnccc3C)C2=O)cc1F
Temperature: 40 °C
Yield: 9.1 %

Procedure:
O-Methyl-hydroxylamine (84 mg, 1.003 mmol) and K2CO3 (207 mg, 1.5 mmol) were added to a solution of 2-fluoro-4-[3-(4-methyl-pyridin-3-yl)-2-oxo-imidazolidin-1-yl]-benzaldehyde-(I-121a: 300 mg, 1.003 mmol) in dimethoxyethane (10 mL). The resulting mixture was heated to 40° C. for 2 hours. The reaction was monitored by TLC (5% MeOH in CHCl3). The reaction mixture was filtered, washed with CHCl3 and the filtrate was concentrated under reduced pressure to afford 30 mg of crude 2-Fluoro-4-[3-(4-methyl-pyridin-3-yl)-2-oxo-imidazolidin-1-yl]-benzaldehyde O-methyl-oxime, which was used in the next step without further purification.