Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]([N+:8]([O-:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[F:11][C:12]1[CH:13]=[C:14]([CH:16]=[C:17]([F:19])[CH:18]=1)[NH2:15].C(=O)([O-])[O-].[Cs+].[Cs+]>CC(N(C)C)=O.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:11][C:12]1[CH:13]=[C:14]([NH:15][C:2]2[C:3]([N+:8]([O-:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=2)[CH:16]=[C:17]([F:19])[CH:18]=1
Reactant: O=[N+]([O-])c1ncccc1Cl
Reactant: Nc1cc(F)cc(F)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=[N+]([O-])c1ncccc1Nc1cc(F)cc(F)c1
Temperature: 100 °C
Reaction time: 12 h

Procedure:
To a degassed solution of 3-chloro-2-nitro-pyridine (1.35 g, 8.51 mmol) and 3,5 difluoroaniline (1.0 g, 7.74 mmol) in dimethyl acetamide (23.2 mL) was added cesium carbonate (6.34 g, 19.35 mmol) and the reaction mixture was further degassed with nitrogen for 15 min. xanthophos (267 mg, 0.46 mmol) and Pd2 (dba)3 (212 mg, 0.23 mmol) were added to the reaction mixture and stirred at 100° C. for 12 h. After completion, the reaction mixture was diluted with water (50 mL) and extracted with ethyl actate (2×25 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo to get the crude material, which was purified by column chromatography using silica gel (100-200 mesh) and 0-30% EtOAc in hexane to provide (3,5-difluorophenyl)-(2-nitro-pyridin-3-yl)-amine: 1H NMR (DMSO-d6, 400 MHz) δ 6.856-6.980 (m, 3H), 7.659-7.691 (m, 1H), 8.017 (dd, J=1.6 Hz, J=1.6 Hz, 1H), 8.126-8.140 (m, 1H), 9.094 (s, 1H); LC-MS (ESI) m/z 252.0 [M+H]+.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[Cl:15][C:16]1[CH:21]=[C:20]([NH:22][CH:23]([CH3:25])[CH3:24])[C:19]([C:26]2[O:27][C:28](S(C)(=O)=O)=[N:29][N:30]=2)=[CH:18][N:17]=1>O1CCOCC1>[Cl:15][C:16]1[N:17]=[CH:18][C:19]([C:26]2[O:27][C:28]([NH:1][CH:2]3[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]3)=[N:29][N:30]=2)=[C:20]([NH:22][CH:23]([CH3:25])[CH3:24])[CH:21]=1
Reactant: CC(C)Nc1cc(Cl)ncc1-c1nnc(S(C)(=O)=O)o1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: C1COCCO1
Product: CC(C)Nc1cc(Cl)ncc1-c1nnc(NC2CCN(C(=O)OC(C)(C)C)CC2)o1
Temperature: 90 °C

Procedure:
tert-butyl 4-aminopiperidine-1-carboxylate (8 mmol, 5 equiv.) was added to a stirred solution of 2-chloro-N-isopropyl-5-(5-(methylsulfonyl)-1,3,4-oxadiazol-2-yl)pyridin-4-amine (44) (500 mg, 1.7 mmol) in Dioxan (5 mL) and heated at 90° C. for 4 h. The reaction mass was concentrated under reduced pressure. The crude material obtained was purified by column chromatography through silica gel and MeOH: DCM as eluent to afford the desired compound, tert-butyl 4-((5-(6-chloro-4-(isopropylamino)pyridin-3-yl)-1,3,4-oxadiazol-2-yl)amino)piperidine-1-carboxylate. LC/MS: Purospher@star RP-18, 4×55 mm, 3 μm; Solvent A=10% ACN: 90% H2O: 20 mM NH4OAc; Solvent B=90% ACN: 10% H2O: 20 mM NH4COOAc; gradient 0-100% B over 1.5 min (3.2 min run time); retention time: 2.049 min; LCMS (ES-API), m/z 437.2 (M+H).
Reaction SMILES: O1CCC[CH2:2]1.[F:6][C:7]([F:16])([F:15])[C:8]1[S:12][C:11]([CH:13]=[O:14])=[CH:10][CH:9]=1.C[Mg]Br>C(O)(=O)C>[F:16][C:7]([F:15])([F:6])[C:8]1[S:12][C:11]([CH:13]([OH:14])[CH3:2])=[CH:10][CH:9]=1
Reactant: O=Cc1ccc(C(F)(F)F)s1
Reactant: C1CCOC1
Agent: C[Mg]Br
Solvent: CC(=O)O
Product: CC(O)c1ccc(C(F)(F)F)s1

Procedure:
To a tetrahydrofuran solution (2.0 mL) of 5-(trifluoromethyl)thiophene-2-carbaldehyde (80.0 mg, 0.444 mmol), methylmagnesium bromide (533 μL, 0.444 mmol) was added at 0° C. and the resultant mixture was stirred at room temperature for 5 minutes. After completion of the reaction, acetic acid was added to the reaction solution and the resultant mixture was concentrated under reduced pressure. To the obtained residue, water was added and extraction from the resultant mixture with ethyl acetate was performed. The organic layer was concentrated under reduced pressure to obtain a crude product of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[CH:8]=[CH:9][N:10]=[C:4]2[CH:3]=1.[I:11]NC(=O)CCC(N)=O>C(#N)C>[I:11][C:8]1[N:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]2=[N:10][CH:9]=1
Reactant: Clc1ccn2ccnc2c1
Reactant: NC(=O)CCC(=O)NI
Solvent: CC#N
Product: Clc1ccn2c(I)cnc2c1
Reaction time: 0.5 h

Procedure:
To a solution of 7-chloro-imidazo[1,2,a]pyridine (6.10 g, 40 mmol) (Yamanaka, Motosuke et al., Chemical & Pharmaceutical Bulletin (1991), 39(6), 1556-67) in dry acetonitrile (100 mL), add N-iodosuccinamide. Stir for 30 minutes. Filter off the precipitate and then wash with acetonitrile. Recrystallize the precipitate from acetonitrile to give a white solid. Concentrate the filtrate, dilute with ethyl acetate, wash with 10% sodium hydrogensulfite (NaHSO3), saturated aqueous sodium bicarbonate, saturated aqueous NaCl, dry over MgSO4, filter and evaporate. Use the combined solid without further purification (8.0 g, 73%). 1H NMR (DMSO) δ 8.33 (d, 1H, J=7.3 Hz), 7.79 (d, 1H, J=2.0 Hz), 7.72 (s, 1H), 7.07 (dd, 1H, J=7.3 and 2.0 Hz).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:52])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([OH:51])[CH2:45]2)[CH:7]([CH3:53])[CH2:6][CH2:5][C:4]1=[O:54])[CH3:2].ClC(Cl)(Cl)C(=N)O[C:59]([CH2:61][CH3:62])=[CH2:60].FC(F)(F)S(O)(=O)=O>>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:52])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][C:59]([CH2:61][CH3:62])=[CH2:60])[CH2:45]2)[CH:7]([CH3:53])[CH2:6][CH2:5][C:4]1=[O:54])[CH3:2]
Reactant: C=C(CC)OC(=N)C(Cl)(Cl)Cl
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(O)C3)C(C)CCC1=O)C(C)CC2OC
Agent: O=S(=O)(O)C(F)(F)F
Product: C=C(CC)OC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CCC2C)C(OC)CC3C)CCC1O
Temperature: 25 °C

Procedure:
To a solution of 17-ethyl-1-hydroxy-12-[2'-(3",4"-dihydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (150 mg in 3 ml 33% methylene chloride in cyclohexane), sec-butenyl trichloroacetimidate (62 μl neat) is added and the reagents allowed to mix for 5 minutes. Trifluoromethanesulfonic acid (2 μl neat) is then added slowly via syringe and the mixture stirred at room temperature. After 15 minutes the reaction is quenched by the addition of saturated sodiumbicarbonate and extracted with ethyl acetate (3×8 ml). The combined organics are washed with brine and dried over magnesium sulfate. Purification of the concentrate by preparative TLC on silica gel the title compounds.
Reaction SMILES: C([O:3][C:4]([C:6]1([CH2:21][C:22]2[C:27]([Cl:28])=[CH:26][C:25]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:24][C:23]=2[Cl:37])[CH2:10][CH2:9][N:8]([CH:11]2[CH2:19][CH2:18][C:14]3[N:15]=[CH:16][NH:17][C:13]=3[CH2:12]2)[C:7]1=[O:20])=[O:5])C.[OH-].[Na+]>CO>[CH2:30]([O:29][C:25]1[CH:26]=[C:27]([Cl:28])[C:22]([CH2:21][C:6]2([C:4]([OH:5])=[O:3])[CH2:10][CH2:9][N:8]([CH:11]3[CH2:19][CH2:18][C:14]4[N:15]=[CH:16][NH:17][C:13]=4[CH2:12]3)[C:7]2=[O:20])=[C:23]([Cl:37])[CH:24]=1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CCOC(=O)C1(Cc2c(Cl)cc(OCc3ccccc3)cc2Cl)CCN(C2CCc3nc[nH]c3C2)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C1(Cc2c(Cl)cc(OCc3ccccc3)cc2Cl)CCN(C2CCc3nc[nH]c3C2)C1=O
Reaction time: 16 h

Procedure:
Dissolve 3-(4-Benzyloxy-2,6-dichloro-benzyl)-2-oxo-1-(4,5,6,7-tetrahydro-3H-benzoimidazol-5-yl)-pyrrolidine-3-carboxylic acid ethyl ester (3 g, 5.5 mmol) (Preparation 11) in 10 ml of Methanol and then add 10 ml of 2N NaOH. Stir this mixture for 16 h, concentrate, and then add dioxane and acetic acid to obtain 3-(4-Benzyloxy-2,6-dichloro-benzyl)-2-oxo-1-(4,5,6,7-tetrahydro-3H-benzoimidazol-5-yl)-pyrrolidine-3-carboxylic acid which is not isolated. Reflux the mixture overnight, quench with water and extract with ethyl acetate. Wash the extracts with saturated bicarbonate and concentrate to 3-(4-Benzyloxy-2,6-dichloro-benzyl)-1-(4,5,6,7-tetrahydro-3H-benzoimidazol-5-yl)-pyrrolidin-2-one product (2.6 g). MS: m/z (M+1)=470.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)=[O:3].C([O-])([O-])=O.[K+].[K+].Br[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].O>CN(C=O)C>[CH2:18]([O:10][C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH3:1])=[CH:5][CH:6]=1)[CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCBr
Reactant: CC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCOc1ccc(C(C)=O)cc1
Temperature: 60 °C
Yield: 86.3 %

Procedure:
To a solution of the 4-hydroxyacetophenone (1.0 g, 7.3 mmol) in 5 mL DMF under Ar was added K2CO3 (1.0 g, 7.3 mmol) and 1-bromopentane (1.1 mL, 8.7 mmol) and heated at 60° C. overnight. The reaction mixture was cooled to room temperature, poured into water (100 mL) and extracted with EtOAc. The organic layer was washed with brine, dried and evaporated to afford a residue which upon purification by combiflash, eluting with 5% EtOAc in Hexane afforded 1.3 g product (86%). 1H NMR (500 MHz, CDCl3): δ 0.98 (t, 3H, J=7.0 Hz), 1.41-1.49 (m, 4H), 1.83-1.86 (m, 2H), 2.59 (s, 3H), 4.09 (t, 2H, J=6.5 Hz), 6.98 (d, 2H, J=7.0 Hz), 7.98 (d, 2H, J=7.0 Hz).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[NH:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.C(N(CC)CC)C.Cl[CH2:24][C:25](Cl)=[O:26].OS([O-])(=O)=O.[K+].[H-].[Na+].Cl.[OH-].[Na+]>C(Cl)Cl.CN(C=O)C.C(OCC)(=O)C>[O:26]=[C:25]1[CH2:24][O:1][CH2:2][CH:3]2[CH2:4][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:6][CH2:7][N:8]12
Reactant: O=C(Cl)CCl
Reactant: CC(C)(C)OC(=O)N1CCNC(CO)C1
Agent: Cl
Agent: O=S(=O)([O-])O
Agent: [H-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN2C(=O)COCC2C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 20.7 %

Procedure:
To a solution of tert-butyl 3-(hydroxymethyl)piperazine-1-carboxylate (360 mg, 1.7 mmol) in methylene chloride (10 mL) was added triethylamine (505 mg, 5.0 mmol) at 0° C. Chloroacetyl chloride (282 mg, 2.5 mmol) was dissolved in methylene chloride (5 mL) and the solution was added to the former solution drop by drop at 0° C. The reaction mixture was stirred at 0° C. for 1 h and then at RT for 3 h. An aqueous solution of KHSO4 (1M, 5 mL) was added and then the organic phase was separated by means of a phase separator column. The solvent was removed by evaporation and the amide intermediate, which was purified by silica gel chromatography, was dissolved in DMF (2 mL). While cooling and under nitrogen the solution was added drop wise to a suspension of NaH (60 mg, 2.5 mmol) in DMF. The mixture was stirred at RT for 48 h, then diluted with ethyl acetate and then pored over aqueous HCl (0.5 M). The pH was adjusted to 12 with NaOH and then the organic phase was separated. The solvent was removed by evaporation and the product was purified by silica gel chromatography. There was obtained 90 mg (21%) of tert-butyl 4-oxohexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-carboxylate. 1H NMR (500 MHz, CDCl3): 1.4 (s, 9H), 2.5-2.7 (m, 2H), 2.8 (m, 1H), 3.4-3.5 (m, 2H), 3.9-4.2 (m, 5H), 4.5 (d, 1H); LCMS: m/z 257 (M+1)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:12])=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[CH:7]=O.[CH3:13][O:14][C:15]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:16]=1[CH2:17][NH2:18].[BH4-].[Na+]>CO.C(Cl)Cl>[Br:1][C:2]1[C:3]([Cl:12])=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[CH2:7][NH:18][CH2:17][C:16]1[CH:19]=[CH:20][C:21]([O:23][CH3:24])=[CH:22][C:15]=1[O:14][CH3:13]
Reactant: COc1cc(Cl)c(Br)cc1C=O
Reactant: COc1ccc(CN)c(OC)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(CNCc2cc(Br)c(Cl)cc2OC)c(OC)c1
Reaction time: 1 h

Procedure:
The solution of 5-bromo-4-chloro-2-methoxybenzaldehyde (300 mg, 1.2 mmol) and 2,4-dimethoxybenzyl amine (167 mg, 1.2 mmol) in MeOH/DCM (4:1, 10 mL) was stirred at room temperature for 5 h. To this mixture, NaBH4 (100 mg, 13 mmol) was added in two portions. The mixture stirred for 1 h and then partitioned between DCM and water. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to afford the desired product. The crude product was used directly in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[N:3]([CH2:12][C:13]#[C:14][CH3:15])[C:4]2[C:9](=[O:10])[NH:8][N:7]=[CH:6][C:5]=2[N:11]=1.Cl[CH2:17][C:18]1[N:27]=[C:26]([CH3:28])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:1][C:2]1[N:3]([CH2:12][C:13]#[C:14][CH3:15])[C:4]2[C:9](=[O:10])[N:8]([CH2:17][C:18]3[N:27]=[C:26]([CH3:28])[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)[N:7]=[CH:6][C:5]=2[N:11]=1
Reactant: Cc1nc(CCl)nc2ccccc12
Reactant: CC#CCn1c(Br)nc2cn[nH]c(=O)c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC#CCn1c(Br)nc2cnn(Cc3nc(C)c4ccccc4n3)c(=O)c21
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of 365 mg 2-bromo-3-(2-butyn-1-yl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one, 265 mg 2-chloromethyl-4-methyl-quinazoline and 210 mg potassium carbonate in 6 ml acetonitrile is stirred for 17 h at ambient temperature. Then the reaction mixture is filtered through 5 g aluminium oxide with ethyl acetate and the filtrate is evaporated down. The residue is triturated in diisopropylether, separated from the ether and dried.
Reaction SMILES: C([N:20]1[CH:24]=[C:23]([CH:25]([CH3:28])[CH2:26][NH2:27])[N:22]=[CH:21]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:29]=O>Cl>[CH3:28][CH:25]1[CH2:26][NH:27][CH2:29][CH:24]2[N:20]=[CH:21][NH:22][CH:23]12
Reactant: C=O
Reactant: CC(CN)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: Cl
Product: CC1CNCC2N=CNC12
Temperature: 95 °C

Procedure:
3.2 g 2-(1-trityl-1H-imidazol-4-yl)-propylamine is suspended in aqueous HCl (1 N). After the addition of 2.9 mL formaldehyde the mixture is heated to 95° C. with stirring. After 5 h it is cooled to RT, suction filtered to remove the precipitate formed and the solvent is eliminated in vacuo. This crude product is used in the following reaction step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:24])[N:10]([CH2:12][CH2:13][C@H:14]2[CH2:19][CH2:18][C@H:17](/[CH:20]=[CH:21]/[CH2:22]O)[CH2:16][CH2:15]2)[CH3:11])=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.CS([Cl:37])(=O)=O>ClCCl.CCOCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:24])[N:10]([CH2:12][CH2:13][C@H:14]2[CH2:19][CH2:18][C@H:17](/[CH:20]=[CH:21]/[CH2:22][Cl:37])[CH2:16][CH2:15]2)[CH3:11])=[CH:4][CH:3]=1
Reactant: CN(CC[C@H]1CC[C@H](/C=C/CO)CC1)C(=O)Oc1ccc(Cl)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: Cc1cccc(C)n1
Product: CN(CC[C@H]1CC[C@H](/C=C/CCl)CC1)C(=O)Oc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To an ice-cooled solution of 135 mg (0.384 mmol) trans-{2-[4-(3-hydroxy-(E)-propenyl)-cyclohexyl]-ethyl}-methyl-carbamic acid 4-chloro-phenyl ester and 0.089 ml (0.77 mmol) 2,6-lutidine in 2 ml of dichloromethane was added under stirring 0.033 ml (0.422 mmol) methane sulfonylchloride. The reaction mixture was stirred for 20 hours at room temperature, then taken up in ether and washed with 1N hydrogen chloride solution and water. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure and the residue then chromatographed on silica gel with a 4:1 v/v mixture of hexane and ethylacetate as the eluent giving 90 mg (63.4%) of trans-{2-[4-(3-chloro-(E)-propenyl)-cyclohexyl]-ethyl}-methyl-carbamic acid 4-chloro-phenyl ester as colorless viscous oil, MS: 370 (MH+, 2 Cl).
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].C([Li])CCC.[O:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[O:19][C@@H:20]1[C@@H:26]([O:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][O:29]2)[C@H:25]([O:34][CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][O:36]2)[C@@H:24]([CH2:41][O:42][CH:43]2[CH2:48][CH2:47][CH2:46][CH2:45][O:44]2)[O:23][C:21]1=[O:22]>C(OCC)C.CCCCCC>[O:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[O:19][C@@H:20]1[C@@H:26]([O:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][O:29]2)[C@H:25]([O:34][CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][O:36]2)[C@@H:24]([CH2:41][O:42][CH:43]2[CH2:48][CH2:47][CH2:46][CH2:45][O:44]2)[O:23][C:21]1([OH:22])[CH2:1][P:2]([O:5][CH3:6])([O:3][CH3:4])=[O:7]
Reactant: O=C1O[C@H](COC2CCCCO2)[C@@H](OC2CCCCO2)[C@H](OC2CCCCO2)[C@H]1OC1CCCCO1
Reactant: COP(C)(=O)OC
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: COP(=O)(CC1(O)O[C@H](COC2CCCCO2)[C@@H](OC2CCCCO2)[C@H](OC2CCCCO2)[C@H]1OC1CCCCO1)OC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of dimethyl methylphosphonate (15.3 ml) in ethyl ether (300 ml) was added dropwise with cooling (-70° to -78° C.) in a stream of argon a solution of n-butyllithium in n-hexane (1.6M solution, 84 ml), and the mixture was stirred for 30 minutes. To the solution was added dropwise with cooling at the same temperature a solution of 2,3,4,6-tetra-O-(tetrahydropyranyl)-D-glucono-1,5-lactone (23.1 g) in ethyl ether (80 ml). The mixture was stirred for one hour, then the cooling bath was removed, and then the mixture was allowed to warm to 0° C. with stirring. The reaction solution was added to an ice-cooled mixture of 10%(W/V) ammonium chloride solution (250 ml) and ethyl ether (120 ml). The ethyl ether layer was separated. The aqueous layer was subjected to extraction with ethyl ether. The organic layers were combined, washed with water, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and dried further under reduced pressure to give 3,4,5,7-tetra-O-(tetrahydropyranyl)-1-deoxy-1-(dimethoxyphosphoryl)-D-gluco-2-heptulopyranose (26.6 g).
Reaction SMILES: [CH2:1]([C:3]1[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[N:4]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:24][CH2:25][CH2:26][N:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>CC(=O)CC.O>[CH2:1]([C:3]1[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:24][CH2:25][CH2:26][N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)=[CH:14][CH:15]=2)[N:4]=1)[CH3:2]
Reactant: ClCCCN1CCCC1
Reactant: CCc1cc(CC)n(-c2ccc(O)cc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: CCc1cc(CC)n(-c2ccc(OCCCN3CCCC3)cc2)n1
Temperature: 80 °C
Yield: 9.3 %

Procedure:
To a solution of 4-(3,5-diethylpyrazol-1-yl)phenol (50 mg, 0.23 mmol) in 2-butanone (2 mL) was added potassium carbonate (35 mg, 0.25 mmol) and 1-(3-chloropropyl)pyrrolidine (37 mg, 0.25 mmol). The vial was capped and the reaction was heated overnight at 80° C. After the reaction was diluted with water and extracted with methylene chloride, the organic layer was dried (MgSO4) and concentrated. The residue was purified by semi-prep LC-MS to give 7.0 mg of the desired product. LC-MS (C20H29N3O calculated 327) m/z 328 (M+H); 1H NMR (300 MHz, CDCl3) δ 7.29 (d, J=9.0 Hz, 2H), 6.94 (d, J=8.7 Hz, 2H), 6.02 (s, 1H), 4.05 (t, J=6.3 Hz, 2H), 2.73-2.54 (m, 10H), 2.06 (quint, J=6.3 Hz, 2H), 1.83 (s, 4H), 1.28 (t, J=7.5 Hz, 3H), 1.19 (t, J=7.5 Hz, 3H).
Reaction SMILES: [ClH:1].[CH:2]1([S:5]([NH:8][C:9]([C@@:11]23[CH2:26][C@H:25]2[CH:24]=[CH:23][CH2:22][CH2:21][C@@H:20]([CH3:27])[CH2:19][C@@H:18]([CH3:28])[C@H:17]([NH:29]C(=O)OC(C)(C)C)[C:16](=[O:37])[N:15]2[CH2:38][C@H:39]([O:41][C:42]4[C:51]5[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=5)[C:45]([O:52][CH3:53])=[CH:44][N:43]=4)[CH2:40][C@H:14]2[C:13](=[O:54])[NH:12]3)=[O:10])(=[O:7])=[O:6])[CH2:4][CH2:3]1>O1CCOCC1>[ClH:1].[NH2:29][C@@H:17]1[C:16](=[O:37])[N:15]2[CH2:38][C@H:39]([O:41][C:42]3[C:51]4[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=4)[C:45]([O:52][CH3:53])=[CH:44][N:43]=3)[CH2:40][C@H:14]2[C:13](=[O:54])[NH:12][C@:11]2([C:9]([NH:8][S:5]([CH:2]3[CH2:3][CH2:4]3)(=[O:6])=[O:7])=[O:10])[CH2:26][C@H:25]2[CH:24]=[CH:23][CH2:22][CH2:21][C@@H:20]([CH3:27])[CH2:19][C@H:18]1[CH3:28]
Reactant: COc1cnc(O[C@@H]2C[C@H]3C(=O)N[C@]4(C(=O)NS(=O)(=O)C5CC5)C[C@H]4C=CCC[C@@H](C)C[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N3C2)c2ccccc12
Agent: COc1cnc(O[C@@H]2C[C@H]3C(=O)N[C@]4(C(=O)NS(=O)(=O)C5CC5)C[C@H]4/C=C\CC[C@@H](C)C[C@@H](C)[C@H](N)C(=O)N3C2)c2ccccc12
Agent: COc1cnc(O[C@@H]2C[C@H]3C(=O)N[C@]4(C(=O)NS(=O)(=O)C5CC5)C[C@H]4/C=C\CC[C@@H](C)C[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N3C2)c2ccccc12
Agent: Cl
Solvent: C1COCCO1
Product: COc1cnc(O[C@@H]2C[C@H]3C(=O)N[C@]4(C(=O)NS(=O)(=O)C5CC5)C[C@H]4C=CCC[C@@H](C)C[C@@H](C)[C@H](N)C(=O)N3C2)c2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of HCl in Dioxane was added Compound 1 (300 mg, 0.39 mmol) and the solution was stirred at room temperature for 30 min. The solvent was concentrated under reduced pressure to afford (2R,6S,7R,9R,13aS,14aR,16aS,Z)-6-amino-N-(cyclopropylsulfonyl)-2-((4-methoxyisoquinolin-1-yl)oxy)-7,9-dimethyl-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide hydrochloride (250 mg, 96%). The material was triturated with diethyl ether and used in step 2 without further purification. MS: MS m/z 655.2 (M++1).
Reaction SMILES: CCN=C=NCCCN(C)C.[I:12][C:13]1[CH:14]=[C:15]([CH:19]=[C:20]([N+:22]([O-:24])=[O:23])[CH:21]=1)[C:16]([OH:18])=O.C1C=CC2N(O)N=NC=2C=1.[NH2:35][CH:36]([CH3:40])[CH2:37][O:38][CH3:39].CN1C(=O)CCC1>C(Cl)Cl.CN(C=O)C>[I:12][C:13]1[CH:14]=[C:15]([CH:19]=[C:20]([N+:22]([O-:24])=[O:23])[CH:21]=1)[C:16]([NH:35][CH:36]([CH3:40])[CH2:37][O:38][CH3:39])=[O:18]
Reactant: COCC(C)N
Reactant: O=C(O)c1cc(I)cc([N+](=O)[O-])c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: COCC(C)NC(=O)c1cc(I)cc([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 27.9 %

Procedure:
EDCI (7.07 g, 36.9 mmol) was added in one portion to a stirred solution of 3-Iodo-5-nitro-benzoic acid (2.31 g, 24.6 mmol), HOBt (4.985 g, 36.9 mmol), 2-Amino-1-methoxypropane (2.73 ml, 24.6 mmol) and NMP (4.06 ml 36.9 mmol) in CH2Cl2 (120 ml) and DMF (10 ml) at 0° C. The reaction was allowed to warm to room temperature and was stirred over night. The reaction mixture was then washed with 2N NaOH, water, brine, and dried over Na2SO4. Solvent was removed in vacuo to give 2.50 g of 3-Iodo-N-(2-methoxy-1-methyl-ethyl)-5-nitro-benzamide as a yellow solid, MS (M+H)=365. This material was used without further purification.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(CC)CC.[C:15]([O:19][CH3:20])(=[O:18])[CH:16]=[CH2:17]>C(Cl)Cl>[C:1]1([S:7][CH2:17][CH2:16][C:15]([O:19][CH3:20])=[O:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Sc1ccccc1
Reactant: C=CC(=O)OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CCSc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Thiophenol (440 mg, 4 mmol) and Et3N (70 μl, 0.5 mmol) were dissolved in CH2Cl2 (5 ml). Methyl acrylate (412 mg, 4.8 mmol) was added dropwise. The reaction was exothermic. After stirring at room temperature for 30 minutes, the excess methyl acrylate was removed in vacuo. TLC: silica gel, Et2O-hexane 1:2, UV Rf =0.58. The crude title ester was used without further purification.
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[CH2:4][N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1.[NH3:15]>CCO>[NH2:15][CH2:3][C@@H:2]([OH:1])[CH2:4][N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1
Reactant: N
Reactant: c1ccc2c(c1)CCN(C[C@H]1CO1)C2
Solvent: CCO
Product: NC[C@@H](O)CN1CCc2ccccc2C1
Temperature: 80 °C
Yield: 90 %

Procedure:
To a solution of (S)-2-(oxiran-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline (2.2 g, 0.012 mol) in EtOH (30 mL), NH3 was bubbled to the solution under −78° C. The reaction mixture was then sealed and heated at 80° C. for 3 h. After LCMS indicated completion of the reaction, the mixture was concentrated and the crude product was used in next step without further purification (2.2 g, Yield 90%). LCMS (m/z): 207.1 (M+1).