Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:15]=[CH:14][C:13]3[N:12]=[C:11]([CH3:16])[NH:10][C:9](=[O:17])[C:8]=3[C:7]=2[CH:18]=1.[NH2:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[C:25](=[O:29])[N:24]([C@@H:30]([CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])[C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:23]2.C([O-])(O)=O.[Na+].C(O)(=O)C>CN(C=O)C.C(O)C>[CH3:16][C:11]1[NH:10][C:9](=[O:17])[C:8]2[C:7]3[CH:18]=[C:3]([CH2:2][NH:19][C:20]4[CH:21]=[C:22]5[C:26](=[CH:27][CH:28]=4)[C:25](=[O:29])[N:24]([C@@H:30]([CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])[C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:23]5)[CH:4]=[CH:5][C:6]=3[CH:15]=[CH:14][C:13]=2[N:12]=1
Reactant: CCOC(=O)CC[C@@H](C(=O)OCC)N1Cc2cc(N)ccc2C1=O
Reactant: Cc1nc2ccc3ccc(CBr)cc3c2c(=O)[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCOC(=O)CC[C@@H](C(=O)OCC)N1Cc2cc(NCc3ccc4ccc5nc(C)[nH]c(=O)c5c4c3)ccc2C1=O
Yield: 49 %

Procedure:
A solution of crude 9-bromomethyl-3-methylbenzo[f]quinazolin-1(2H)-one (4.32 g), (S)-diethyl 2-(5-amino-1-oxo-2-isoindolinyl)glutarate (4.0 g, 12 mmol), and NaHCO3 (2.0 g, 24 mmol) in DMF (30 ml) was stirred under nitrogen at 105° C. for 1.5 hours. After cooling, acetic acid (1 ml, 17 mmol) was added, the reaction mixture transferred to a larger round bottom flask with ethanol, and then concentrated in vacuo onto silica gel (30 g). The absorbed material was purified by chromatography on silica gel eluting with methanol:methylene chloride (1:24) and then precipitation of the solid from methylene chloride (~20 ml) with ethyl acetate (~45 ml) and methanol (~5 ml). The white solid was filtered under nitrogen and dried under high vacuum to give diethyl (S)-2-(5-(((1,2-dihydro-3-methyl-1-oxobenzo[f]-quinazolin-9-yl)methyl)amino)-1-oxo-2-isoindolinyl)glutarate (3.27 g). 1H NMR (DMSO-d6, 300 MHz, δ: 1.10 (t, J=7 Hz, 3H, ester CH3), 1.15 (t, J=7 Hz, 3H, ester CH3), 1.93-2.33 (m, 4H, glu CH2CH2), 2.43 (s, 3H, C3 -CH3) 3.87-4.03 (m, 2H, ester CH2), 4.09 (q, J=7 Hz, 2H, ester CH2), 4.25 (very strongly coupled AB pair, 2H, glu NCH2Ar), 4.58 (d, J=6 Hz, 2H, C9 -CH2N), 4.74-4.83 (m, 1H, glu CH), 6.71 (br d, J=2 Hz, 1H, Ar), 6.74 (dd, J=8,2 Hz, 1H, Ar), 7.20 (t, J=6 Hz, 1H, ArNH), 7.37 (d, J=8 Hz, 1H Ar), 7.59 (d, J=9 Hz, 1H, Ar), 7.63 (dd, J=8,2 Hz, 1H, Ar), 8.00 (d, J=8 Hz, 1H, Ar), 8.21 (d, J=9 Hz, 1H, Ar), 9.87 (s, 1H, Ar), 12.54 (s, 1H, N2H). Mass spectrum (CI-CH4) 557 (M+1, 100%). Anal. Calculated for C31H32N4O6 : C, 66.89; H, 5.79; N, 10.07. Found: C, 66.80; H, 5.82; N, 10.10.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([NH:16][C:17]2[CH:25]=[CH:24][C:20]([C:21]([OH:23])=O)=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH2:47][CH2:48][C:49]([N:51]1[CH2:56][CH2:55][N:54]([C:57](=[O:69])[C:58]2[CH:63]=[C:62]([C:64]([F:67])([F:66])[F:65])[CH:61]=[CH:60][C:59]=2[Cl:68])[CH2:53][CH2:52]1)=[O:50].Cl>CN(C=O)C.O>[Cl:68][C:59]1[CH:60]=[CH:61][C:62]([C:64]([F:67])([F:65])[F:66])=[CH:63][C:58]=1[C:57]([N:54]1[CH2:53][CH2:52][N:51]([C:49](=[O:50])[CH2:48][NH:47][C:21](=[O:23])[C:20]2[CH:19]=[CH:18][C:17]([NH:16][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)=[CH:25][CH:24]=2)[CH2:56][CH2:55]1)=[O:69]
Reactant: O=C(O)c1ccc(Nc2ccccc2)cc1
Reactant: NCC(=O)N1CCN(C(=O)c2cc(C(F)(F)F)ccc2Cl)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCN(C(=O)c2cc(C(F)(F)F)ccc2Cl)CC1)c1ccc(Nc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52 %

Procedure:
DIPEA (74 mg, 0.1 mL, 0.63 mmol) was added drop wise to 4-(phenyl-amino)-benzoic acid (45 mg, 0.21 mmol) in DMF (5 mL). EDCI (100 mg, 0.52 mmol) and HOBT (34 mg, 0.25 mmol) were added consecutively and, after 10 minutes, 2-amino-1-[4-(2-chloro-5-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone in its HCl salt form (97 mg, 0.25 mmol) was added. The resulting mixture was stirred at room temperature overnight. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to get the residue. The obtained residue was purified by column chromatography (using silica gel of 60-120 mesh and 70% EtOAc in Hexane as eluent) to afford 60 mg (52% yield) of N-{2-[4-(2-chloro-5-trifluoromethyl-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-4-phenylamino-benzamide. LC-MS purity: 98.43%. 1H-NMR (DMSO-d6): δ 8.6 (s, 1H), 8.3 (t, 1H), 7.9 (d, 1H), 7.8 (m, 4H), 7.3 (t, 2H), 7.2 (d, 2H), 7.1 (d, 2H), 6.9 (t, 1H), 4.1 (dd, 2H), 3.6 (m, 6H), 3.2 (m, 2H).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:6])[CH2:4][OH:5].[O:7]=[C:8]1[NH:16][CH:15]=[N:14][C:13]2[N:12]([CH2:17][CH2:18][C:19](OCC)=[O:20])[CH:11]=[N:10][C:9]1=2>C(#N)C.CO>[O:7]=[C:8]1[NH:16][CH:15]=[N:14][C:13]2[N:12]([CH2:17][CH2:18][C:19]([NH:1][CH2:2][CH:3]([OH:6])[CH2:4][OH:5])=[O:20])[CH:11]=[N:10][C:9]1=2
Reactant: NCC(O)CO
Reactant: CCOC(=O)CCn1cnc2c(=O)[nH]cnc21
Solvent: CC#N
Solvent: CO
Product: O=C(CCn1cnc2c(=O)[nH]cnc21)NCC(O)CO
Temperature: 110 °C
Reaction time: 1 h
Yield: 91.2 %

Procedure:
0.500 g (5.49 mmol) of 3-amino-1,2-propanediol was placed into a 10 ml round bottom flask with a magnetic stirring bar. The flask was heated to 110° C. and 0.250 g (1.06 mmol) of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)propionic acid, ethyl ester (AIT-0027) was added to the stirring solution. The solution was stirred at 100°-110° C. for one hour. The flask was allowed to cool to room temperature and 10 ml of 1:1 acetonitrile/methanol was added and the solution was stirred vigorously for 30 minutes. The resulting white precipitate was collected using Buchner funnel filtration to yield 272 mg of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)-N-(2,3-dihydroxyprop-1-yl)propanamide (AIT-0062) as a white solid. 91% yield.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:20]#[N:21])[C:5]2[CH:6]=[N:7][N:8]([S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:9]=2[CH:10]=1.CC1(C)C(C)(C)OB([C:30]2[CH:38]=[CH:37][CH:36]=[C:35]3[C:31]=2[CH:32]=[CH:33][N:34]3[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>O>[C:20]([C:4]1[CH:3]=[C:2]([C:30]2[CH:38]=[CH:37][CH:36]=[C:35]3[C:31]=2[CH:32]=[CH:33][N:34]3[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][N:8]2[S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12])#[N:21]
Reactant: N#Cc1cc(Br)cc2c1cnn2S(=O)(=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)n1ccc2c(B3OC(C)(C)C(C)(C)O3)cccc21
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)n1ccc2c(-c3cc(C#N)c4cnn(S(=O)(=O)c5ccccc5)c4c3)cccc21
Yield: 44.8 %

Procedure:
To a round bottomed flask was charged 6-bromo-1-(phenylsulfonyl)-1H-indazole-4-carbonitrile (10 g, 27.6 mmol), 1,1-dimethylethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-1-carboxylate (14.21 g, 41.4 mmol) and potassium phosphate tribasic (17.58 g, 83 mmol). The resulting mixture was treated with 1,4-dioxane (120 ml) and water (12 ml) that had previously been purged with nitrogen. The mixture was then treated with 1′-bis(diphenylphosphino)ferrocene palladium dichloride (1.547 g, 2.76 mmol) and heated to reflux, under nitrogen for 2 h. Additional 1′-bis(diphenylphosphino)ferrocene palladium dichloride (1.547 g, 2.76 mmol) was added and the mixture heated at reflux for a further 1 h. The hot reaction mixture was filtered through Celite, washed well with chloroform and the filtrate concentrated in vacuo. The residue was dissolved in DCM/cyclohexane (1:1, 50 ml) and purified by column chromatography on silica (750 g cartridge), eluting with 0-40% ethyl acetate/cyclohexane. The pure fractions were combined and concentrated to give the title compound as a yellow solid (6.16 g).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH2:13][CH2:14][C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[CH:18]=2)=[O:16])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12].[C:24]([O:28][C:29](=[O:32])[CH2:30]Br)([CH3:27])([CH3:26])[CH3:25]>CN(C=O)C>[C:24]([O:28][C:29]([CH2:30][O:23][C:19]1[CH:18]=[C:17]([C:15](=[O:16])[CH2:14][CH2:13][C:7]2[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:5]([O:4][CH3:3])[CH:6]=2)[CH:22]=[CH:21][CH:20]=1)=[O:32])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COc1ccc(CCC(=O)c2cccc(O)c2)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CCC(=O)c2cccc(OCC(=O)OC(C)(C)C)c2)cc1OC
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 82.3 %

Procedure:
A 60% mineral oil suspension of NaH (279 mg, 6.98 mmol) in anhydrous DMF (10 mL) was cooled to 0° C. in an ice bath and solid 3-(3,4-Dimethoxyphenyl)-1-(3-hydroxyphenyl)propan-1-one (7) (2 g, 6.98 mmol) added in one portion. The resulting yellow solution was stirred for 5 min after which time tert-butylbromoacetate (1.18 mL, 7.33 mmol) was added. Stirring was continued at 0° C. for 15 min after which time the reaction mixture was warmed to room temperature and partitioned between diethyl ether (50 mL) and water (50 mL). The organic layer was washed with a saturated NaCl solution (2×50 mL), dried over MgSO4, filtered, evaporated, and flash chromatographed (silica gel, 30% EtOAc/hexanes) to afford 2.30 g (82%) of a clear colorless oil: IR (neat) 2980, 1750, 1685, 1590, 1515, 1260, 1155 cm-1 ; 1H NMR (CDCl3, 300 MHz) 7.59 (d, J=7.7 Hz, 1H), 7.49 (s, 1H), 7.39 (app t, J=8.0 Hz, 1H), 7.14 (dd, J=8.2, 2.6 Hz, 1H), 6.81-6.79 (m, 3H), 4.58 (s, 2H), 3.89 (s, 3H), 3.88 (s, 3H), 3.28 (t, J=7.3 Hz, 2H), 3.02 (t, J=7.8 Hz, 2H), 1.51 (s, 9H); 13C NMR (CDCl3, 75 MHz) 199.2, 168.0, 158.6, 149.3, 147.8, 138.7, 134.2, 130.1, 121.8, 120.6, 113.5, 112.2, 111.8, 108.1, 83.0, 66.1, 56.2, 41.1, 30.2, 28.4.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[CH:13]1([NH2:16])[CH2:15][CH2:14]1.CC(OC1C=CC=C(OC(C)C)C=1C1C(P(C2CCCCC2)C2CCCCC2)=CC=CC=1)C>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:13]1([NH:16][C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=2[N+:10]([O-:12])=[O:11])[CH2:15][CH2:14]1
Reactant: COc1ccc(I)c([N+](=O)[O-])c1
Reactant: NC1CC1
Agent: [Pd]
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COc1ccc(NC2CC2)c([N+](=O)[O-])c1
Temperature: 100 °C

Procedure:
To a stirred solution of 1-iodo-4-methoxy-2-nitrobenzene (0.2 g, 0.0007 mol) in toluene (6.0 mL) was added cyclopropylamine (0.068 ml, 0.0008 mol) potassium tert-butoxide (0.094 g, 0.0098 mol) and Ruphos (0.049 g, 0.00010 mol) at room temperature and purged with argon for 15 min. Then Pd2(dba)3 (0.064 g, 0.00007 mol) was added and resulting mixture was heated to 100° C. in CEM microwave for 30 min. After the reaction was complete the reaction mixture was filtered through CELITE® bed and the bed was thoroughly washed with ethyl acetate. The filtrate was washed with water brine dried over Na2SO4 and concentrated under reduced pressure to afford the crude compound, which was purified by column chromatography to obtain title compound cyclopropyl-(4-methoxy-2-nitro-phenyl)-amine (yellow solid). C10H12N2O3; 1H NMR (400 MHz, CDCl3), δ: 7.98 (s, 1H), 7.60 (d, J=2.8 Hz, 1H), 7.30 (s, 1H), 7.19-7.16 (m, 1H), 4.12 (q, J=6.8, 1H), 3.80 (s, 1H), 0.89 (dd, J1=12.0 Hz, J2=6.0 Hz, 2H), 0.64 (t, J=6.8 Hz, 2H). MS (M+1): 209.1.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[CH3:21][C:22]1([CH3:27])[CH2:26][CH2:25][CH2:24][NH:23]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:23]3[CH2:24][CH2:25][CH2:26][C:22]3([CH3:27])[CH3:21])=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: CC1(C)CCCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)CCCN1C(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with 2,2-dimethylpyrrolidine (CAN 35018-15-6) in the presence of TBTU and DIEA to obtain the title compound as colorless oil; MS (EI): m/e=366.4 [MH+].
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][N:13]=2)=[N:8][O:9][C:10]=1[CH3:11])=[O:5])C.[OH-].[Na+].C(O)C.Cl>O.O1CCCC1>[F:18][C:17]1[C:12]([C:7]2[C:6]([C:4]([OH:5])=[O:3])=[C:10]([CH3:11])[O:9][N:8]=2)=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(=O)c1c(-c2ncccc2F)noc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: Cc1onc(-c2ncccc2F)c1C(=O)O

Procedure:
Combine 3-(3-fluoro-pyridin-2-yl)-5-methyl-isoxazole-4-carboxylic acid ethyl ester (0.515 g, 0.002 mol) with aqueous sodium hydroxide (2N, 8.0 mL, 0.016 mol), ethanol (2 mL), and tetrahydrofuran (2 mL) and stir overnight at ambient temperature. Add water and adjust to approx. pH 2.0 with aqueous hydrochloric acid. Extract with ethyl acetate and dry over sodium sulfate and concentrate in vacuo. Drying nets the desired isoxazole acid (0.44 g, 97%). MS(ES): (M+1)+ 221.9, 222.9 m/z.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1/[C:6](=[N:20]/[O:21][CH:22]([CH2:32][NH:33]C(OC(C)(C)C)=O)[CH2:23][NH:24]C(OC(C)(C)C)=O)/[C:7]([NH:9][C@H:10]1[C@H:13]([CH3:14])[N:12]([S:15]([OH:18])(=[O:17])=[O:16])[C:11]1=[O:19])=[O:8].[K].[F:42][C:43]([F:48])([F:47])C(O)=O>C(Cl)Cl>[OH:18][S:15]([C:43]([F:48])([F:47])[F:42])(=[O:16])=[O:17].[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1/[C:6](=[N:20]/[O:21][CH:22]([CH2:32][NH2:33])[CH2:23][NH2:24])/[C:7]([NH:9][C@H:10]1[C@H:13]([CH3:14])[N:12]([S:15]([OH:18])(=[O:17])=[O:16])[C:11]1=[O:19])=[O:8]
Reactant: C[C@H]1[C@H](NC(=O)/C(=N\OC(CNC(=O)OC(C)(C)C)CNC(=O)OC(C)(C)C)c2cccs2)C(=O)N1S(=O)(=O)O
Reactant: O=C(O)C(F)(F)F
Agent: [K]
Solvent: ClCCl
Product: C[C@H]1[C@H](NC(=O)/C(=N\OC(CN)CN)c2cccs2)C(=O)N1S(=O)(=O)O
Product: O=S(=O)(O)C(F)(F)F
Reaction time: 4 h
Yield: 66 %

Procedure:
To a solution of (3S)-trans-3-[(E)-2-(2-thienyl)-2-{1,3-di(t-butoxycarbonylamino)-prop-2-oxyimino} acetamido]-4-methyl-2-oxoazetidine-1-sulfonic acid, potassium salt (step 4, Example 2, 4.04 gm, 5.2756 mmol) in methylene chloride (12 ml) cooled to -5° C. was added trifluoroacetic acid (18 gm, 156.890 mmol) dropwise and stirred at this temperature for 4 hr. The mixture was diluted with methylene chloride and concentrated under reduced pressure to give a foam which was triturated with ether to afford a white solid. Purification of the product over HP-20 column with acetonitrile-water (1:9) as eluant and freeze-drying of the desired fractions gave the target compound as a white solid, 2.15 gm (66% yield). 1H-NMR (DMSO-d6): δ 9.04 (d, 1H, J=8.05 Hz); 7.96-8.05 (m, 8H); 7.24 (t, 1H, J=4.5 Hz); 4.70-4.90 (m, 1H); 4.53 (dd, 1H, J=2.68 and 8.04 Hz); 3.70-3.84 (m, 1H); 3.18-3.40 (m, 4H); 1.44 (d, 3H, J=6.07 Hz).
Reaction SMILES: [CH3:1][N:2]([C@@H:11]([CH2:15][CH:16]=[CH2:17])[C:12]([OH:14])=O)[S:3]([CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])(=[O:5])=[O:4].CCN=C=NCCC[N+](C)(C)C.[I-].ON1C2C=CC=CC=2N=N1.[CH2:41]([O:44][C@H:45]1[C:53]2[C:48](=[CH:49][C:50]([O:54][CH3:55])=[CH:51][CH:52]=2)[C@@H:47]([NH:56][CH2:57][C@@H:58]([OH:70])[C@@H:59]([NH2:69])[CH2:60][C:61]2[CH:66]=[C:65]([Cl:67])[CH:64]=[C:63]([Cl:68])[CH:62]=2)[CH2:46]1)[CH:42]=[CH2:43]>C(N(CC)CC)C.CN(C)C=O>[CH2:41]([O:44][C@H:45]1[C:53]2[C:48](=[CH:49][C:50]([O:54][CH3:55])=[CH:51][CH:52]=2)[C@@H:47]([NH:56][CH2:57][C@@H:58]([OH:70])[C@@H:59]([NH:69][C:12](=[O:14])[C@@H:11]([N:2]([CH3:1])[S:3]([CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])(=[O:4])=[O:5])[CH2:15][CH:16]=[CH2:17])[CH2:60][C:61]2[CH:62]=[C:63]([Cl:68])[CH:64]=[C:65]([Cl:67])[CH:66]=2)[CH2:46]1)[CH:42]=[CH2:43]
Reactant: C=CC[C@@H](C(=O)O)N(C)S(=O)(=O)CCCCC
Reactant: C=CCO[C@@H]1C[C@H](NC[C@@H](O)[C@@H](N)Cc2cc(Cl)cc(Cl)c2)c2cc(OC)ccc21
Agent: CCN=C=NCCC[N+](C)(C)C
Agent: On1nnc2ccccc21
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C=CCO[C@@H]1C[C@H](NC[C@@H](O)[C@H](Cc2cc(Cl)cc(Cl)c2)NC(=O)[C@H](CC=C)N(C)S(=O)(=O)CCCCC)c2cc(OC)ccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 44 %

Procedure:
Step DL (1): A mixture of 28.7 mg (S)-2-(N-methylpentylsulfonamido)pent-4-enoic acid (0.11 mmol, from Preparation J), 24.8 mg 1-[3-(dimethyamino)propyl]-3-ethyl carbodiimide methiodide (0.083 mmol), 18 mg 1-hydroxybenzotriazole, 3 drops triethylamine and 1 mL dimethyl-formamide was stirred for 15 minutes at rt. The mixture was then added to 21 mg (2R,3S)-1-((1S,3R)-3-(allyloxy)-6-methoxy-2,3-dihydro-1H-inden-1-ylamino)-3-amino-4-(3,5-dichloro-phenyl)butan-2-ol (0.046 mmoles, from Preparation BG) and the reaction mixture was allowed to stand at rt overnight. The reaction mixture was subjected to preparative HPLC, with the peak at 9.8 min collected to yield 14.1 mg (S)-N-((2S,3R)-4-((1S,3R)-3-(allyloxy)-6-methoxy-2,3-dihydro-1H-inden-1-yl-amino)-1-(3,5-dichlorophenyl)-3-hydroxybutan-2-yl)-2-(N-methylpentyl-sulfon-amido)pent-4-enamide as a clear oil. LC-MS Rt 2.18 min (method A), (M+H)+=696.0, 698.0; HRMS (M+H)+=696.2653; 1H NMR (500 MHz, CDCl3) δ 7.31 (d, J=8.2, 1H) 7.19 (s, 1H) 7.14 (s, 2H) 6.94 (d, J=2.1, 1H) 6.84 (d of d, J=8.2, 2.4, 1H) 6.68 (d, J=9.1, 1H) 5.95 (m, 1H) 5.69 (m, 1H) 5.31 (d, J=17, 1H) 5.2-5.08 (m, 3H) 4.77 (t, J=5.5, 1H) 4.17 (d of d, J=9.5, 5.7, 1H) 4.10 (m, 1H) 3.80 (s, 3H) 3.51 (m, 1H) 3.12 (d of d, J=14.3, 3.7, 1H) 2.90 (m, 4H) 2.67 (m, 4H) 2.54 (s, 3H) 2.31 (m, 2H) 1.93 (d, J=13.4 of t, J=4.6, 1H) 1.75 (m, 2H) 1.33 (m, 4H) 0.90 (t, J=7, 3H).
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)[CH3:3].Cl[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15].Cl>[OH-].[Na+]>[CH2:17]([O:16][C:14]([NH:1][C@H:2]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)[CH3:3])=[O:15])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C[C@H](N)c1ccc(C(=O)O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: C[C@H](NC(=O)OCc1ccccc1)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.6 %

Procedure:
To a cooled (0° C.) mixture of 4-[(1S)-1-aminoethyl]benzoic acid (Chem. Eur. J. 1999, 5, 1095, 16.2 g, 98 mmol) and 2 N sodium hydroxide aqueous solution (100 mL) was added benzyl chloroformate (20.5 g, 120 mmol) dropwise over 30 min period followed by the addition of additional 2 N sodium hydroxide aqueous solution (70 mL). The reaction mixture was stirred overnight at room temperature and then acidified to pH 1 with concentrated hydrochloric acid. The resulting precipitate was filtered, washed with water (100 mL), and then vacuum dried to yield 26 g (88%) of the title compounds as white solids: 1H-NMR (CDCl3) δ 7.95 (2H, d, J=8.1 Hz), 7.40–7.15 (7H, m), 5.12–4.94 (3H, m), 4.82 (1H, br.s), 1.40 (3H, d, J=7.0 Hz); MS (ESI) m/z 300 (M+H)+, 298 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:18])=[O:17])[C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([S:14][CH3:15])=[CH:9][CH:8]=2)=O.P(Cl)(Cl)(Cl)=O.O.[NH2:31][NH2:32]>C(O)C>[C:19]1([S:16]([N:6]2[C:7]3[C:12](=[CH:11][C:10]([S:14][CH3:15])=[CH:9][CH:8]=3)[CH:13]=[C:5]2[C:3]2[O:2][CH:1]=[N:31][N:32]=2)(=[O:18])=[O:17])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)c1cc2cc(SC)ccc2n1S(=O)(=O)c1ccccc1
Reactant: NN
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: CCO
Product: CSc1ccc2c(c1)cc(-c1nnco1)n2S(=O)(=O)c1ccccc1

Procedure:
To a solution of 1-benzenesulfonyl-5-methylthio-1H-indole-2-carboxylic acid methyl ester (370 mg) in ethanol (12 ml), hydrazine monohydrate (0.55 ml) was added at 15 to 30° C. and the mixture was heated under reflux for 13 hours. Further, to the mixture was added hydrazine monohydrate (0.55 ml) and the mixture was heated under reflux for 5 hours. The reaction solution was concentrated under reduced pressure. To the resulting residue was added water, and the insolubles were filtered off and washed with water and ether. To the filtered crude product was added formic acid (9 ml) and the mixture was heated under reflux for 1 hour. The reaction solution was concentrated under reduced pressure. To the resulting residue was added ethyl acetate and the insolubles were filtered off and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to obtain 330 mg of the crude product of 1-benzenesulfonyl-5-methylthio-1H-indole-2-carboxylic acid-N′-formylhydrazide. A mixture solution of 509 mg of the crude product thus obtained and phosphorus oxychloride (15 ml) was stirred at 15 to 30° C. for 6 hours. The reaction solution was concentrated under reduced pressure. The resulting residue was separated using silica gel column chromatography (ethyl acetate:hexane 1:2) to obtain 265 mg of the desired product.
Reaction SMILES: CS[CH2:3][C:4]1([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:6][CH2:5]1.O[O:16][S:17]([O-:19])=O.[K+].[C:21]([O-])(O)=O.[Na+]>CO.O>[CH3:21][S:17]([CH2:3][C:4]1([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:5][CH2:6]1)(=[O:19])=[O:16]
Reactant: O=C([O-])O
Reactant: CSCC1(NC(=O)OC(C)(C)C)CC1
Reactant: O=S([O-])OO
Agent: [K+]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NC1(CS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of tert-butyl 1-(methylthiomethyl)cyclopropylcarbamate (crude), Oxone (4.8 g, 7.8 mmol) and NaHCO3 (2.6 g, 31.3 mmol) in MeOH (28 ml) and Water (7 ml) was stirred at room temperature for 1.5 h, at which time LC/MS analysis confirmed full consumption of starting material. Solvent was removed in vacuo and the crude was redissolved in EtOAc (100 ml), washed with water (1×20 ml), brine (1×20 ml), dried over MgSO4. Solvent was removed in vacuo to give tert-butyl 1-(methylsulfonylmethyl)cyclopropylcarbamate as a crude product (white solid, 1.1 g) which was used for the next step without any purification.
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:18][CH2:17][C:16]2[S:15][C:14]3[C:9](=[C:10]([O:19][CH:20]4[CH2:25][CH2:24][CH:23]([N:26]5[CH2:32][C:28]6([CH2:31][O:30][CH2:29]6)[CH2:27]5)[CH2:22][CH2:21]4)[N:11]=[CH:12][N:13]=3)[C:8]1=2)(=O)=O.[C-:33]#[N:34].[Na+]>CS(C)=O>[CH2:31]1[C:28]2([CH2:27][N:26]([CH:23]3[CH2:24][CH2:25][CH:20]([O:19][C:10]4[N:11]=[CH:12][N:13]=[C:14]5[C:9]=4[C:8]4[C@@H:7]([CH2:6][C:33]#[N:34])[CH2:18][CH2:17][C:16]=4[S:15]5)[CH2:21][CH2:22]3)[CH2:32]2)[CH2:29][O:30]1
Reactant: [C-]#N
Reactant: CS(=O)(=O)OC[C@H]1CCc2sc3ncnc(OC4CCC(N5CC6(COC6)C5)CC4)c3c21
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CC[C@H]1CCc2sc3ncnc(OC4CCC(N5CC6(COC6)C5)CC4)c3c21
Yield: 65.6 %

Procedure:
A solution of [(3S)-12-[(4-[2-oxa-6-azaspiro[3.3]heptan-6-yl]cyclohexyl)oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-3-yl]methyl methanesulfonate (250 mg, 0.52 mmol, 1.00 equiv) and NaCN (153 mg, 3.12 mmol, 5.99 equiv) in DMSO (10 mL) was stirred for 3 h at 60° C. After cooling, the reaction was quenched by the addition of 30 mL of saturated aqueous sodium bicarbonate and extracted with 3×50 mL of ethyl acetate. The combined organic layers combined were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (10:1) to give 2-[(3R)-12-[(4-[2-oxa-6-azaspiro[3.3]heptan-6-yl]cyclohexyl)oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-3-yl]acetonitrile (140 mg, 65%) as a colorless oil.