Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH2:6][C:5]2[S:8][C:9]([C:11]([O-:13])=O)=[N:10][C:4]=2[CH2:3]1.[Li+].[Cl:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH:22]=[C:21]([S:26]([N:29]1[CH2:34][CH2:33][NH:32][CH:31]([CH2:35][C:36]([O:38][CH3:39])=[O:37])[CH2:30]1)(=[O:28])=[O:27])[CH:20]=[CH:19]2>>[Cl:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH:22]=[C:21]([S:26]([N:29]1[CH2:34][CH2:33][N:32]([C:11]([C:9]3[S:8][C:5]4[CH2:6][NH:7][CH:2]([CH3:1])[CH2:3][C:4]=4[N:10]=3)=[O:13])[CH:31]([CH2:35][C:36]([O:38][CH3:39])=[O:37])[CH2:30]1)(=[O:27])=[O:28])[CH:20]=[CH:19]2
Reactant: COC(=O)CC1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1
Reactant: CC1Cc2nc(C(=O)[O-])sc2CN1
Agent: [Li+]
Product: COC(=O)CC1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1C(=O)c1nc2c(s1)CNC(C)C2

Procedure:
Starting materials: lithium 6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate, 1-[(6-chloronaphthalen-2-yl)sulfonyl]-3-[methoxycarbonylmethyl]piperazine
Reaction SMILES: Cl[P:2]1[N:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[P:4](Cl)[N:3]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH:19]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]([CH3:30])[CH3:29])[C:23]=1[OH:31])([CH3:21])[CH3:20]>C(N(CC)CC)C>[CH:28]([C:24]1[CH:25]=[CH:26][CH:27]=[C:22]([CH:19]([CH3:21])[CH3:20])[C:23]=1[O:31][P:2]1[N:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[P:4]([O:31][C:23]2[C:24]([CH:28]([CH3:29])[CH3:30])=[CH:25][CH:26]=[CH:27][C:22]=2[CH:19]([CH3:21])[CH3:20])[N:3]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH3:30])[CH3:29]
Reactant: ClP1N(c2ccccc2)P(Cl)N1c1ccccc1
Reactant: CC(C)c1cccc(C(C)C)c1O
Solvent: CCN(CC)CC
Product: CC(C)c1cccc(C(C)C)c1OP1N(c2ccccc2)P(Oc2c(C(C)C)cccc2C(C)C)N1c1ccccc1

Procedure:
The procedure of Example 1 is repeated using 2,4-dichloro-1,3-diphenyl-1,3,2,4-diazadiphosphetidine, 2,6-diisopropylphenol and triethylamine to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([CH2:30][CH3:31])[CH:24]([OH:29])[C:25]([F:28])([F:27])[F:26])=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(#N)C>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([CH2:30][CH3:31])[C:24](=[O:29])[C:25]([F:26])([F:27])[F:28])=[CH:4][CH:3]=1
Reactant: CCC(c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)C(O)C(F)(F)F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CC#N
Product: CCC(C(=O)C(F)(F)F)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Reaction time: 1 h

Procedure:
To a stirred solution of 3-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]-1,1,1-trifluoropentan-2-ol (47.4 mg, 0.0961 mmol) in acetonitrile (0.6 mL) was added Dess-Martin reagent (48.9 mg, 0.115 mmol) at room temperature. After 1 h, the reaction mixture was concentrated in vacuo and purified by flash column chromatography on NH silica gel eluting with a 0-10% methanol/ethyl acetate gradient mixture to give the title compound as a colorless amorphous (33.3 mg, 0.0678 mmol, 71%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[SH:9].[Br:10][C:11]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:12]=1I>>[Br:10][C:11]1[CH:16]=[C:15]([C:17]([F:18])([F:19])[F:20])[CH:14]=[CH:13][C:12]=1[S:9][C:3]1[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[CH3:1]
Reactant: FC(F)(F)c1ccc(I)c(Br)c1
Reactant: Cc1ccc(S)c(C)c1
Product: Cc1ccc(Sc2ccc(C(F)(F)F)cc2Br)c(C)c1

Procedure:
Prepared from 2,4-dimethyl-benzenethiol and 2-bromo-1-iodo-4-trifluoromethyl-benzene.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Br)(Br)(Br)[Br:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(C)=O>C(Cl)Cl>[Br:16][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCCCCCCCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: BrCCCCCCCc1ccccc1
Reaction time: 0.01 h
Yield: 147.6 %

Procedure:
To a solution of 7-phenyl-1-heptanol (29.1 g, 151.3 mmol) in 800 mL CH2Cl2 at room temperature was added CBr4 (60.2 g, 181.6 mmol) then triphenylphosphine (47.6 g, 181.6 mmol). After 30 s, the reaction had turned a light green color. TLC indicated that the reaction was complete at this point. The solvent was removed in vacuo to give a greenish-white semisolid. To this material was added 10% EtOAc: 90% Hexanes and the resulting suspension was filtered through a pad of silica gel washing well with the same solvent system. There yielded 57 g of a colorless oil as the desired bromide and triphenylphosphine oxide. This oil was then flash chromatographed (Hexanes) to yield 38.6 g, 100% of the bromide as a colorless oil. 1H NMR (CDCl3) δ 1.30–1.49 (m, 6H); 1.60 (quintet, J=8.18 Hz, 2H); 2.60 (t, J=8.18 Hz, 2H); 3.39 (t, J=8.18 Hz, 2H); 7.13–7.20 (m, 3H); 7.21–7.31 (m, 2H).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:9]1([CH3:14])[O:13][CH2:12][CH2:11][O:10]1)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[F:15][C:16]1[CH:26]=[CH:25][C:24]([F:27])=[C:18]2[C:19]([O:21][C:22](=O)[C:17]=12)=[O:20]>>[F:15][C:16]1[CH:26]=[CH:25][C:24]([F:27])=[C:18]2[C:17]=1[C:22](=[O:21])[N:1]([CH2:2][CH:3]([C:9]1([CH3:14])[O:10][CH2:11][CH2:12][O:13]1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:19]2=[O:20]
Reactant: O=C1OC(=O)c2c(F)ccc(F)c21
Reactant: CCOC(=O)C(CN)C1(C)OCCO1
Product: CCOC(=O)C(CN1C(=O)c2c(F)ccc(F)c2C1=O)C1(C)OCCO1

Procedure:
Ethyl 3-(4,7-difluoro-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2-(2-methyl-[1,3]dioxolan-2-yl)propionate was prepared in the same manner as described in the above example 5 (20) from ethyl 3-amino-2-(2-methyl-[1,3]dioxolan-2-yl)propionate (0.80 g, 3.94 mmol) and 3,6-difluorophthalic anhydride (0.94 g, 4.33 mmol), and the obtained product was identified with the following NMR data.
Reaction SMILES: [F:1]C1C=CC(OC)=C(C2C(C(O)=O)=CC([N+]([O-])=O)=CC=2)C=1.C[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=1[C:31]1[C:32]([C:41]([O:43]C)=[O:42])=[CH:33][C:34]([N+:38]([O-:40])=[O:39])=[CH:35][C:36]=1C>>[F:1][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=1[C:31]1[C:32]([C:41]([OH:43])=[O:42])=[CH:33][C:34]([N+:38]([O-:40])=[O:39])=[CH:35][CH:36]=1
Reactant: COc1ccc(F)cc1-c1ccc([N+](=O)[O-])cc1C(=O)O
Reactant: COC(=O)c1cc([N+](=O)[O-])cc(C)c1-c1cc(OC)ccc1C
Product: COc1ccc(F)c(-c2ccc([N+](=O)[O-])cc2C(=O)O)c1
Yield: 99 %

Procedure:
This compound was prepared in a manner similar to that of 5′-fluoro-2′-methoxy-4-nitro-2-biphenylcarboxylic acid (EXAMPLE 107) from methyl 2′-methyl-5′-methoxy-6-methyl-4-nitro-2-biphenylcarboxylate (0.77 g) to afford 0.73 g (99%) of 2′-fluoro-5′-methoxy-4-nitro-2-biphenylcarboxylic acid as a white solid, which was used in the next step without further purification.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH:20]([C:22]1[CH:31]=[CH:30][C:25]([O:26][CH2:27][C:28]#[N:29])=[CH:24][CH:23]=1)=O>>[F:19][C:16]([F:17])([F:18])[C:13]1[N:11]2[N:12]=[C:7]([N:1]3[CH2:2][CH2:3][N:4]([CH2:20][C:22]4[CH:31]=[CH:30][C:25]([O:26][CH2:27][C:28]#[N:29])=[CH:24][CH:23]=4)[CH2:5][CH2:6]3)[CH:8]=[CH:9][C:10]2=[N:15][N:14]=1
Reactant: N#CCOc1ccc(C=O)cc1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: N#CCOc1ccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 2-(4-formylphenoxy)acetonitrile was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 2-[4-[[4-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperazin-1-yl]methyl]phenoxy]acetonitrile.
Reaction SMILES: O1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[O:15])[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1.[C:16](C1CCCCC1)(=O)[CH3:17]>>[CH:2]1([C:6](=[O:15])[CH:7]=[CH:8][C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[CH2:17][CH2:16][CH2:5][CH2:4][CH2:3]1
Reactant: CC(=O)C1CCCCC1
Reactant: O=C(C=Cc1ccncc1)c1ccco1
Product: O=C(C=Cc1ccncc1)C1CCCCC1

Procedure:
1-(2-Furyl-3-(4-pyridyl)-2-propene-1-one: MS (m/z): 200.0 (M+H)+ ; C12H9NO2 requir. 199.2. 1-Cyclohexyl-3-(4-pyridyl)-2-propene-1-one was prepared in the same way using acetylcyclohexane: MS (m/z): 216.2 (M+H)+ ; C14H17NO requir. 215.3.
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:24][C:25]4[CH:26]=[N:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=4)=[N:18][CH:19]=[C:20]([CH:23]=3)[CH:21]=O)[N:10]=2)=CC=1.[N:44]1[CH:45]=[N:46][N:47]2[CH2:52][CH2:51][NH:50][CH2:49][C:48]=12>>[N:44]1[CH:45]=[N:46][N:47]2[CH2:52][CH2:51][N:50]([CH2:21][C:20]3[CH:23]=[C:16]([C:11]4[N:12]=[C:13]([CH3:15])[N:14]=[C:9]([NH2:8])[N:10]=4)[C:17]([NH:24][C:25]4[CH:26]=[N:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=4)=[N:18][CH:19]=3)[CH2:49][C:48]=12
Reactant: c1nc2n(n1)CCNC2
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C=O)cnc3Nc3ccc(OC)nc3)n2)cc1
Product: COc1ccc(Nc2ncc(CN3CCn4ncnc4C3)cc2-c2nc(C)nc(N)n2)cn1

Procedure:
The title compound was synthesized following an analogous procedure to Example 220 using 5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)nicotinaldehyde (178 mg, 0.308 mmol) and 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine (GeneTech, Indianapolis, Ind.) (57.4 mg, 0.462 mmol). 1H NMR (400 MHz, CDCl3) δ 11.70 (s, 1H); 8.78 (d, J=2.54 Hz, 1H); 8.36 (d, J=2.74 Hz, 1H); 8.25 (d, J=2.35 Hz, 1H); 8.10 (dd, J=8.80, 2.74 Hz, 1H); 7.87 (s, 1H); 6.78 (d, J=8.61 Hz, 1H); 5.59 (s, 2H); 4.20 (t, J=5.38 Hz, 2H); 3.94 (s, 3H); 3.84 (s, 2H); 3.73 (s, 2H); 3.00 (t, J=5.48 Hz, 2H); 2.56 (s, 3H). m/z (ESI, +ve ion) 445.9 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:28])[N:19]([C@H:23]5[CH2:27][CH2:26][NH:25][CH2:24]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:31]([F:34])([F:33])[F:32])[CH:3]=1.[CH2:35](I)[CH3:36]>>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:28])[N:19]([C@H:23]5[CH2:27][CH2:26][N:25]([CH2:35][CH3:36])[CH2:24]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:31]([F:34])([F:33])[F:32])[CH:3]=1
Reactant: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1[C@H]1CCNC1
Reactant: CCI
Product: CCN1CC[C@H](N2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)C1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[(3S)-1-ethylpyrrolidin-3-yl]-1,3-thiazolidine-2,4-dione was prepared from (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[(3S)-pyrrolidin-3-yl]-1,3-thiazolidine-2,4-dione (Example 114) and ethyl iodide at rt following General Procedure S.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)#[N:2].[CH2:13]([Mg]Br)[CH3:14].B(F)(F)F.CCOCC.Cl>C(OCC)C.[Ti+4]>[NH2:2][C:1]1([C:3]2[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=2)[CH2:14][CH2:13]1
Reactant: CC[Mg]Br
Reactant: COC(=O)c1ccc(C#N)cc1
Agent: [Ti+4]
Agent: Cl
Agent: FB(F)F
Solvent: CCOCC
Product: COC(=O)c1ccc(C2(N)CC2)cc1
Reaction time: 1 h

Procedure:
To the solution of methyl 4-cyanobenzoate (100 g, 620 mmol) in diethyl ether (3 L) was added titanium (IV) isospropoxide (194 g, 682 mmol), followed by dropwise addition of ethylmagnesium bromide 3M solution in diethylether (450 ml, 1.36 mol) at −70° C. The mixture was stirred for 1 h, and then boron trifluoride etherate (157 ml, 1.24 mol) was added at once. After 2 hours, aqueous HCl (5%) was added until the pH showed acidy, then the mixture was filtered. The solid was washed with ethylacetate. The aqueous phase was separated and the organic layer was washed with water. All aqueous layers were collected together, basified with 1M NaOH and extracted with ethylacetate. The organic layer was dried (Na2SO4) and concentrated to afford the title compound (D6) (32.0 g).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:4]=[C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=2[C:19]([CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:20])=[O:10])[S:6][CH:7]=1.[CH3:26][N:27]([CH3:32])[S:28](Cl)(=[O:30])=[O:29]>>[CH:21]1([C:19]([C:13]2[CH:14]=[C:15]([CH3:18])[CH:16]=[CH:17][C:12]=2[NH:11][C:9](=[O:10])[NH:8][C:5]2[S:6][CH:7]=[C:3]([CH2:2][NH:1][S:28]([N:27]([CH3:32])[CH3:26])(=[O:30])=[O:29])[N:4]=2)=[O:20])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CN(C)S(=O)(=O)Cl
Reactant: Cc1ccc(NC(=O)Nc2nc(CN)cs2)c(C(=O)C2CCCC2)c1
Product: Cc1ccc(NC(=O)Nc2nc(CNS(=O)(=O)N(C)C)cs2)c(C(=O)C2CCCC2)c1
Yield: 89.3 %

Procedure:
N-{2-[3-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-4-ylmethyl)-N′,N′-dimethylsulfamide (104 mg, 89%) was prepared from 1-(4-aminomethyl-thiazol-2-yl)-3-(2-cyclopentanecarbonyl-4-methyl-phenyl)-urea (90 mg, 0.25 mmol) and dimethylsulfamoyl chloride (0.06 mL, 0.5 mmol) following the general procedure T.
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)=[N:4][C:3]=1[C:14]([O:16]CC)=O.[NH2:19][NH2:20]>O>[CH3:1][C:2]1[NH:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][CH:12]=2)=[N:4][C:3]=1[C:14]([NH:19][NH2:20])=[O:16]
Reactant: CCOC(=O)c1nc(-c2ccc(C)cc2)[nH]c1C
Reactant: NN
Solvent: O
Product: Cc1ccc(-c2nc(C(=O)NN)c(C)[nH]2)cc1

Procedure:
A mixture of 4.9 g of the above ester and 15 ml of anhydrous hydrazine was stirred and refluxed overnight. Water was added, the mixture was evaporated and the residue recrystallized from ethanol, giving 3.45 g of 5-methyl-2-(4-methylphenyl)-1H-imidazole-4-carboxylic acid, hydrazide.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:10]=O)=[N:6][C:7]=1[O:8][CH3:9].[NH2:12][CH3:13].[BH4-].[Na+]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:10][NH:12][CH3:13])=[N:6][C:7]=1[O:8][CH3:9]
Reactant: CN
Reactant: COc1nc(C=O)ccc1Br
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CNCc1ccc(Br)c(OC)n1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
5-Bromo-6-methoxypicolinaldehyde of preparation 78 (69 mg, 0.32 mmol) in a solution of NH2CH3 in THF (2M, 3 mL) was stirred under nitrogen at room temperature for 45 mins, and LCMS showed a mass of 230 which indicated the presence of the iminium ion. Sodium borohydride (36.2 mg, 0.957 mmol) was added, and the reaction was stirred at room temperature overnight. The desired product was detected by LCMS, and the reaction was quenched with MeOH (0.5 mL) and water (10 ml), then partitioned with EtOAc (10 mL). The organic layer was dried over sodium sulfate, filtered and evaporated to give the title compound as a yellow oil (47 mg), which was taken into the next step without further purification.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5](O)=[O:6].S(Cl)(C1C=CC(C)=CC=1)(=O)=O.Cl.[CH3:24][NH2:25]>>[CH3:24][NH:25][C:5]([C:4]1[CH:8]=[CH:9][C:10]([CH3:11])=[C:2]([I:1])[CH:3]=1)=[O:6]
Reactant: CN
Reactant: Cc1ccc(C(=O)O)cc1I
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Product: CNC(=O)c1ccc(C)c(I)c1
Reaction time: 5 h

Procedure:
A solution of 1.0 mmol of 3-iodo-4-methylbenzoic acid, 1.2 mmol of TsCl, and 25 mmol of Py was stirred for 3 h and then 5 mmol of methylamine hydrochloride was added and stirring continued for 5 h. Chromatography provided N-methyl-(3-iodo-4-methylphenyl)carboxamide.
Reaction SMILES: [CH2:1]([NH:8][C:9]([NH:11][N:12]([CH2:14][C:15]([OH:17])=O)[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:18][C@H:19]([C:28]([N:30]([C@@H:42]([CH3:50])[CH:43]([O:47][CH2:48][CH3:49])[O:44][CH2:45][CH3:46])[CH2:31][C:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34][CH:33]=1)=[O:29])[CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]>>[CH2:1]([NH:8][C:9]([NH:11][N:12]([CH2:14][C:15]([NH:18][C@H:19]([C:28]([N:30]([C@@H:42]([CH3:50])[CH:43]([O:47][CH2:48][CH3:49])[O:44][CH2:45][CH3:46])[CH2:31][C:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34][CH:33]=1)=[O:29])[CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:25])[CH3:26])=[O:22])=[O:17])[CH3:13])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@@H](N)CC(=O)OC(C)(C)C
Reactant: CN(CC(=O)O)NC(=O)NCc1ccccc1
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)CN(C)NC(=O)NCc1ccccc1

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(2-(benzylcarbamoyl)-1-methylhydrazinyl)acetic acid (Compound VI-3) 78 mg (0.33 mmol) was coupled with (S)-tert-butyl 3-amino-4-(((S)-1,1-diethoxypropan-2-yl)-(naphthalen-1-ylmethyl)amino)-4-oxobutanoate (Compound IV-16) 100 mg (0.22 mmol) to obtain the title compound.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]([N:17]=[O:18])[C:5](=O)[O:6]C1C=CC=CC=1[N+]([O-])=O.[NH2:19][C@@H:20]1[O:28][C@H:27]([CH2:29][OH:30])[C@@H:25]([OH:26])[C@H:23]([OH:24])[C@H:21]1[OH:22]>CN(C)C=O.C(O)C>[C@@H:20]1([NH:19][C:5](=[O:6])[N:4]([CH2:3][CH2:2][Cl:1])[N:17]=[O:18])[O:28][C@H:27]([CH2:29][OH:30])[C@@H:25]([OH:26])[C@H:23]([OH:24])[C@H:21]1[OH:22]
Reactant: N[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reactant: O=NN(CCCl)C(=O)Oc1ccccc1[N+](=O)[O-]
Solvent: CN(C)C=O
Solvent: CCO
Product: O=NN(CCCl)C(=O)N[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reaction time: 0.17 h
Yield: 78.7 %

Procedure:
3.28 g (12 mmol) of o-nitrophenyl N-(2-chloroethyl)-N-nitrosocarbamate is dissolved in a mixture of 10 ml anhydrous dimethylformamide and 10 ml anhydrous ethanol, and to this solution is added little by little 1.79 g (10 mmol) of 1-amino-1-deoxy-β-D-glucopyranose powder, while stirring, at 5°-10° C. over 10 minutes. The resultant mixture is, after adding 5 ml of anhydrous dimethylformamide thereto, stirred further at 10° C. for 5 hours, and the thus reacted solution is concentrated at 40° C. and below, under reduced pressure. The crystalline residue obtained is washed with anhydrous ethyl ether and then with acetone, dried under reduced pressure, and recrystallized from anhydrous ethanol-ethyl ether (1:5) to give 2.47 g of 3-(β-D-glucopyranosyl)-1-(2-chloroethyl)-1-nitrosourea. Yield 78.7%. mp 77°-78° C. (decomp.). [α]D25 -10.3° (C 1.0, water). Analysis for C9H16N3O7Cl (MW 313.69):
Reaction SMILES: [Cl:1][CH2:2][O:3][C:4](F)(F)[CH:5]([C:10]([F:13])([F:12])[F:11])[C:6]([F:9])([F:8])[F:7].[Si](=O)=[O:17].S(=O)(=O)(O)O>>[F:7][C:6]([F:9])([F:8])[CH:5]([C:10]([F:13])([F:12])[F:11])[C:4]([O:3][CH2:2][Cl:1])=[O:17]
Reactant: FC(F)(F)C(C(F)(F)F)C(F)(F)OCCl
Reactant: O=[Si]=O
Agent: O=S(=O)(O)O
Product: O=C(OCCl)C(C(F)(F)F)C(F)(F)F
Reaction time: 21 h
Yield: 92.8 %

Procedure:
In a four necked 1 liter flask equipped with a thermometer, a condenser and a stirrer, 1-chloromethoxy-1,1-difluoro-2-trifluoromethyl-3,3,3-trifluoropropane (276.6 g, 1.04 mol) and silicon dioxide (50.8 g, 0.85 mol) were charged, and concentrated sulfuric acid (60 g, 0.61 mol) was dropwise added thereto while stirring. The reaction was continued at 110° C. for 21 hours. Then, the reaction mixture was distilled to give monochloromethyl 2-trifluoromethyl-3,3,3-trifluoropropanoate (192.9 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[C:23]([C:27]4[CH:32]=[C:31]([NH2:33])[N:30]=[C:29]([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=5)[CH:28]=4)[CH:24]=[N:25][CH:26]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:11]1([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[C:23]([C:27]4[CH:32]=[C:31]([NH2:33])[N:30]=[C:29]([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=5)[CH:28]=4)[CH:24]=[N:25][CH:26]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(-c3cncc(-c4cc(N)nc(-c5ccccn5)c4)c3)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1cc(-c2cncc(-c3ccc(CN4CCNCC4)cc3)c2)cc(-c2ccccn2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-[4-(6′-Amino-[2,2′;4′,3″]terpyridin-5″-yl)-benzyl]-piperazine-1-carboxylic acid tert-butyl ester (1.0 eq, 0.105 mmol, 55.1 mg) in DCM (1.0 ml) is added TFA (24.0 eq, 2.60 mmol, 0.2 ml). The reaction mixture is allowed to stir at room temperature for 30 minutes. The organic solvent is reduced in vacuo. The residue is purified by reverse phase chromatography (Isolute™ C18, 0-20% acetonitrile in water—0.1% TFA). The appropriate fractions by HPLC are combined and concentrated in vacuo. The resulting residue is dissolved in MeOH and loaded onto a SCX-2 cartridge eluting with MeOH and 2M NH3 in MeOH. The methanolic ammonia fractions are combined, concentrated in vacuo and dried under vacuum to afford the title compound; [M+H]+ 423.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][C@@H:15]([C:18]1[CH:23]=[CH:22][C:21]([CH:24]=[C:25]2[S:29][C:28](=[O:30])[NH:27][C:26]2=[O:31])=[CH:20][CH:19]=1)[O:16][CH3:17].[S]>C1COCC1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][CH2:14][CH:15]([C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C@@H:25]2[S:29][C:28](=[O:30])[NH:27][C:26]2=[O:31])=[CH:20][CH:19]=1)[O:16][CH3:17]
Reactant: CO[C@@H](CCc1nc(-c2ccccc2)oc1C)c1ccc(C=C2SC(=O)NC2=O)cc1
Agent: [S]
Solvent: C1CCOC1
Product: COC(CCc1nc(-c2ccccc2)oc1C)c1ccc(C[C@@H]2SC(=O)NC2=O)cc1
Yield: 35 %

Procedure:
The title compound of Example 17 (640 mg, 1.5 mmol) was dissolved in THF (50 mL) and hydrogenated in the presence of sulfur-resistant 10% palladium on carbon (640 mg) on a Parr Shaker at 50 PSI for 20 hours. The catalyst was removed via filtration through diatomaceous earth and the filtrate was concentrated in vacuo. The residue was purified on silica gel, eluting with hexane/ethyl acetate (3/1) plus 5% acetic acid, to afford crude material which was further purified by (dissolving the residue in 50 mL of ethyl acetate, washing with water (25 mL), saturated aqueous sodium bicarbonate (25 mL), brine (25 mL) and drying (MgSO4), to afford a colorless gum (229 mg, 35%). 1HNMR (300 MHz, CDCl3): δ2.0 (m, 2H), 2.3 (s, 3H), 2.5 (t, 2H), 3.1 (dd, 1H), 3.2 (s, 3H), 3.5 (dd, 1H), 4.1 (dd, 1H), 4.4 (dd, 1H), 7.2 (m, 4H), 7.4 (m, 3H), 7.9 (m, 2H), 8.1 (bs, 1H, NH).
Reaction SMILES: C([O:3][C:4](=[O:24])[CH2:5][C@H:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:18]3[CH:23]=[N:22][CH:21]=[CH:20][N:19]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)C.[Li+].[OH-].Cl>CO.O>[OH:11][B:9]1[C:8]2[CH:12]=[C:13]([O:17][C:18]3[CH:23]=[N:22][CH:21]=[CH:20][N:19]=3)[CH:14]=[C:15]([CH3:16])[C:7]=2[C@@H:6]([CH2:5][C:4]([OH:24])=[O:3])[O:10]1
Reactant: CCOC(=O)C[C@H]1OB(O)c2cc(Oc3cnccn3)cc(C)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(Oc2cnccn2)cc2c1[C@@H](CC(=O)O)OB2O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (3R)-[1-hydroxy-4-methyl-6-(pyrazin-2-yloxy)-1,3-dihydro-benzo[c][1,2]-oxaborol-3-yl]-acetic acid ethyl ester (0.90 g, 2.74 mmol, 1st peak) in methanol (15 mL) was added a solution of LiOH (0.328 g, 13.7 mmol) in water (12 mL) at 0° C. The resulting mixture was stirred at room temperature for 3 hours then acidified to pH=2 with dilute hydrochloric acid and extracted with EtOAc (2×30 mL). The organic extracts were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel flash column chromatography (DCM/MeOH/AcOH=20:1:trace) to give pure product as a white powder after lyophilization (0.681 g, 82.8%). 1HNMR (400 MHz, DMSO-d δ 9.20 (s, 1H), 8.53 (d, J=1.17 Hz, 1H), 8.35 (d, J=2.64 Hz, 1H), 8.19 (dd, J=2.63, 1.46 Hz, 1H), 7.25 (d, J=2.05 Hz, 1H), 7.10 (d, J=1.46 Hz, 1H), 5.51 (dd, J=9.51, 2.20 Hz, 1H), 3.07 (dd, J=15.52, 2.63 Hz, 1H), 2.28 (s, 3H), 2.13 (dd, 1H). MS (ESI) m/z=301 [M+H]+.