Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([C:13]2[NH:14][CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=3)[N:17]=2)[N:10]([C:25](=[O:35])[CH:26]([NH:30][C:31]([O:33][CH3:34])=[O:32])[CH:27]([CH3:29])[CH3:28])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:36][O:37][C:38](=[O:71])[NH:39][CH:40]([C:44]([N:46]1[CH2:50][CH2:49][CH2:48][CH:47]1[C:51]1[NH:52][CH:53]=[C:54]([C:56]2[CH:61]=[CH:60][C:59](B3OC(C)(C)C(C)(C)O3)=[CH:58][CH:57]=2)[N:55]=1)=[O:45])[CH:41]([CH3:43])[CH3:42].C(=O)([O-])[O-].[K+].[K+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([C:13]2[NH:17][C:16]([C:18]3[CH:23]=[CH:22][C:21]([C:59]4[CH:60]=[CH:61][C:56]([C:54]5[NH:55][C:51]([CH:47]6[CH2:48][CH2:49][CH2:50][N:46]6[C:44](=[O:45])[CH:40]([NH:39][C:38]([O:37][CH3:36])=[O:71])[CH:41]([CH3:43])[CH3:42])=[N:52][CH:53]=5)=[CH:57][CH:58]=4)=[CH:20][CH:19]=3)=[CH:15][N:14]=2)[N:10]([C:25](=[O:35])[CH:26]([NH:30][C:31]([O:33][CH3:34])=[O:32])[CH:27]([CH3:29])[CH3:28])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)NC(C(=O)N1CN(C(=O)OC(C)(C)C)CC1c1nc(-c2ccc(Br)cc2)c[nH]1)C(C)C
Reactant: COC(=O)NC(C(=O)N1CCCC1c1nc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c[nH]1)C(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(C5CN(C(=O)OC(C)(C)C)CN5C(=O)C(NC(=O)OC)C(C)C)[nH]4)cc3)cc2)[nH]1)C(C)C
Temperature: 120 °C
Yield: 48.1 %

Procedure:
4-(4-Bromo-phenyl)-3′-(2-methoxycarbonylamino-3-methyl-butyryl)-2′,3′,4′,5′-tetrahydro-1H-[2,4′]biimidazolyl-1′-carboxylic acid tert-butyl ester (75 mg, 0.136 mmol) was combined with [2-Methyl-1-(2-{4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamic acid methyl ester (67.6 mg, 0.136 mmol) under an argon atmosphere. Potassium carbonate (37.5 mg, 0.272 mmol) and Pd(PPh3)4 (15.7 mg, 0.014 mmol) were added, followed by DME (3 mL) and water (0.6 mL). The mixture was heated under microwave conditions for 20 minutes at 120° C. All volatiles were removed in vacuo and the crude material was dissolved in DMF and purified via RP-HPLC (eluent: water/MeCN w 0.1% TFA) to yield the product (55 mg): LCMS-ESI+: calc'd for C44H57N9O8: 839.9 (M+). Found: 840.5 (M+H+); 1H-NMR: 300 MHz, (MeOH-d4) δ: 7.90-7.81 (m, 10H), 5.58 (m, 1H), 5.43 (m, 1H), 5.25-5.20 (m, 2H), 4.24 (d, J=7.5 Hz, 1H), 4.11 (m, 1H), 3.99 (m, 1H), 3.86 (m, 2H), 3.67 (s, 3H), 3.66 (s, 3H), 3.46 (d, J=7.2 Hz, 1H), 2.59 (m, 1H), 2.22-2.10 (m, 5H), 1.53 & 1.44 (s, 9H) 1.04-0.89 (m, 12H).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([Br:19])[CH:18]=[C:13]3[C:12]([CH:20]=O)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NO.Cl.[N:25]1C=CC=CC=1.[O-]S([O-])(=O)=O.[Mg+2].[Se](=O)=O>C(Cl)(Cl)Cl.CCO>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([Br:19])[CH:18]=[C:13]3[C:12]([C:20]#[N:25])=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccncc1
Reactant: O=Cc1cn(S(=O)(=O)c2ccccc2)c2ncc(Br)cc12
Agent: Cl
Agent: NO
Agent: O=S(=O)([O-])[O-]
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: N#Cc1cn(S(=O)(=O)c2ccccc2)c2ncc(Br)cc12
Reaction time: 6 h
Yield: 64 %

Procedure:
To a refluxing mixture of 7 (6.00 g, 16.4 mmol), CHCl3 (30 mL), EtOH (12 mL) and NH2OH.HCl (2.28 g, 32.9 mmol) was added dropwise a solution of pyridine (2.66 mL, 32.9 mmol) in CHCl3 (9 mL). When the addition was complete, a Soxhlet extractor containing MgSO4 was attached and the refluxing continued for 6 h. Selenium dioxide (2.73 g, 24.6 mmol) was then added portionwise over 1 h during reflux. Each time selenium dioxide was added an exothermic reaction occurred. When the addition was complete the reaction mixture was heated at reflux overnight. More SeO2 (1.00 g, 9.0 mmol) was added in one portion and the reflux continued for a further 1.5 h. The reaction mixture was cooled, sorbent (HM-N, Jones chromatography) added and the solvent evaporated. Purification by means of SGC using dichloromethane:hexane (1:1) (gradient elution) gave the product 8 (3.80 g, 64%) as a white solid; 1H NMR (400 MHz, CDCl3) δ 8.56 (d, J=2.2 Hz, 1H), 8.22 (m, 3H), 8.16 (d, J=2.1 Hz, 1H), 7.68 (tt, J=7.5, 1.2 Hz, 1H), 7.56 (t, 7.5 Hz, 2H).
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([CH2:9][S:10](/[CH:13]=[CH:14]/[C:15]2[S:25][C:24]3[N:26]4[C:17](=[CH:18][N:19]=[C:20]4[CH:21]=[CH:22][CH:23]=3)[CH:16]=2)(=[O:12])=[O:11])[CH2:5][CH2:4]1.Br[CH2:28][CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>C(O)C>[C:31]1([CH2:30][CH2:29][CH2:28][N:3]2[CH2:8][CH2:7][CH:6]([CH2:9][S:10](/[CH:13]=[CH:14]/[C:15]3[S:25][C:24]4[N:26]5[C:17](=[CH:18][N:19]=[C:20]5[CH:21]=[CH:22][CH:23]=4)[CH:16]=3)(=[O:12])=[O:11])[CH2:5][CH2:4]2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: BrCCCc1ccccc1
Reactant: O=S(=O)(/C=C/C1=Cc2cnc3cccc(n23)S1)CC1CCNCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=S(=O)(/C=C/C1=Cc2cnc3cccc(n23)S1)CC1CCN(CCCc2ccccc2)CC1

Procedure:
A solution of 0.402 g (0.925 mM) of (E)-4-[2-(piperidin-4-ylmethanesulfonyl)vinyl]-5-thia-1,8b-diazaacenaphthylene dihydrochloride, 0.28 g (1.39 mM) of 1-bromo-3-phenylpropane, and 0.45 ml (3.24 mM) of triethylamine in 20 ml of ethanol was refluxed for 1 day. This reaction mixture was poured in aqueous solution of sodium hydrogen carbonate and extracted with 2 portions of ethyl acetate. The organic layers were pooled and dried over MgSO4 and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate˜ethyl acetate/methanol : 9/1-1/1) to provide the title compound.
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:34])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20][OH:21])[CH:19]=[C:15]3[N:14]=[C:13]([CH3:22])[C:12]=2[C@H:23]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH2:1]([O:4][C:5]1([CH3:34])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH:20]=[O:21])[CH:19]=[C:15]3[N:14]=[C:13]([CH3:22])[C:12]=2[C@H:23]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:7][CH2:6]1)[CH:2]=[CH2:3]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(CO)nn23)CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(C=O)nn23)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.7 %

Procedure:
To a solution of (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(hydroxymethyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.2747 g, 0.579 mmol) in wet DCM (5 mL) was added Dess-Martin periodinane (0.319 g, 0.752 mmol) and the mixture was stirred at room temperature. After 3 h, the solids were removed by filtration. The filtrate was washed with aq Na2S2O3, dried (Na2SO4), filtered and concentrated. The resulting oil was purified by flash chromatography (Biotage; 0%-50% EtOAc/hexane; 10 CV) to give the title compound (0.1962 g, 0.415 mmol, 71.7% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 10.17 (s, 1H), 7.02 (s, 1H), 6.19-5.98 (m, 1H), 5.96-5.76 (m, 1H), 5.57-5.37 (m, 2H), 5.24 (dd, J=10.4, 1.6 Hz, 1H), 4.24 (dd, J=15.9, 7.1 Hz, 2H), 4.03 (d, J=4.9 Hz, 2H), 2.65 (s, 3H), 2.08-1.93 (m, 5H), 1.81-1.66 (m, 1H), 1.37 (s, 3H), 1.29-1.25 (m, 12H). 2 piperidine protons not seen by NMR. LCMS (M+H) calcd for C25H37N4O5: 473.27. found: 473.3.
Reaction SMILES: [C:1]1([C:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([CH2:10][CH2:11][N:12]2[CH2:18][CH:17]3[CH2:19][CH2:20][CH:14]([CH2:15][CH2:16]3)[CH2:13]2)[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N-:27]=[N+:28]=[N-:29].[Na+].[Cl-].[NH4+].[Cl-].[Li+]>CN(C)C=O>[C:21]1([C:7]([C:8]2[NH:29][N:28]=[N:27][N:9]=2)([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:10][CH2:11][N:12]2[CH2:18][CH:17]3[CH2:16][CH2:15][CH:14]([CH2:20][CH2:19]3)[CH2:13]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: N#CC(CCN1CC2CCC(CC2)C1)(c1ccccc1)c1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: c1ccc(C(CCN2CC3CCC(CC3)C2)(c2ccccc2)c2nnn[nH]2)cc1

Procedure:
36 Parts of 2,2-diphenyl-4-(3-azabicyclo[3.2.2]non-3-yl)butyronitrile (U.S. Pat. No. 3,318,864), 9.8 parts of sodium azide, 8.06 parts of ammonium chloride, and 0.15 part of lithium chloride are placed in 50 parts by volume of dimethylformamide and heated at 125° for 12 hours. The solution is cooled and a white solid is filtered off. The solid is washed with dimethylformamide and water and then dried. This procedure provides 5-[1,1-diphenyl-3-(3-azabicyclo[3.2.2]non-3-yl)propyl]-1H-tetrazole melting at 284°-286°.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][CH2:16][CH2:17][C:18]#[N:19])[CH:10]=[CH:9]2.[N:25]([Si](C)(C)C)=[N+:26]=[N-:27].C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][CH2:16][CH2:17][C:18]1[NH:27][N:26]=[N:25][N:19]=1)[CH:10]=[CH:9]2
Reactant: N#CCCCn1ccc2cc(OCc3c(Cl)cccc3Cl)ccc21
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: Clc1cccc(Cl)c1COc1ccc2c(ccn2CCCc2nnn[nH]2)c1
Yield: 59.5 %

Procedure:
To a solution of 4-[5-(2,6-dichlorobenzyloxy)indole-1-yl]butyronitrile (0.1 g, 0.28 mmol) in toluene (3 mL) was added azidotrimethylsilane (0.11 mL, 0.83 mmol) and dibutyltin oxide (0.021 g, 0.083 mmol). The reaction was refluxed for 16 h. The solvent was removed under reduced pressure and the crude product was purified by flash column chromatography (silica gel, dichloromethane/methanol) to yield a white foaming solid (0.067 g, 59%). MS(ES) m/e 402.0 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C@H:8]([C:14](=[O:22])[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:9][CH2:10][CH2:11][CH:12]=[CH2:13])([CH3:4])([CH3:3])[CH3:2].[C:24]([OH:27])(=[S:26])[CH3:25].CC(N=NC(C#N)(C)C)(C#N)C.C1CCCCC=1>O1CCOCC1>[C:1]([O:5][C:6]([NH:7][C@H:8]([C:14](=[O:22])[NH:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][S:26][C:24](=[O:27])[CH3:25])=[O:23])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(O)=S
Reactant: C=CCCC[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccccc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: C1COCCO1
Solvent: C1=CCCCC1
Product: CC(=O)SCCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
To a stirred solution of ((S)-1-phenylcarbamoyl-hex-5-enyl)-carbamic acid tert-butyl ester (250 mg, 0.78 mmol), thioacetic acid (564 μl, 7.8 mmol) at 75° C. in degassed dioxane was added AIBN (129 mg, 0.78 mmol). The reaction mixture was stirred for 1 hour. The reaction mixture was cooled to 0° C. and an excess of cyclohexene was added under stirring, the latter being maintained for 20 mn. The reaction mixture was concentrated under reduced pressure, and the resulting crude product was rinsed more times with hexane to afford the desired adduct.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH2:10][C:11]#[N:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[NH2:14][C:15]1[NH:19][N:18]=[C:17]([C:20]([OH:22])=[O:21])[CH:16]=1>N1C=CC=CC=1>[NH2:12][C:11]1[N:19]2[N:18]=[C:17]([C:20]([OH:22])=[O:21])[CH:16]=[C:15]2[N:14]=[C:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH:10]=1
Reactant: N#CCC(=O)c1ccc(Cl)c(Cl)c1
Reactant: Nc1cc(C(=O)O)n[nH]1
Solvent: c1ccncc1
Product: Nc1cc(-c2ccc(Cl)c(Cl)c2)nc2cc(C(=O)O)nn12
Yield: 8.3 %

Procedure:
3-(3,4-Dichloro-phenyl)-3-oxo-propionitrile (1.00 g, 4.67 mmol) and 5-amino-1H-pyrazole-3-carboxylic acid (0.593 g, 4.67 mmol) in pyridine (50 mL) was heated at reflux for 3 days. The reaction was concentrated under reduced pressure and the crude product was purified by column chromatography on silica gel to give 7-amino-5-(3,4-dichloro-phenyl)-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid (0.125 g, 8%).
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]2[C:23]3[C:18](=[CH:19][C:20]([O:24][C:25](=[O:27])[CH3:26])=[CH:21][CH:22]=3)[CH:17]=[C:16]2[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:10][C:9]=1I.C(N(CC)CC)C>C(#N)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][N:15]2[C:23]3[C:18](=[CH:19][C:20]([O:24][C:25](=[O:27])[CH3:26])=[CH:21][CH:22]=3)[CH:17]=[C:16]2[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:12][C:13]=1[C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1]
Reactant: CCOC(=O)c1cc2cc(OC(C)=O)ccc2n1Cc1ccc(Cl)c(I)c1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc2cc(OC(C)=O)ccc2n1Cc1ccc(Cl)c(C#C[Si](C)(C)C)c1
Reaction time: 12 h

Procedure:
Trimethylsilylacetylene (114 il) was added to a degassed solution of ethyl N-[(4-chloro-3-iodophenyl) methyl]-5-acetoxyindole-2-carboxylate (0.2 g), bis(triphenylphosphine)palladium (II) chloride (2 mg), triethylamine (56 il) and copper (I) iodide (1 mg) in acetonitrile and the mixture was stirred under an argon atmosphere for 12 hours. A further aliquot of bis(triphenylphosphine)palladium (II) chloride (2 mg) and trimethylsilylacetylene (114 il) was added and stirring continued for 2 hours. A further aliquot of trimethylsilylacetylene (114 il) was added and stirring was continued for 12 hours. A small amount of silica was added to the reaction mixture and the solvent was evaporated. The residue was added to a 5 g silica Isolute column and eluted with an ethyl acetate iso-hexane mixture (1:4) to give the title compound as a colourless oil (0.15 g). NMR (CD3SOCD3): d 0.0 (s, 9H), 1.1 (t, 31H), 2.1 (s, 3H), 4.1 (m, 2H), 5.6 (s, 2H), 6.7 (m, 2H), 6.9 (m, 2H), 7.1 (m, 1H), 7.2 (m, 2H), 7.3 (n, 1H), 7.4 (m, 1H); m/z 468.5 (M+H).
Reaction SMILES: Cl.[F:2][C@H:3]1[CH2:7][NH:6][C@@H:5]([C:8]([O:10][CH3:11])=[O:9])[CH2:4]1.N1(O)C2C=CC=CC=2N=N1.[CH:22]1[C:34]2[CH:33]([CH2:35][O:36][C:37]([CH2:39][C:40](O)=[O:41])=[O:38])[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]=2[CH:25]=[CH:24][CH:23]=1.C(N(C(C)C)C(C)C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl.CN(C=O)C>[CH:31]1[C:32]2[CH:33]([CH2:35][O:36][C:37]([CH2:39][C:40]([N:6]3[CH2:7][C@H:3]([F:2])[CH2:4][C@@H:5]3[C:8]([O:10][CH3:11])=[O:9])=[O:41])=[O:38])[C:34]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:27]=2[CH:28]=[CH:29][CH:30]=1
Reactant: O=C(O)CC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: COC(=O)[C@H]1C[C@@H](F)CN1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)[C@H]1C[C@@H](F)CN1C(=O)CC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A pyrex reaction tube was charged with (2S,4R), (2R,4R)-methyl 4-fluoropyrrolidine-2-carboxylate hydrochloride (350 mg, 1906 μmol), 1H-benzo[d][1,2,3]triazol-1-ol (309 mg, 2287 μmol), 2-(((9H-fluoren-9-yl)methoxy)carbonyl)acetic acid (567 mg, 1906 μmol), N-ethyl-N-isopropylpropan-2-amine (996 μl, 5719 μmol) and 7.6 mL DMF. The mixture was stirred for 5 min at RT, and benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (1012 mg, 2287 μmol) was added, and the mixture was stirred at RT overnight. The mixture was diluted with DCM and washed with water. The organic portion was dried with MgSO4, filtered, concentrated, and then was concentrated twice from toluene to remove DMF. The crude oil was purified by silica gel chromatography DCM to 5% MeOH/DCM to provide (2S,4R), (2R,4R)-methyl 1-(2-(((9H-fluoren-9-yl)methoxy)carbonyl)acetyl)-4-fluoropyrrolidine-2-carboxylate as a waxy solid. MS: [M+H]=427.
Reaction SMILES: [NH2:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([F:13])[CH:3]=1.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[NH2:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:5]([C:6]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[O:8])=[C:4]([F:13])[CH:3]=1
Reactant: C1COCCN1
Reactant: COc1cc(C(=O)O)c(F)cc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)N2CCOCC2)c(F)cc1N
Temperature: 25 °C
Reaction time: 6 h
Yield: 68 %

Procedure:
A mixture of 4-amino-2-fluoro-5-methoxybenzoic acid (600 mg, 3.24 mmol), morpholine (564 mg, 6.48 mmol), HATU ((O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, 1.85 g, 4.86 mmol), DIPEA (diisopropyl ethylamine, 836 mg, 6.48 mmol), and CH2Cl2 (20 mL) was stirred at room temperature for 6 h. The solvent was removed under reduced pressure and the residue was purified by silica-gel column chromatography to afford the title compound (560 mg, 68%).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15](=[O:32])[NH:16][C:17]2[S:18][C:19]3[CH2:25][C@@H:24]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)[CH2:23][CH2:22][C:20]=3[N:21]=2)[CH:10]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:7][CH2:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=1)[C:15]([NH:16][C:17]1[S:18][C:19]2[CH2:25][C@@H:24]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[CH2:23][CH2:22][C:20]=2[N:21]=1)=[O:32]
Reactant: CC(C)(C)OC(=O)NCc1cccc(C(=O)Nc2nc3c(s2)C[C@@H](N2CCOCC2)CC3)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCc1cccc(C(=O)Nc2nc3c(s2)C[C@@H](N2CCOCC2)CC3)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.8 %

Procedure:
Dissolve [3-((S)-6-morpholin-4-yl-4,5,6,7-tetrahydro-benzothiazol-2-ylcarbamoyl)-benzyl]-carbamic acid tert-butyl ester (4.82 g, 10.2 mmol) in DCM (5 mL) and add TFA (trifluoroacetic acid) (20 mL). Stir the mixture at rt for 1 h. LCMS analysis indicates the desired deprotected material. Concentrate to give the desired product 3-aminomethyl-N—((S)-6-morpholin-4-yl-4,5,6,7-tetrahydro-benzothiazol-2-yl)-benzamide as a foam (4.80 g, 9.87 mmol).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][NH:6][CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[N+:25]([O-:27])=[O:26])=[N:16][N:17]=1)(=[O:12])=[O:11])[CH3:2].[CH2:29]([O:39][C:40]([NH:42][C:43]1[NH:44][C:45](=[O:56])[C:46]2[N:47]=[CH:48][N:49]([CH2:52][C:53](O)=[O:54])[C:50]=2[N:51]=1)=[O:41])[C:30]1[CH:38]=[CH:37][C:36]2[O:35][CH2:34][O:33][C:32]=2[CH:31]=1>>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][N:6]([CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[N+:25]([O-:27])=[O:26])=[N:16][N:17]=1)(=[O:12])=[O:11])[C:53](=[O:54])[CH2:52][N:49]1[CH:48]=[N:47][C:46]2[C:45](=[O:56])[NH:44][C:43]([NH:42][C:40]([O:39][CH2:29][C:30]3[CH:38]=[CH:37][C:36]4[O:35][CH2:34][O:33][C:32]=4[CH:31]=3)=[O:41])=[N:51][C:50]1=2)[CH3:2]
Reactant: CCOC(=O)CNCCNS(=O)(=O)c1nnc(-c2ccc(Cl)cc2[N+](=O)[O-])s1
Reactant: O=C(O)Cn1cnc2c(=O)[nH]c(NC(=O)OCc3ccc4c(c3)OCO4)nc21
Product: CCOC(=O)CN(CCNS(=O)(=O)c1nnc(-c2ccc(Cl)cc2[N+](=O)[O-])s1)C(=O)Cn1cnc2c(=O)[nH]c(NC(=O)OCc3ccc4c(c3)OCO4)nc21

Procedure:
The title compound was synthesized by the reaction of N-{2-[5-(4-chloro-2-nitrophenyl)-1,3,4-thiadiazole-2-sulfonylamino]-ethyl}-glycine ethyl ester with N-{[2-N-(piperonyloxycarbonyl)-guanin-9-yl]-acetic acid as per the procedure of example 13. 1H NMR (400 MHz; DMSO-d6) δ 11.37 (brs, 0.4H), 11.35 (brs, 0.6H), 9.20 (brs, 1H), 8.39 (s, 1H), 8.03–7.99 (m, 1H), 7.95 (d, 0.6H), 7.92 (d, 0.4H), 7.82 (s, 0.6H), 7.79 (s, 0.4H), 7.01 (s, 1H), 6.94 (d, 1H), 6.91 (d, 1H), 6.02 (s, 2H), 5.14 (s, 3.2H), 4.93 (s, 0.8H), 4.45 (s, 0.8H), 4.21 (q, 0.8H), 4.08 (s, 1.2H), 4.07 (q, 1.2H), 3.65 (t, 1.2H), 3.48 (t, 1.2H), 3.43 (t, 0.8H), 3.27 (t, 0.8H), 1.25 (t, 1.2H), 1.16 (t, 1.8H).
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:15]=2[C:14](=[O:16])[N:13]([CH:17]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH:29]([F:31])[F:30])=[C:24]([O:32][CH2:33][CH3:34])[CH:23]=2)[CH2:18][C:19]([OH:21])=O)[CH2:12]3)=[O:5])[CH2:3][CH2:2]1.C1N=[CH:38][N:37](C(N2C=NC=C2)=O)[CH:36]=1.CNC>C1COCC1>[F:30][CH:29]([F:31])[O:28][C:25]1[CH:26]=[CH:27][C:22]([CH:17]([N:13]2[C:14](=[O:16])[C:15]3[C:11](=[CH:10][CH:9]=[CH:8][C:7]=3[NH:6][C:4]([CH:1]3[CH2:2][CH2:3]3)=[O:5])[CH2:12]2)[CH2:18][C:19](=[O:21])[N:37]([CH3:38])[CH3:36])=[CH:23][C:24]=1[O:32][CH2:33][CH3:34]
Reactant: CCOc1cc(C(CC(=O)O)N2Cc3cccc(NC(=O)C4CC4)c3C2=O)ccc1OC(F)F
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CNC
Solvent: C1CCOC1
Product: CCOc1cc(C(CC(=O)N(C)C)N2Cc3cccc(NC(=O)C4CC4)c3C2=O)ccc1OC(F)F
Yield: 46.9 %

Procedure:
Cyclopropanecarboxylic acid {2-[1-(4-difluoromethoxy-3-ethoxy-phenyl)-2-dimethylcarbamoyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide was prepared by the procedure of example 13 from 3-[7-(cyclopropanecarbonyl-amino)-1-oxo-1,3-dihydro-isoindol-2-yl]-3-(4-difluoromethoxy-3-ethoxy-phenyl)-propionic acid (0.8 g, 1.7 mmol), CDI (0.41 g, 2.5 mmol) and dimethylamine (1.7 ml, 3.4 mmol) in THF (30 ml) to give cyclopropanecarboxylic acid {2-[1-(4-difluoromethoxy-3-ethoxy-phenyl)-2-dimethylcarbamoyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide as white solid (0.4 g, 50% yield): mp:135–137° C.; 1HNMR (CDCl3): δ 0.89(m, 2H, c-CH2), 1.43 (t, J=7.0 Hz, 3H, OCH2CH3), 1.66 (m, 1H, c-CH), 2.93 (s, 3H, CH3CO), 3.04 (dd,J=5, 15 Hz, 1H, CH2), 3.10 (s, 3H, NCH3), 3.60 (dd, J=10, 15 Hz, 1H, CH2), 4.09 (q, J=7.0 Hz, 2H, OCH2CH3), 4.33 (d, J=17.5 Hz, 1H, CH2N), 4.44 (d, J=17.5 Hz, 1H, CH2N), 5.60 (m, 1H, CHN), 6.55 (t, JH-F=75 Hz, 1H, CF2H), 7.07 (m, 4H, Ar), 7.43 (t, J=7.5 Hz, 1H, Ar), 8.42(d, J=7.5 Hz, 1H, Ar), 10.57 (s, 1H, NHCO). 13CNMR (CDCl3): δ 8.2, 14.6, 16.1, 35.6, 36.1, 37.3, 49.2, 54.0, 58.6, 64.7, 111.9, 113.5, 116.1, 116.7, 117.5, 117.6, 117.8, 119.2, 120.2, 122.7, 133.1, 138.0, 138.2, 139.7, 141.5, 159.7,169.4, 169.7, 172.6; Anal. Calcd. for C26H29F2N3O5: C, 62.27; H, 5.83; N, 8.38. Found: C, 62.07; H, 5.65; N, 8.28.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10]C=1N)[C:6]([OH:8])=[O:7].[H-].[Na+].CI.[CH3:17][N:18]([CH:20]=O)[CH3:19]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:20]=1[N:18]([CH3:17])[CH3:19])[C:6]([OH:8])=[O:7]
Reactant: COc1cc(C(=O)O)ccc1N
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: COc1cc(C(=O)O)ccc1N(C)C
Reaction time: 0.5 h

Procedure:
To a solution of 3-methoxy-4-aminobenzoic acid (1.5 g, 9 mmol) in DMF (10 mL) was added sodium hydride (60% in mineral oil, 1.5 g, 37.5 mmol) at 0° C. in portions. After stirring for 30 minutes, methyl iodide (6 g, 45 mmol) was added. The mixture was stirred overnight and quenched by addition of water. The aqueous mixture was extracted with dichloromethane (2×20 mL), dried over sodium sulfate and concentrated in vacuo. Purification by flash chromatography eluting with hexane/EtOAc (4:1) afforded 3-methoxy-4-dimethylaminobenzoic acid as an oil (1.8 g).