Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1C(Cl)=O)([CH3:3])[CH3:2].[Cl:14][Sn](Cl)(Cl)Cl.[2H][C:20]([2H])([2H])[O:21][2H].[2H]O[2H]>>[CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([C:20]([Cl:14])=[O:21])=[CH:10][CH:6]=1)([CH3:3])[CH3:2]
Reactant: Cl[Sn](Cl)(Cl)Cl
Reactant: [2H]OC([2H])([2H])[2H]
Reactant: CC(C)Oc1ccccc1C(=O)Cl
Agent: [2H]O[2H]
Product: CC(C)Oc1ccc(C(=O)Cl)cc1

Procedure:
A sample vial was filled with 2 g of isopropoxy benzoyl chloride and SnCl4 was injected. The mixture was homogenized and then kept at the reaction temperature chosen. After the reaction 50 mg of the solidified red-brown reaction mixture was hydrolyzed in 1 ml of a mixture of CD3OD/D2O/NaOD (12:3:1, weight ratios) (2 hours, 60° C.) and the degree of polymerization (dp) was determined by NMR end-group analysis.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9]C)=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:20])[CH2:18][CH3:19])=[CH:13][C:12]=1[CH2:21][CH2:22][CH3:23])[CH3:2].Cl.N1C=CC=CC=1>O>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:20])[CH2:18][CH3:19])=[CH:13][C:12]=1[CH2:21][CH2:22][CH3:23])[CH3:2]
Reactant: CCCc1cc(C(=O)CC)ccc1-c1cc(OC)ccc1CC
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CCCc1cc(C(=O)CC)ccc1-c1cc(O)ccc1CC
Temperature: 30 °C

Procedure:
413 g (1.33 mol) of 1-(2′-ethyl-5′-methoxy-2-propylbiphenyl-4-yl)propan-1-one and 768 g (6.64 mol) of pyridine hydrochloride are placed in a round-bottomed flask. The mixture is heated at 160°-170° C. for 4 hours with stirring. The reaction medium is allowed to return to 100°-110° C. and 800 ml of water are added. The mixture is cooled to 30° C. and extracted with 1.6 liters of ethyl acetate. After separating by settling, the aqueous phase is extracted with 600 ml of ethyl acetate. The organic phases are combined and washed twice with 800 ml of water. After evaporating under reduced vacuum, 410 g of 1-(2′-ethyl-5′-hydroxy-2-propylbiphenyl-4-yl)propan-1-one are obtained in the form of an oil.
Reaction SMILES: C(CN1CCC[C@H]1C(N(CC1C=CC=CC=1)[C:10](=[O:17])[C@H:11]([C@H:13]([CH2:15][CH3:16])[CH3:14])[NH2:12])=O)(O)=O.C(N(CC)CC)C.ClC(OCC(C)C)=[O:37].NCCO>C(#N)C>[NH2:12][C@H:11]([C:10]([OH:17])=[O:37])[C@H:13]([CH2:15][CH3:16])[CH3:14]
Reactant: CC[C@H](C)[C@H](N)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)O
Reactant: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: NCCO
Solvent: CC#N
Product: CC[C@H](C)[C@H](N)C(=O)O
Yield: 166.9 %

Procedure:
A -5° C. solution of L-isoleucine, N-[1-(carboxymethyl)-L-prolyl] benzylamide (0.215 g, 0.58 mmol, 1.0 eq), and triethylamine (96 uL, 70 mg, 0.64 mmol, 1.20 eq), in acetonitrile (10 mL) was treated with isobutyl chloroformate (83 uL, 86 mg, 0.63 mmol, 1.1 eq) followed by 2-aminoethanol (69 uL, 70 mg, 1.15 mmol, 2.0 eq). Workup as above provided 127 mg (53%) of L-isoleucine, N-[1-(2-(2-hydroxyethylamine)-2-oxoethyl)-L-prolyl] benzylamide.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:11]([NH:13][C@@H:14]([C:16]([NH:18][CH2:19][C:20]([NH:22][C@H:23]([C:31]([OH:33])=[O:32])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:21])=[O:17])[CH3:15])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[NH2:41][C@H:42]([CH2:47][OH:48])[CH2:43][CH2:44][S:45][CH3:46]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:1][C@H:2]([C:11]([NH:13][C@@H:14]([C:16]([NH:18][CH2:19][C:20]([NH:22][C@H:23]([C:31]([OH:33])=[O:32])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:21])=[O:17])[CH3:15])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1.[NH2:41][C@H:42]([CH2:47][OH:48])[CH2:43][CH2:44][S:45][CH3:46]
Reactant: C[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: CSCC[C@H](N)CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](NC(=O)[C@@H](N)Cc1ccc(O)cc1)C(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reaction time: 0.5 h

Procedure:
2.0 g of Boc-Tyr-(D)Ala-Gly-Phe-methioninol are dissolved in 20 ml of TFA--CH2Cl2 (1:1) and left to stand for 30 minutes at 0°. After reducing the volume under vacuum, the title compound is precipitated with ether and filtered off. The title compound is obtained as an amorphous salt.
Reaction SMILES: [OH:1][CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].N1C=CN=C1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O.O>[Si:18]([O:1][CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4])([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C(O)C(O)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OC(Cc1ccccc1)C(=O)O
Temperature: 0 °C
Reaction time: 12 h
Yield: 39.6 %

Procedure:
(±)-2-Hydroxy-3-phenylpropanoic acid (Sigma, 3.0 g, 18 mmol) was dissolved in 13 mL of DMF and chilled to 0° C. Imidazole (2.5 g, 36 mmol) and tert-butyldimethylsilylchloride (10 g, 69 mmol) were added. The mixture was allowed to warm to room temperature. After 12 hours, the mixture was diluted with 450 mL of 1:1 EtOAc:hexanes. The mixture was washed with 300 mL of 1M citric acid, 300 mL of water, and 150 mL of sat. Na2SO4, and the organic layer was evaporated. The residue was taken up in 170 mL of MeOH. The resulting mixture was chilled to 0° C. and potassium carbonate (5.7 g, 42 mmol) and 60 mL of water were added. The mixture was warmed to room temperature and stirred for 4 hours. The solvent was evaporated under reduced pressure. The residue was taken up in 5 mL of water and 1 M citric acid was added until the mixture reached pH 4.0. The mixture was extracted with EtOAc (3×100 mL), and the combined organic extracts were dried over MgSO4. The mixture was filtered and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluting with a gradient of 10% to 30% EtOAc in hexanes) to afford (±)-2-(tert-butyldimethylsilyloxy)-3-phenylpropanoic acid (2.0 g, 40%) as a clear oil. 1H NMR (400 MHz, CDCl3): ppm 7.49-7.37 (m, 5H), 4.60 (dd, J=3.7 Hz, 7.6 Hz, 1H), 3.30 (dd, J=3.7 Hz, 13.7 Hz, 1H), 3.12 (dd, J=7.8 Hz, 13.6 Hz, 1H), 1.03 (s, 9H), 0.12 (s, 3H), 0.00 (s, 3H). Carboxyl H was not detected.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([NH2:10])[C:7]([NH:11][CH3:12])=[C:6]([Cl:13])[C:5]=1[NH2:14].Cl.[CH:17]1(C(N)=N)[CH2:19][CH2:18]1.[CH3:23]CO>>[CH3:1][O:2][C:3]([C:4]1[C:5]([NH2:14])=[C:6]([Cl:13])[C:7]2[N:11]([CH3:23])[C:12]([CH:17]3[CH2:19][CH2:18]3)=[N:10][C:8]=2[CH:9]=1)=[O:15]
Reactant: CCO
Reactant: CNc1c(N)cc(C(=O)OC)c(N)c1Cl
Reactant: N=C(N)C1CC1
Agent: Cl
Product: COC(=O)c1cc2nc(C3CC3)n(C)c2c(Cl)c1N
Yield: 10 %

Procedure:
To a suspension of 1 g (3.48 mmol) of 2,5-diamino-3-chloro-4-methylamino-benzoic acid methyl ester (synthesis described in example H7) in 153 ml of EtOH, is added 866 mg (6.97 mmol) of cyclopropane carboxamidine hydrochloride. After 24 hours of reaction under reflux, 866 mg (6.97 mmol) of cyclopropane carboxamidine hydrochloride were added more and the reaction is stirred under reflux 2 days more. Again 433 mg (3.48 mmol) of cyclopropane carboxamidine hydrochloride is added and after again 2 days of reaction under reflux, the reaction is stopped and the solvent is evaporated. The residue is suspended in EtOAc and the precipitate is filtrated. The filtrate obtained is evaporated and purified by flash chromatography on silica gel and gives 100 mg (0.36 mmol, 10%) of a brown solid. LC/MS: 280/282 (M+1)+
Reaction SMILES: C([Li])[CH2:2][CH2:3][CH3:4].[C:6]([N:13]1[CH:17]=[CH:16][CH:15]=[CH:14]1)([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[B:18](OC)([O:21]C)[O:19][CH3:20].Cl>C1COCC1>[CH:3]([NH:13][CH:17]([CH3:16])[CH3:20])([CH3:4])[CH3:2].[C:9]([O:8][C:6]([N:13]1[CH:14]=[CH:15][CH:16]=[C:17]1[B:18]([OH:21])[OH:19])=[O:7])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)n1cccc1
Reactant: COB(OC)OC
Reactant: [Li]CCCC
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1cccc1B(O)O
Product: CC(C)NC(C)C
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 51 %

Procedure:
A solution of anhydrous diisopropylamine (3.35 mL, 23.9 mmol) was prepared in 100 mL of anhydrous THF and cooled at −78° C. A solution of 2.5 M of n-butyllithium (10.5 mL, 26.3 mmol) was slowly added to the THF solution over 10 minutes. The resulting mixture was stirred at −78° C. for 15 minutes and was then warmed to 0° C. for 15 minutes. The resulting mixture was cooled again at −78° C. and the tert-butyl 1-pyrrole carboxylate (73) (4.00 mL, 23.9 mmol) was added. The resulting solution was stirred for 1 hour at −78° C. and trimethyl borate (2.70 mL, 23.9 mmol) was added. The resulting solution was allowed to warm up to room temperature overnight. 20 mL of dilute HCl (0.25N) was added to the room temperature solution, which was stirred at room temperature for 15 minutes. The THF was removed under reduced pressure. The residue was extracted with diethyl ether (3×100 mL). The organic layer was dried over sodium sulfate, filtered and then concentrated in vacuo. Trituration with hexane (10 mL) and filtration gave the Compound 8 as beige solid (2.56 g, 51%). 1H NMR (500 MHz, CDCl3): δ (ppm), 7.71 (s, 2H); 7.48 (t, 1H, J=2 Hz); 7.15 (t, 1H, J=1.8 Hz); 6.29 (t, 1H, J=3.1 Hz); 1.65 (3, 9H). 13C NMR (500 MHz, CDCl3): δ (ppm), 153.22; 129.67; 127.92; 112.96; 86.47; 28.84.
Reaction SMILES: [N:1]1([CH2:5][CH2:6][CH2:7][N:8]2[C:16]([O:17][CH3:18])=[N:15][C:14]3[C:9]2=[N:10][C:11]([O:20][CH2:21][CH2:22][CH2:23][CH3:24])=[N:12][C:13]=3[NH2:19])[CH2:4][CH2:3][CH2:2]1.F[C:26](F)(F)C(O)=O.C(OC1NC(N)=C2C(N=1)=NC(OC)=N2)CCC.BrCCCBr.N1CCCC1>>[CH2:21]([O:20][C:11]1[N:10]=[C:9]2[C:14]([N:15]=[C:16]([O:17][CH3:18])[N:8]2[CH2:7][CH2:6][CH2:5][N:1]2[CH2:2][CH2:26][CH2:3][CH2:4]2)=[C:13]([NH2:19])[N:12]=1)[CH2:22][CH2:23][CH3:24]
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCN3CCC3)c2n1
Reactant: O=C(O)C(F)(F)F
Agent: BrCCCBr
Agent: CCCCOc1nc2nc(OC)nc-2c(N)[nH]1
Solvent: C1CCNC1
Product: CCCCOc1nc(N)c2nc(OC)n(CCCN3CCCC3)c2n1

Procedure:
Prepared similarly to Intermediate 20 from 2-(butyloxy)-8-(methyloxy)-1H-purin-6-amine trifluoroacetate, 1,3-dibromopropane and pyrrolidine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C@H:9]([C:13]([OH:15])=[O:14])[CH:10]([CH3:12])[CH3:11])=[CH:4][CH:3]=1.N([CH2:23][CH2:24][OH:25])(CCO)CCO.S.CN([CH:30]=[O:31])C>>[C:24]([C:30]([N:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[C@H:9]([C:13]([OH:15])=[O:14])[CH:10]([CH3:12])[CH3:11])=[O:31])(=[O:25])[CH3:23]
Reactant: CN(C)C=O
Reactant: OCCN(CCO)CCO
Reactant: CC(C)[C@H](Nc1ccc(Cl)cc1)C(=O)O
Agent: S
Product: CC(=O)C(=O)N(c1ccc(Cl)cc1)[C@H](C(=O)O)C(C)C
Reaction time: 8 h

Procedure:
To a mixture of the α-cyano-m-phenoxybenzyl ester of N-(4-chlorophenyl)valine (0.79 g) and about 20 ml of dry DMF is added about one ml of triethanolamine at RT. Into the mixture is slowly bubbled H2S gas for about 3 hours. The reaction is then stirred overnight. The reaction is worked up by partition with ether/water. The organic phase is washed with brine (3×), dried over sodium sulfate, filtered and evaporated. The residue is plated up on a prep. TLC plate eluting with 20% ethyl acetate/hexane to yield the desired thioamide, MS m/e 181.9 (100), IR (film) 3180 cm-1 (NH) and 1740 cm-1 (C=O). ##STR25##
Reaction SMILES: CC(N=NC(C#N)(C)C)(C#N)C.C1C(=O)N([Br:20])C(=O)C1.[CH3:21][C:22]([Si:25]([CH3:35])([CH3:34])[O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH3:33])([CH3:24])[CH3:23]>C(Cl)(Cl)(Cl)Cl>[Br:20][CH2:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[O:26][Si:25]([C:22]([CH3:21])([CH3:23])[CH3:24])([CH3:34])[CH3:35]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccccc1O[Si](C)(C)C(C)(C)C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)[Si](C)(C)Oc1ccccc1CBr

Procedure:
Add TBDMSCl (4.6 g, 30.5 mmol) to a solution of o-cresol (3 g, 28 mmol) and imidazole (2.08 g, 30.5 mmol) in 25 ml of dry DMF and stir at room temperature. After 7 h, pour the reaction into H2O and extract with hexane twice. Combine the organic layers, wash with H2O, dry over Na2SO4, filter and concentrate under reduced pressure to give a residue. Purify the residue by column chromatography on silica gel eluting with hexane to afford pure (1,1-dimethylethyl)dimethyl(2-methylphenoxy)silane as colourless oil. Add AIBN (330 mg, 1.98 mmol) to a solution of NBS (3.87 g, 21.76 mmol) and (1,1-dimethylethyl)dimethyl(2-methylphenoxy)silane (4.4 g, 19.78 mmol) in 100 ml of CCl4 and stir at reflux for 6 h. Concentrate the solvent under reduced pressure, add hexane and filter the solid. Wash the hexane with a saturated aqueous solution of NaHCO3 and H2O. Dry the organic phase over Na2SO4, filter and concentrate under reduced pressure to obtain [2-(bromomethyl)phenoxy](1,1-dimethylethyl)dimethylsilane as colourless oil.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([Cl:13])=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].[O-][C:15]#[N:16].[Na+]>CN(C)C=O.C(OCC)(=O)C.CCCCCC>[Cl:13][C:4]1[C:3]([CH2:2][C:15]#[N:16])=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cccc(CBr)c1Cl
Reactant: N#C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(CC#N)c1Cl
Temperature: 80 °C
Reaction time: 1 h
Yield: 78.9 %

Procedure:
To a solution of methyl 3-(bromomethyl)-2-chlorobenzoate (748 mg, 2.84 mmol) in N,N-dimethylformamide (7 mL) was added sodium cyanate (412 mg, 8.41 mmol), and the mixture was stirred at 80° C. for 1 hr. The reaction mixture was diluted with a mixed solvent of ethyl acetate/hexane (1:1). The solution was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=2/98→20/80), and the fractions containing the object product were concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate and hexane to give the title compound (470 mg, 79%) as white crystals.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH3:9])=[N:6][C:5]([Br:10])=[CH:4][N:3]=1.[H-].[Na+].[CH2:13]([O:20][C:21]([N:23]([C:25]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:26]=1[CH:27]=[CH:28][CH:29]=[C:30]2[S:35](Cl)(=[O:37])=[O:36])[CH3:24])=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>C(COC)OC>[CH2:13]([O:20][C:21]([N:23]([C:25]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:26]=1[CH:27]=[CH:28][CH:29]=[C:30]2[S:35]([NH:1][C:2]1[C:7]([O:8][CH3:9])=[N:6][C:5]([Br:10])=[CH:4][N:3]=1)(=[O:36])=[O:37])[CH3:24])=[O:22])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CN(C(=O)OCc1ccccc1)c1cccc2c(S(=O)(=O)Cl)cccc12
Reactant: COc1nc(Br)cnc1N
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1nc(Br)cnc1NS(=O)(=O)c1cccc2c(N(C)C(=O)OCc3ccccc3)cccc12
Reaction time: 0.17 h
Yield: 61 %

Procedure:
2-Amino-5-bromo-3-methoxypyrazine (0.3 g) was added to a stirred suspension of sodium hydride (60% dispersion in oil; 0.15 g) in dimethoxyethane (5 ml). After 10 minutes, 5-(N-benzyloxycarbonyl-N-methylamino)-1-naphthalenesulphonyl chloride (0.6 g) in dimethoxyethane (2 ml) was added and stirring was continued for 2 hours. The mixture was poured into water (20 ml) and washed with ethyl acetate (20 ml). The aqueous layer was acidified with concentrated hydrochloric acid to pH2 and extracted with ethyl acetate (3×50 ml). The combined organic extracts were dried (MgSO4) and evaporated. The residue was purified by flash chromatography on silica gel (25 g), eluting with a gradient of 20-50% ethyl acetate in hexane to give 5-(N-benzyloxycarbonyl-N-methylamino)-N-(5-bromo-3-methoxy-2-pyrazinyl)-1-naphthalenesulphonamide (0.50 g) as a white foam; 1H NMR (d6 -DMSO): 3.34 (s,3H), 3.90 (s,3H), 5.08 (br,2H), 6.95 (br,1H), 7.19 (br,2H), 7.22-7.56 (m,2H), 7.6-7.77 (m,3H), 7.79 (s,1H), 8.07 (d,1H), 8.37 (dd,1H), 8.80 (d,1H), 11.58 (br,1H); mass spectrum (+ve FAB, DMSO/NBA): 557(M+H)+.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]([C:13]2[CH:14]=[C:15]([N:19]3[CH2:28][C:27]4[CH:26]=[N:25][CH:24]=[C:23]([C:29]([OH:31])=O)[C:22]=4[CH2:21][CH2:20]3)[CH:16]=[CH:17][CH:18]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.CCCP(=O)=O.Cl.[CH3:48][O:49][C:50](=[O:53])[CH2:51][NH2:52]>CN(C1C=CN=CC=1)C.ClCCCl>[CH:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]([C:13]2[CH:14]=[C:15]([N:19]3[CH2:28][C:27]4[CH:26]=[N:25][CH:24]=[C:23]([C:29]([NH:52][CH2:51][C:50]([O:49][CH3:48])=[O:53])=[O:31])[C:22]=4[CH2:21][CH2:20]3)[CH:16]=[CH:17][CH:18]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1)([CH3:2])[CH3:3]
Reactant: CC(C)c1cccc(NC(=O)c2cccc(N3CCc4c(cncc4C(=O)O)C3)c2)c1
Reactant: COC(=O)CN
Agent: CCCP(=O)=O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CNC(=O)c1cncc2c1CCN(c1cccc(C(=O)Nc3cccc(C(C)C)c3)c1)C2
Temperature: 25 °C
Reaction time: 0.1 h
Yield: 64.2 %

Procedure:
To a mixture of 7-(3-{[(3-isopropylphenyl)amino]carbonyl}phenyl)-5,6,7,8-tetrahydro-2,7-naphthyridine-4-carboxylic acid (40 mg, 0.096 mmol), N,N-diisopropylethylamine (0.067 mL, 0.39 mmol), and catalytic DMAP in 2.5 mL 1,2-dichloroethane at rt was added propylphosphonic anhydride solution (50 wt % in EtOAc, 0.069 mL, 0.116 mmol). After 6 min at rt, glycine methyl ester hydrochloride (18.1 mg, 0.144 mmol) was added and the reaction stirred at rt for 4 hours. The reaction was quenched with aqueous NaHCO3 solution, extracted with EtOAc, the EtOAc layer washed with H2O, aqueous NaHCO3 solution, brine, dried with anhydrous Na2SO4 and rotary evaporated. This material was chromatographed eluting with CHCl3/EtOAc plus 10% MeOH to give the title compound as a light yellow solid (30 mg, 64%). 1H NMR (CDCl3) δ: 8.55 (s, 1H), 8.47 (s, 1H), 7.93 (s, 1H), 7.53 (d, J=11.4 Hz, 2H), 7.47 (d, J=7.3 Hz, 1H), 7.33-7.40 (m, 1H), 7.20-7.32 (m, 2H), 7.11 (d, J=7.9 Hz, 1H), 7.03 (d, J=7.6 Hz, 1H), 6.62 (t, J=5.1 Hz, 1H), 4.47 (s, 2H), 4.24 (d, J=5.3 Hz, 2H), 3.81 (s, 3H), 3.56-3.61 (m, 2H), 3.20 (t, J=5.6 Hz, 2H), 2.85-2.99 (m, 1H), 1.27 (d, J=6.7 Hz, 6H)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:23]=[CH:24][CH:25]=1)[CH2:7][NH:8][CH:9]1[CH2:14][CH2:13][CH:12]([NH:15]C(=O)OC(C)(C)C)[CH2:11][CH2:10]1)([O-:3])=[O:2]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]([CH:23]=[CH:24][CH:25]=1)[CH2:7][NH:8][CH:9]1[CH2:10][CH2:11][CH:12]([NH2:15])[CH2:13][CH2:14]1)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)NC1CCC(NCc2cccc([N+](=O)[O-])c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1CCC(NCc2cccc([N+](=O)[O-])c2)CC1
Temperature: 30 °C
Reaction time: 8 h
Yield: 149.1 %

Procedure:
Tert-butyl N-(4-[(3-nitrobenzyl)amino]cyclohexyl)carbamate (30.0 g, 86.1 mmol, 1.0 eq) was dissolved in 300 mL of TFA:DCM (1:10) and the resulting solution was stirred at 30° C. overnight. The reaction mixture was then concentrated under vacuum to provide crude 1-N-(3-nitrobenzyl)cyclohexane-1,4-diamine (32 g, TFA salt) as a white solid.
Reaction SMILES: [Cl:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([CH:9](Cl)[CH3:10])=[CH:5][N:4]=1.[CH3:14][S-:15].[Na+]>C(O)C>[Cl:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]([S:15][CH3:14])[CH3:10])=[CH:5][N:4]=1
Reactant: CC(Cl)c1ccc(C(F)(F)Cl)nc1
Reactant: C[S-]
Agent: [Na+]
Solvent: CCO
Product: CSC(C)c1ccc(C(F)(F)Cl)nc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 40.7 %

Procedure:
To a solution of 2-[chloro(difluoro)methyl]-5-(1-chloroethyl)pyridine (D) (0.81 g, 3.6 mmol) in ethanol (10 mL) was added sodium thiomethoxide (0.52 g, 7.4 mmol) under stirring in one portion at 0° C. After 10 min, the mixture was allowed to warm to room temperature and stirred overnight. The solvent ethanol was then removed under reduced pressure and the residue was re-taken into ether/CH2Cl2 and brine. The two phases were separated and the organic layer was extracted with CH2Cl2 one more time. The combined organic layer was dried over anhydrous Na2SO4, filtered, concentrated, purified on silica gel using 5% ethyl acetate in hexane to give 0.348 g of the 2-[chloro(difluoro)methyl]-5-[1-(methylthio)ethyl]pyridine (E) in 40% yield GC-MS: mass calcd for C9H10ClF2NS [M]+ 237. Found 237.
Reaction SMILES: [N:1]1([N:7]2[NH:11][CH:10]=[C:9]([C:12]3[N:13]([CH3:20])[C:14]([N+:17]([O-:19])=[O:18])=[CH:15][N:16]=3)[S:8]2)[CH2:6]CC[CH2:3][CH2:2]1.CNCC[OH:25].N1CCCCC1>>[OH:25][CH2:3][CH2:2][N:1]([CH3:6])[N:7]1[NH:11][CH:10]=[C:9]([C:12]2[N:13]([CH3:20])[C:14]([N+:17]([O-:19])=[O:18])=[CH:15][N:16]=2)[S:8]1
Reactant: CNCCO
Reactant: Cn1c([N+](=O)[O-])cnc1C1=CNN(N2CCCCC2)S1
Solvent: C1CCNCC1
Product: CN(CCO)N1NC=C(c2ncc([N+](=O)[O-])n2C)S1

Procedure:
The preparation of the above compound is carried out essentially as described for the 2-piperidino derivative (Example 28), an equivalent of N-methylethanolamine replacing the piperidine. The pure compound melts at 158°-160° C. after recrystallization from methanol.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.Br[CH2:11][CH2:12][CH2:13][Cl:14]>>[Cl:14][CH2:13][CH2:12][CH2:11][N:2]1[NH:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[NH:1]1
Reactant: c1ccc2[nH]nnc2c1
Reactant: ClCCCBr
Product: ClCCCN1Nc2ccccc2N1
Yield: 36.3 %

Procedure:
Benzotriazole (303 mg, 2.54 mmol) and 1-bromo-3-chloro propane (437 mg, 2.77 mmol) were used according to the method of Example 291, Step A to yield 2-(3-chloropropyl)-1H-1,2,3-benzotriazole (182 mg, 37%). The title compound was prepared according to Example 286, Step C as a yellow oil (20 mg, 40%) from (8aS,12aR)-6,7,8a,9,10,11,12,12a-octahydro-5H-pyrido[4,3-b][1,4]thiazepino[2,3,4-hi]indole (30 mg, 0.12 mmol) and 2-(3-chloropropyl)-1H-1,2,3-benzotriazole (48 mg, 0.24 mmol). 1H NMR (CDCl3) δ1.84-1.94 (m, 3H), 1.99-2.20 (m, 2H), 2.25-2.52 (m, 5H), 2.64-2.72 (m, 1H), 2.74-2.82 (m, 1H), 2.88-3.00 (m, 1H), 3.02-3.18 (m, 2H), 3.22-3.28 (m, 1H), 3.51-3.61 (m, 1H), 3.74-3.85 (m, 1H), 4.80 (t, 2H, J=6.7 Hz), 6.61 (t, 1H, J=7.5 Hz), 6.92 (dd, 2H, J=6.6, 24.9 Hz), 7.35-7.41 (m, 2H), 7.83-7.85 (m, 2H) ppm.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]([NH:24][C:25](=S)[NH:26][C:27]1[CH:32]=[CH:31][C:30](/[N:33]=[CH:34]/[N:35](C)C)=[C:29]([C:38]#N)[CH:28]=1)([CH3:23])[CH2:21][OH:22])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:41]1[CH:42]=[N:43][N:44]2[CH:49]=[CH:48][C:47]([O:50][C:51]3[CH:56]=[CH:55][C:54]([NH2:57])=[CH:53][C:52]=3[CH3:58])=[CH:46][C:45]=12>>[N:41]1[CH:42]=[N:43][N:44]2[CH:49]=[CH:48][C:47]([O:50][C:51]3[CH:56]=[CH:55][C:54]([NH:57][C:38]4[C:29]5[C:30](=[CH:31][CH:32]=[C:27]([NH:26][C:25]6[O:22][CH2:21][C:20]([CH2:19][O:18][Si:1]([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]7[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=7)[C:2]7[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=7)([CH3:23])[N:24]=6)[CH:28]=5)[N:33]=[CH:34][N:35]=4)=[CH:53][C:52]=3[CH3:58])=[CH:46][C:45]=12
Reactant: CN(C)/C=N/c1ccc(NC(=S)NC(C)(CO)CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1C#N
Reactant: Cc1cc(N)ccc1Oc1ccn2ncnc2c1
Product: Cc1cc(Nc2ncnc3ccc(NC4=NC(C)(CO[Si](c5ccccc5)(c5ccccc5)C(C)(C)C)CO4)cc23)ccc1Oc1ccn2ncnc2c1

Procedure:
Prepared according to the method of Example 1, using (E)-N′-(4-(3-(1-(tert-butyldiphenylsilyloxy)-3-hydroxy-2-methylpropan-2-yl)thioureido)-2-cyanophenyl)-N,N-dimethylformimidamide in place of 1-(3-cyano-4-((dimethylamino)methyleneamino)phenyl)-3-(1-hydroxy-2-methylpropan-2-yl)thiourea and 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylbenzenamine in place of 4-(imidazo[1,2-a]pyridin-7-yloxy)-3-methylaniline.