Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[CH:19]=3)=[O:17])[CH:12]=[CH:11][C:10]=2[CH3:30])[CH:5]=[CH:4][N:3]=1.[CH:31]([NH2:34])([CH3:33])[CH3:32]>>[CH:31]([NH:34][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([N:24]4[CH2:25][CH2:26][O:27][CH2:28][CH2:29]4)[CH:19]=3)=[O:17])[CH:12]=[CH:11][C:10]=2[CH3:30])[CH:5]=[CH:4][N:3]=1)([CH3:33])[CH3:32]
Reactant: CC(C)N
Reactant: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1Nc1ccnc(Cl)n1
Product: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1Nc1ccnc(NC(C)C)n1
Temperature: 100 °C

Procedure:
A mixture of 2-chloro-4-[2-methyl-5-(2-morpholinopyrid-4-ylcarbonylamino)anilino]pyrimidine (0.2 g) and isopropylamine (5 ml) was heated to 100° C. in a sealed tube for 24 hours. The mixture was evaporated and the residue was partitioned between methylene chloride and water. The organic phase was washed with brine, dried over sodium sulphate and evaporated. The resultant solid was recrystallised from tert-butyl methyl ether to give the title compound (0.145 g); NMR Spectrum: (DMSOd6) 1.04 (s, 3H), 1.06 (s, 3H), 2.17 (s, 3H), 3.5 (m, 4H), 3.7 (m, 4H), 3.97 (m, 1H), 5.82 (m, 1H), 6.2 (br m, 1H), 7.07 (m, 1H), 7.19 (m, 2H), 7.45 (m, 1H), 7.78 (m, 1H), 7.87 (br m, 1H), 8.25 (m, 1H), 8.31 (s, 1H), 10.18 (s, 1H); Mass Spectrum: M+H+ 448.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:23]([N:25]([CH3:42])[C@@H:26]([C@@H:38]([CH3:41])[CH2:39][CH3:40])[C@H:27]([O:36][CH3:37])[CH2:28][C:29](OC(C)(C)C)=[O:30])=[O:24])[CH:20]([CH3:22])[CH3:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.[CH3:44][O:45][C@@H:46]([C@@H:64]1[CH2:68][CH2:67][CH2:66][NH:65]1)[C@@H:47]([CH3:63])[C:48]([NH:50][C@H:51]([C:59]([O:61][CH3:62])=[O:60])[CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)=[O:49].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>ClCCl>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:23]([N:25]([CH3:42])[C@@H:26]([C@@H:38]([CH3:41])[CH2:39][CH3:40])[C@H:27]([O:36][CH3:37])[CH2:28][C:29]([N:65]3[CH2:66][CH2:67][CH2:68][C@H:64]3[C@H:46]([O:45][CH3:44])[C@@H:47]([CH3:63])[C:48]([NH:50][C@H:51]([C:59]([O:61][CH3:62])=[O:60])[CH2:52][C:53]3[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=3)=[O:49])=[O:30])=[O:24])[CH:20]([CH3:22])[CH3:21])=[O:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)[C@@H](OC)[C@@H]1CCCN1
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)OC(C)(C)C)OC)N(C)C(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC)OC)N(C)C(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Temperature: 25 °C
Reaction time: 15 h
Yield: 69 %

Procedure:
To a stirring mixture of dimer acid #5 (12.1 g, 23.0 mM) and #67 (11.5 g, 23.0 mM) in 75 mL of dichloromethane under nitrogen, HATU (10.8 g, 27.6 mM) was added followed by Hunig's base (12.1 mL, 69.0 mM). The reaction was allowed to stir at room temperature for 15 hours. Reaction was concentrated to a smaller volume, taken up with ethyl acetate and washed with 1 N HCl two times. The organic layer was then washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. Residue was then purified by silica gel chromatography (Gradient: 0% to 70% acetone in heptanes), producing #113 (12.3 g, 62%) as a white solid. LC-MS (Protocol Q): m/z 855.3 [M+H+], 877.2 [M+Na+], retention time=2.32 minutes; HPLC (Protocol R): /z 855.5 [M+H+], retention time=9.596 minutes (purity >97%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.CN(C)C=O.Cl[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>O>[CH2:16]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: ClCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(OCCc2ccccc2)cc1
Reaction time: 10 h
Yield: 50.4 %

Procedure:
12.2 g of 4-hydroxybenzaldehyde is mixed with 35 ml of dimethylformamide, 16.9 g of (2-chloroethyl)benzene and 16.6 g of potassium carbonate. The resulting mixture is stirred in a stream of nitrogen at 80°-90° C. for 10 hours and then cooled. The cooled mixture is added to 500 ml of water and then extracted with 500 ml of chloroform. The extract is washed with water until it becomes neutral. The washed extract is dried with anhydrous sodium sulfate and then chloroform is distilled away. The resulting residue is distilled under reduced pressure to obtain 11.4 g of 4-phenethyloxybenzaldehyde. Thus obtained 4-phenethyloxybenzaldehyde has a boiling point of 173°-181° C./2-3 mmHg.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:16](=[O:24])[C:17]2[CH:22]=[CH:21][C:20](F)=[CH:19][CH:18]=2)[N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[CH:8][C:7]=12)#[N:2].[CH3:25][N:26]([CH3:31])[CH2:27][CH2:28][CH2:29][NH2:30]>>[C:1]([C:3]1[CH:4]=[C:5]([C:16](=[O:24])[C:17]2[CH:22]=[CH:21][C:20]([NH:30][CH2:29][CH2:28][CH2:27][N:26]([CH3:31])[CH3:25])=[CH:19][CH:18]=2)[N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[CH:8][C:7]=12)#[N:2]
Reactant: CN(C)CCCN
Reactant: N#Cc1cc(C(=O)c2ccc(F)cc2)n2c1ccc1ccccc12
Product: CN(C)CCCNc1ccc(C(=O)c2cc(C#N)c3ccc4ccccc4n23)cc1

Procedure:
The title compound was prepared as described for Example 21, using 3-cyano-(4-fluoro-benzoyl)-pyrrolo[1,2-a]quinoline (65 mg, 0.206 mmol) and N1,N1-dimethyl-propane-1,3-diamine (200 mg, 1.96 mmol) and yielded 68 mg (83%). 1H NMR (CDCl3): 7.98 (m, 2H), 7.81 (dd, J=7.5, 1.8 Hz, 1H), 7.55 (m, 4H), 7.31 (s, 1H), 6.63 (d, J=9.0 Hz, 2H), 5.78 (s, broad, 1H), 3.34 (m, 2H), 2.51 (t, J=6.3 Hz, 2H), 2.31 (s, 6H), 1.85 (m, 2H).
Reaction SMILES: [CH2:1]([N:3]([CH2:26][CH3:27])[C:4](=[O:25])[CH2:5][C:6]1[C:7]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([I:24])[CH:18]=2)=[N:8][N:9]2[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[N:11][C:10]=12)[CH3:2].[C:28]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[CH2:26]([N:3]([CH2:1][CH3:2])[C:4](=[O:25])[CH2:5][C:6]1[C:7]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:28])=[C:19]([I:24])[CH:18]=2)=[N:8][N:9]2[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[N:11][C:10]=12)[CH3:27]
Reactant: CCN(CC)C(=O)Cc1c(-c2ccc(O)c(I)c2)nn2c(C)cc(C)nc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCN(CC)C(=O)Cc1c(-c2ccc(OC)c(I)c2)nn2c(C)cc(C)nc12
Reaction time: 8 h
Yield: 952.4 %

Procedure:
To a solution of 4 (30 mg, 0.063 mmol) in DMF (5 mL) was added K2CO3 (300 mg, 2.2 mmol) and MeI (100 μL×2M, 0.2 mmol). The reaction was stirred overnight and the solvent was removed under vacuum and the residue was purified by silica gel column chromatography (EtOAc as eluent) to give 1 (29 mg, 0.60 mmol, 95%). 1H NMR (CD3OD, 400 MHz) δ 1.15 (t, J=7.2 Hz, 3H), 1.29 (t, J=7.2 Hz, 3H), 2.57 (s, 3H), 2.77 (s, 3H), 3.43 (q, J=7.2 Hz, 2H), 3.58 (q, J=7.2 Hz, 2H), 3.92 (s, 3H), 3.97 (s, 2H), 6.80 (s, 1H), 7.06 (d, J=8 Hz, 1H), 7.74 (d, J=8 Hz, 1H), 8.09 (s, 1H). ESI MS m/z: [M+H]+ C21H26IN4O2: calculated 493.1, found 493.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[Br:14]N1C(=O)CCC1=O>>[Br:14][CH2:8][C:6]1[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: CCOC(=O)c1ccc(F)cc1C
Reactant: O=C1CCC(=O)N1Br
Product: CCOC(=O)c1ccc(F)cc1CBr

Procedure:
Reaction of ethyl 5-fluoro-o-toluate with N-bromosuccinimide as described in Example 1a provides ethyl α-bromo-5-fluoro-o-toluate as an oil.
Reaction SMILES: [C:1]1([CH2:7][C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2-].[Na+].[OH-].[Na+].Br[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1>O.C1(C)C=CC=CC=1>[C:1]1([CH:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Brc1ccccn1
Reactant: N#CCc1ccccc1
Agent: [NH2-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: N#CC(c1ccccc1)c1ccccn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Phenylacetonitrile 46.8 grams (0.40 mole) was added dropwise to a stirred suspension of 31.2 g. (0.80 mole) of powdered sodium amide in 200 ml. of dry toluene in an oven-dried, 2-liter, three-neck round bottom flask, equipped with dropping funnel, thermometer, stirrer and sodium hydroxide-protected condenser. During the addition, the temperature was maintained at 30°-35°C. with ice bath cooling. Afterwards, the mixture was brought slowly to reflux and maintained there for 41/2 hours with continuous stirring. Then 63.6 grams (0.40 mole) of 2-bromopyridine in 100 ml. of toluene was added dropwise at a rate which maintained refluxing of the solution. After complete addition, stirring and refluxing was continued for 3 hours. The mixture was then cooled at 25°C. and ca. 300 ml. of water was added, at first very cautiously and then in a steady stream. The phases were separated and the toluene layer extracted with ca. 150 ml. of water, and then with several portions of cold 6 N hydrochloric acid. The acid extracts were basified with 50% sodium hydroxide with cooling and extracted with ether. The ether extract was washed with water, dried over sodium sulfate and concentrated, and the residue was distilled. Yield, 41.7 g. (54 %); b.p. 134°-136°C./0.07 mm. The distillate crystallized and after recrystallization from isopropyl ether melted at 87°-88.5°C.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:6]=1[O:13][CH3:14])=O.[NH2:15][C:16]([NH2:18])=[S:17]>CCO>[CH3:14][O:13][C:6]1[CH:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]=1[C:3]1[N:15]=[C:16]([NH2:18])[S:17][CH:2]=1
Reactant: COc1ccc(C(=O)CBr)c(OC)c1
Reactant: NC(N)=S
Solvent: CCO
Product: COc1ccc(-c2csc(N)n2)c(OC)c1
Yield: 82.7 %

Procedure:
A mixture of 2-bromo-1-(2,4-dimethoxyphenyl)ethanone (14.5 g, 55.8 mmol) and thiourea (4.32 g, 56.7 mmol) in 95% EtOH (110 mL) was heated at reflux for 60 min. The solution was concentrated and mixed with water (100 mL) and saturated aqueous Na2CO3 (5.0 mL). The resultant precipitate was filtered and recrystallized in toluene. The solids were filtered and dried under vacuum to give 4-(2,4-dimethoxyphenyl)thiazol-2-amine (10.9 g) as yellow solids in 62% yield: 1H NMR (500 MHz, DMSO-d6) δ 8.60 (s, 2 H), 7.53 (s, 1 H), 6.97 (s, 1 H), 6.69 (s, 1 H), 6.67-6.63 (m, 1 H), 3.86 (s, 3 H), 3.80 (s, 3 H).
Reaction SMILES: C(O)C.[C:4](=[S:6])=S.[NH2:7][C:8]1[CH:9]=[C:10]([O:15][CH3:16])[CH:11]=[CH:12][C:13]=1[NH2:14].[OH-].[Na+]>O>[SH:6][C:4]1[NH:7][C:8]2[CH:9]=[C:10]([O:15][CH3:16])[CH:11]=[CH:12][C:13]=2[N:14]=1
Reactant: COc1ccc(N)c(N)c1
Reactant: S=C=S
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc2nc(S)[nH]c2c1

Procedure:
70 ml of ethanol and 15 ml of carbon disulfide were added to 2.6 g of 3,4-diaminoanisole and then a solution of 1.5 g of sodium hydroxide in 5 ml of water was added thereto. After heating with a water bath for 3.5 hours, the mixture was cooled with ice, filtered and then the solvent in the filtrate was distilled off under reduced pressure. The residue was dissolved in ethanol. The solution was filtrated to remove the insoluble matter and then the solvent in the filtrate was distilled off under reduced pressure. The residue was recrystallized from water-containing methanol to obtain 2.0 g of the titled compound (13).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3[C:14](=[O:26])[N:15]([C:18]4[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=4)[CH2:16][CH2:17][C:12]=3[C:11]([CH3:27])=[N:10]2)=[CH:5][CH:4]=1.[CH3:28][NH:29][CH3:30]>CO.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:13]3[C:14](=[O:26])[N:15]([C:18]4[CH:19]=[CH:20][C:21]([C:22]([N:29]([CH3:30])[CH3:28])=[NH:23])=[CH:24][CH:25]=4)[CH2:16][CH2:17][C:12]=3[C:11]([CH3:27])=[N:10]2)=[CH:7][CH:8]=1
Reactant: CNC
Reactant: COc1ccc(-n2nc(C)c3c2C(=O)N(c2ccc(C#N)cc2)CC3)cc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1ccc(-n2nc(C)c3c2C(=O)N(c2ccc(C(=N)N(C)C)cc2)CC3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.5 %

Procedure:
Part A. 4-[1-(4-Methoxy-phenyl)-3-methyl-7-oxo-1,4,5,7-tetrahydro-pyrazolo[3,4-c]pyridin-6-yl]-benzonitrile (0.250 g, 0.98 mmol) was dissolved in 1:1 MeOH/CHCl3 (30 mL). Hydrogen chloride gas was bubbled through the solution for 15 min, and it was then tightly capped and sealed. The reaction was stirred overnight at rt and then concentrated to dryness. The crude intermediate was dissolved in methanol (30 mL) and 2M dimethylamine (5.23 mL, 10.5 mmol) was added. The reaction was tightly capped and sealed and stirred overnight at rt. The reaction was concentrated and purified by reverse phase HPLC and freeze-dried to yield 4-[1-(4-methoxy-phenyl)-3-methyl-7-oxo-1,4,5,7-tetrahydro-pyrazolo[3,4-c]pyridin-6-yl]-N,N-dimethyl-benzamidine (0.255 g, 71%): 1H NMR (CHCl3) δ 9.66 (s, 0.5H), 8.73 (s, 0.5H), 7.51–7.38 (m, 6H), 6.91 (d, j=8.8 Hz, 2H), 4.13(t, j=6.6 Hz, 2H), 3.80 (s, 3H), 3.33 (s, 3H), 3.06 (s, 3H), 2.96 (t,j=6.4 Hz, 2H), 2.35 (s, 3H) ppm; Mass Spec 404.3 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([CH3:19])([CH3:18])[C:15](O)=[O:16])[N:5]=[C:4]([CH3:20])[C:3]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22].[CH:26]1([NH2:29])[CH2:28][CH2:27]1>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([CH3:18])([CH3:19])[C:15]([NH:29][CH:26]2[CH2:28][CH2:27]2)=[O:16])[N:5]=[C:4]([CH3:20])[C:3]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: NC1CC1
Reactant: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)C(=O)O)c2c1N
Product: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)C(=O)NC3CC3)c2c1N

Procedure:
Prepared as in Example Da from 3-((4-amino-3-(ethoxycarbonyl)-2-methylquinolin-5-yl)oxy)-2,2-dimethylpropanoic acid (Example 47b) and cyclopropanamine as a pale yellow solid (64%). 1H NMR (400 MHz, DMSO-d6) δ 0.14-0.45 (m, 2H), 0.57-0.62 (m, 2H), 1.25 (s, 6H), 1.35 (t, J=8.0 Hz, 3H), 2.58 (s, 3H), 2.62-2.65 (m, 1H), 4.13 (s, 2H), 4.35 (q, J=8.0 Hz, 2H), 6.90 (d, 1H), 7.27 (d, 1H), 7.53 (t, J=8.0 Hz, 1H), 7.79 (d, J=4.0 Hz, 1H), 8.09 (s, 2H). MS 386 (MH+).
Reaction SMILES: [ClH:1].[NH2:2][C:3]([NH2:5])=[NH:4].[O-]CC.[Na+].C([O:12][C:13](=O)[CH2:14][O:15][C:16]1[CH:17]=[CH:18][C:19]2[CH2:25][CH2:24][CH2:23][CH:22]([NH:26][CH2:27][C@H:28]([OH:37])[CH2:29][O:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:21][C:20]=2[CH:38]=1)C>CN(C)C=O>[ClH:1].[OH:37][C@H:28]([CH2:29][O:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[CH2:27][NH:26][CH:22]1[CH2:21][C:20]2[CH:38]=[C:16]([O:15][CH2:14][C:13]([NH:4][C:3]([NH2:5])=[NH:2])=[O:12])[CH:17]=[CH:18][C:19]=2[CH2:25][CH2:24][CH2:23]1
Reactant: N=C(N)N
Reactant: CCOC(=O)COc1ccc2c(c1)CC(NC[C@H](O)COc1ccccc1)CCC2
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: N=C(N)NC(=O)COc1ccc2c(c1)CC(NC[C@H](O)COc1ccccc1)CCC2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 54.3 %

Procedure:
To a solution of guanidine hydrochloride (463 mg) in N,N-dimethylformamide (20 ml) was added 28% sodium ethoxide (0.22 ml) under ice-cooling, and the mixture was stirred at room temperature for 5 minutes. To the resulting mixture was added 2-[8-[(2S)-2-hydroxy-3-phenoxypropyl]amino-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]acetic acid ethyl ester (400 mg). After being stirred at room temperature for 2 hours, the precipitates were collected by filtration and treated with 4N hydrogen chloride in ethyl acetate to afford N-[2-[8-[(2S)-2-hydroxy-3-phenoxypropyl]amino-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]acetyl]guanidine hydrochloride (243 mg).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:15][CH:14]=1)=[C:7]([O:28][S:29]([C:32]([F:35])([F:34])[F:33])(=[O:31])=[O:30])[CH:6]=[CH:5]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:55](O)[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(OCC)(=O)C.O1CCCC1>[CH2:55]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][N:22]3[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]3)=[CH:15][CH:14]=1)=[C:7]([O:28][S:29]([C:32]([F:34])([F:35])[F:33])(=[O:31])=[O:30])[CH:6]=[CH:5]2)[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1
Reactant: OCc1ccccc1
Reactant: O=S(=O)(Oc1ccc2cc(O)ccc2c1Oc1ccc(OCCN2CCCCC2)cc1)C(F)(F)F
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=S(=O)(Oc1ccc2cc(OCc3ccccc3)ccc2c1Oc1ccc(OCCN2CCCCC2)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.8 %

Procedure:
Combine trifluoromethanesulfonic acid 6-hydroxy-1-[4-(2-piperidin-1-yl-ethoxy)-phenoxy]-naphthalen-2-yl ester (247 mg, 0.48 mmol), triphenylphosphine (190 mg, 0.725 mmol), benzyl alcohol (0.075 mL, 0.725 mmol) and tetrahydrofuran (5 mL) in a flask placed in an ice bath. Add diisopropyl azodicarboxylate (0.14 mL, 0.725 mmol), stir for 1 hour, warm to ambient temperature and stir for 30 minutes. Dilute with ethyl acetate and wash with 50% saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, dry with magnesium sulfate and remove solvent under vacuum. Chromatograph on silica gel with dichloromethane/methanol mixtures to give 213 mg of the title compound (73%).
Reaction SMILES: C[O:2][C:3](=[O:21])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[NH:5]C(OC(C)(C)C)=O.[CH2:22]([C:24]1[S:28][C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[N:26][C:25]=1[CH2:35]O)[CH3:23].C(O)(C(F)(F)F)=O.[OH-].[Na+]>O>[NH2:5][C@@H:4]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH2:35][C:25]2[N:26]=[C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[S:28][C:24]=2[CH2:22][CH3:23])=[CH:18][CH:19]=1)[C:3]([OH:2])=[O:21]
Reactant: CCc1sc(-c2ccccc2)nc1CO
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCc1sc(-c2ccccc2)nc1COc1ccc(C[C@H](N)C(=O)O)cc1
Yield: 92 %

Procedure:
Intermediate 62 was prepared as described above for the preparation of intermediate 52. From 3.27 g of N-(Boc)-L-Tyrosine methyl ester and 2.43 g of Intermediate 9C was prepared 5.07 g of BOC-protected intermediate methyl ester (92% yield; 1H NMR (CDCl3, 300 MHz) δ7.89-7.86 (m, 2H), 7.42-7.38 (m, 3H), 7.01 (d, 2H, J=6.3), 6.94 (d, 2H, J=6.3), 5.11 (s, 2H), 4.94 (d, 1H, J=6.0), 4.53-4.50 (m, 1H), 3.68 (s, 3H), 3.02-2.98 (m, 2H), 2.90 (q, 2H, J=5.7), 1.39 (s, 9H), 1.30 (t, 3H, J=5.7); From 5.05 g of BOC-protected ester intermediate was prepared the crude TFA salt of intermediate 62 as in example 52. The TFA salt was suspended into water and the pH adjusted to ˜7.0 with 10% NaOH. The resulting solids were filtered and dried to yield 4.28 g of intermediate 62; 1H NMR (DMSO-d6, 400 MHz) δ7.85-7.83 (m, 2H), 7.45-7.43 (m, 3H), 7.16-7.14 (m, 2H), 6.96-6.94 (m, 2H), 5.07 (s, 2H), 3.53 (s, 2H), 3.05-3.02 (m, 1H), 2.91-2.81(m, 4H), 1.21 (t, 3H, J=7.4); low resolution MS (ES+)m/e 382.94 (MH+); TLC Rf=0.33 (4/1, DCM/MeOH).
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[H-].[Na+].[CH3:13]I>CN(C=O)C>[Cl:1][C:2]1[N:6]([CH3:13])[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1
Reactant: Clc1nc2ccccc2[nH]1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(Cl)nc2ccccc21
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 70.9 %

Procedure:
According to the procedure D. Harrison, et al., J. Chem. Soc., 2930, 1963, to a cooled (5° C.), stirred solution of 2-chlorobenzimidazole (26.1 g, 0.171 mol) in DMF (125 mL) was added NaH (60% dispersion in mineral oil; 7.2 g, 0.180 mol) in several portions. After 30 minutes MeI (25.5 g, 0.180 mol) was added. The cooling bath was removed and stirring was continued for 30 minutes. The mixture was recooled, H2O (200 mL) was added, and the resulting precipitate was collected by filtration to give 20.2 g (71%) of product as an off-white solid m.p. 107°-109° C.
Reaction SMILES: [C:1]([NH:4][C:5]([NH2:7])=[S:6])(=[NH:3])[NH2:2].N1CC[CH2:11][CH2:10][CH2:9]1>CC(C)=O>[NH2:3][C:1]1[NH:2][C:10]([CH3:11])([CH3:9])[N:7]=[C:5]([SH:6])[N:4]=1
Reactant: C1CCNCC1
Reactant: N=C(N)NC(N)=S
Solvent: CC(C)=O
Product: CC1(C)N=C(S)N=C(N)N1
Yield: 80 %

Procedure:
In the 200 ml of acetone was refluxed for 3 hours 7.1 g (0.06 mole) of amidinothiourea in the presence of 6 ml of piperidine. After having been allowed to cool, the reaction mixture was filtered to collect 7.6 g (in 80% yield) of colorless powder as deposited. Recrystallization from alcohol gave 7.0 g (in 74% yield) of colorless branch-like crystals, m.p. 186.5°-187.5° C.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([C:6]2[C:11]([N:12]3[CH2:16][CH2:15][CH:14]([CH3:17])[CH2:13]3)=[N:10][CH:9]=[CH:8][N:7]=2)[CH2:3]1.Cl[C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[CH3:17][CH:14]1[CH2:15][CH2:16][N:12]([C:11]2[C:6]([CH:4]3[CH2:5][N:2]([C:19]4[CH:28]=[CH:27][C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[N:20]=4)[CH2:3]3)=[N:7][CH:8]=[CH:9][N:10]=2)[CH2:13]1
Reactant: CC1CCN(c2nccnc2C2CNC2)C1
Reactant: Clc1ccc2ccccc2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1CCN(c2nccnc2C2CN(c3ccc4ccccc4n3)C2)C1
Temperature: 100 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
To a solution of 2-Azetidin-3-yl-3-(3-methyl-pyrrolidin-1-yl)-pyrazine hydrochloride (44) (127 mg, 0.5 mmol, PREPARATION 13) and 2-chloro-quinoline (81.5 mg 0.5 mmol) in DMF (5 mL) was added Cs2CO3 (325 mg, 1 mmol). The reaction mixture was stirred at 100° C. overnight. The reaction mixture was diluted with water, extracted with EtOAc (2×20 mL). The combined organic extracts were washed with water (15 mL) and brine (15 mL), dried over Na2SO4 and filtered. The filtrate was evaporated in vacuo and the residue was purified by flash column chromatography on silica gel to give (rac)-2-{3-[3-(3-methyl-pyrrolidin-1-yl)-pyrazin-2-yl]-azetidin-1-yl}-quinoline (127.65 mg, 0.37 mmol, yield 74%).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:6]([N:8]1[CH2:46][CH2:45][CH2:44][C@H:9]1[C:10]([NH:12][CH2:13][C:14]([NH:16][C@H:17]([C:28]([NH:30][CH2:31][C:32]([O:34][C:35]1[CH:43]=[CH:42][C:38]([N+:39]([O-:41])=[O:40])=[CH:37][CH:36]=1)=[O:33])=[O:29])[CH2:18][CH:19](OC(C)(C)C)[C:20](=[O:22])[OH:21])=[O:15])=[O:11])=[O:7])[CH:3]([CH3:5])[CH3:4].[F:54][C:55]([F:60])([F:59])[C:56]([OH:58])=[O:57]>C(Cl)Cl>[NH2:1][C@H:2]([C:6]([N:8]1[CH2:46][CH2:45][CH2:44][C@H:9]1[C:10]([NH:12][CH2:13][C:14]([NH:16][C@H:17]([C:28]([NH:30][CH2:31][C:32]([O:34][C:35]1[CH:36]=[CH:37][C:38]([N+:39]([O-:41])=[O:40])=[CH:42][CH:43]=1)=[O:33])=[O:29])[CH2:18][CH2:19][C:20](=[O:21])[OH:22])=[O:15])=[O:11])=[O:7])[CH:3]([CH3:4])[CH3:5].[F:54][C:55]([C:56]([OH:58])=[O:57])([F:60])[F:59]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)NCC(=O)N[C@@H](CC(OC(C)(C)C)C(=O)O)C(=O)NCC(=O)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@H](N)C(=O)N1CCC[C@H]1C(=O)NCC(=O)N[C@@H](CCC(=O)O)C(=O)NCC(=O)Oc1ccc([N+](=O)[O-])cc1
Reaction time: 0.5 h

Procedure:
A solution of XX (1.1 g, 1.50 mmol) in 9 ml of 30% trifluoroacetic acid in methylene chloride was allowed to stand for 30 min. at room temperature. The reaction mixture was treated in the same manner as described for the preparation of XI in part (j). The resulting solid was recrystallized from chloroform-petroleum ether; yield 0.923 g (90%), m.p. 130-133° C., Rf1 0.06, Rf2 0.12, Rf3 0.21. Calcd. for C27H35N6O12F3.1/2H2O: C, 46.22; H, 5.17; N, 11.98%. Found: C, 46.06; H, 5.16; N, 11.82%. Amino acid analysis: Glu, 0.98; Pro, 0.90; Gly, 2.10; Val, 1.00.