Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH2:9][CH2:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16](=[O:21])[CH2:15][CH2:14]3)[CH2:3][CH2:2]1>NC1C=CC=CC=1>[C:18]1([N:17]2[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH2:9][CH2:10][C:11]3[CH:12]=[C:13]4[C:18](=[CH:19][CH:20]=3)[NH:17][C:16](=[O:21])[CH2:15][CH2:14]4)[CH2:3][CH2:2]2)[CH:19]=[CH:20][CH:11]=[CH:12][CH:13]=1
Reactant: O=C1CCc2cc(CCCCN3CCOCC3)ccc2N1
Solvent: Nc1ccccc1
Product: O=C1CCc2cc(CCCCN3CCN(c4ccccc4)CC3)ccc2N1

Procedure:
2.88 Grams of 6-(4-morpholinobutyl)-3,4-dihydro-carbostyril and 10 ml of aniline were enclosed in a sealed tube and heated at 170°-200° C. for 5 hours. The reaction mixture was concentrated under a reduced pressure by removing aniline and the residue thus obtained was separated and purified by a silica-gel chromatography. Recrystallized from iropropanoldiisopropyl ether to obtain 0.36 g of 6-[4-(4-phenyl-1-piperazinyl)butyl]-3,4-dihydrocarbostyril in colorless prism-like crystals having the melting point of 151°-152° C.
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]([C:10]1[N:15]=[CH:14][C:13]([NH:16][CH2:17][CH:18]([NH:23]C(=O)OC(C)(C)C)[C:19]([NH:21][CH3:22])=[O:20])=[CH:12][C:11]=1[NH:31][C:32]1[CH:37]=[C:36]([CH3:38])[CH:35]=[C:34]([CH3:39])[N:33]=1)#[N:9]>C(Cl)Cl>[C:8]([C:10]1[N:15]=[CH:14][C:13]([NH:16][CH2:17][C@@H:18]([C:19]([NH:21][CH3:22])=[O:20])[NH2:23])=[CH:12][C:11]=1[NH:31][C:32]1[CH:37]=[C:36]([CH3:38])[CH:35]=[C:34]([CH3:39])[N:33]=1)#[N:9]
Reactant: CNC(=O)C(CNc1cnc(C#N)c(Nc2cc(C)cc(C)n2)c1)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)[C@@H](N)CNc1cnc(C#N)c(Nc2cc(C)cc(C)n2)c1
Reaction time: 0.5 h

Procedure:
TFA (1.0 ml, 13 mmol) was added to a solution of tert-butyl [3-({6-cyano-5-[(4,6-dimethylpyridin-2-yl)amino]pyridin-3-yl}amino)-1-(methylamino)-1-oxopropan-2-yl]carbamate (72 mg, 0.16 mmol) in DCM (2 ml) at room temperature. After 30 minutes, the reaction mixture was concentrated under reduced pressure to afford 3-({6-cyano-5-[(4,6-dimethylpyridin-2-yl)amino]pyridin-3-yl}amino)-N-methylalaninamide. The material was used in the next step without purification. MS ESI calc'd. for C17H22N7O [M+H]+ 340. found 340.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](B2OC(C)(C)C(C)(C)O2)=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.Br[C:36]1[C:41]([CH3:42])=[CH:40][C:39]([C:43]2[CH:44]=[CH:45][C:46](=[O:50])[N:47]([CH3:49])[CH:48]=2)=[CH:38][C:37]=1[CH3:51].BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[CH3:42][C:41]1[CH:40]=[C:39]([C:43]2[CH:44]=[CH:45][C:46](=[O:50])[N:47]([CH3:49])[CH:48]=2)[CH:38]=[C:37]([CH3:51])[C:36]=1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[C:10]2[C:6]=1[CH2:7][CH2:8][C@H:9]2[O:11][C:12]1[CH:25]=[CH:24][C:15]2[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=2[CH:13]=1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Reactant: Cc1cc(-c2ccc(=O)n(C)c2)cc(C)c1Br
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(-c6ccc(=O)n(C)c6)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from methyl 2-((S)-6-((R)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydro-benzofuran-3-yl)acetate and 5-(4-bromo-3,5-dimethylphenyl)-1-methylpyridin-2(1H)-one following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 11): tR=1.19 min; Mass spectrum (ESI+): m/z=554 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][C:9]3=[N:10][CH:11]=[CH:12][CH:13]=[C:8]3[C:7](=[O:15])[C:6]=2[CH:16]=1.[Br:17]N1C(=O)CCC1=O>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[Br:17][CH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][C:9]3=[N:10][CH:11]=[CH:12][CH:13]=[C:8]3[C:7](=[O:15])[C:6]=2[CH:16]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2oc3ncccc3c(=O)c2c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=c1c2cc(CBr)ccc2oc2ncccc12
Reaction time: 2 h
Yield: 81.6 %

Procedure:
A mixture of 42 g of 7-methyl-5-oxo-5H-[1]benzopyrano[2,3-b]pyridine, 36 g of N-bromosuccinimide, 0.4 g of benzoyl peroxide and 420 ml of carbon tetrachloride is refluxed with stirring under ultraviolet light for 2 hours. The reaction mixture is quickly filtered while it is hot. The crystals are suspended in hot water (about 60°C), and the suspension is thoroughly stirred and filtered again. The crystals are recrystallized from dioxane to give 47.1 g of 7-bromomethyl-5-oxo-5H-[1]benzopyrano[2,3-b]pyridine melting at 211°-212.5°C.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH3:38][O:39][C:40](=[O:49])[CH2:41][C:42]1[CH:47]=[CH:46][C:45](Br)=[CH:44][CH:43]=1.[CH2:50]([C:52]([OH:84])([CH2:82][CH3:83])/[CH:53]=[CH:54]/[C:55]1[CH:60]=[CH:59][C:58]([C:61]([CH2:79][CH3:80])([C:64]2[CH:69]=[CH:68][C:67](B3OC(C)(C)C(C)(C)O3)=[CH:66][CH:65]=2)[CH2:62][CH3:63])=[CH:57][C:56]=1[CH3:81])[CH3:51]>O.C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:38][O:39][C:40](=[O:49])[CH2:41][C:42]1[CH:47]=[CH:46][C:45]([C:67]2[CH:66]=[CH:65][C:64]([C:61]([CH2:79][CH3:80])([C:58]3[CH:59]=[CH:60][C:55](/[CH:54]=[CH:53]/[C:52]([CH2:82][CH3:83])([OH:84])[CH2:50][CH3:51])=[C:56]([CH3:81])[CH:57]=3)[CH2:62][CH3:63])=[CH:69][CH:68]=2)=[CH:44][CH:43]=1
Reactant: COC(=O)Cc1ccc(Br)cc1
Reactant: CCC(O)(/C=C/c1ccc(C(CC)(CC)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)cc1C)CC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Solvent: O
Product: CCC(O)(/C=C/c1ccc(C(CC)(CC)c2ccc(-c3ccc(CC(=O)OC)cc3)cc2)cc1C)CC
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 93.1 %

Procedure:
A solution of palladium acetate (3.3 mg, 0.0146 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (12.0 mg, 0.0293 mmol) and potassium phosphate (62.3 mg, 0.29 mmol) in water (0.05 mL) and toluene (0.20 mL) was stirred for three minutes. A solution of (4-bromo-phenyl)acetic acid methyl ester (Tetrahedron Letters 44 (2003) 331-334; 36.0 mg, 0.15 mmol) and (E)-3-ethyl-1-(4-{1-ethyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenyl)-1-penten-3-ol (Example 39-(5); 50.0 mg, 0.1049 mmol) in toluene (0.20 mL) was added, and the mixture was stirred in a nitrogen atmosphere at 100° C. for 1.5 hours. After filtration through cotton plug, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (17% ethyl acetate/hexane) to give the title compound (48.7 mg, 93%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:19]=[C:18]([CH2:20][C:21]([NH:23][CH:24]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)=[O:22])[CH:17]=[CH:16][C:5]=1[C:6]([O:8]CC1C=CC=CC=1)=[O:7])[CH3:2].[H][H]>C(O)C.[Pd]>[CH2:1]([O:3][C:4]1[CH:19]=[C:18]([CH2:20][C:21]([NH:23][CH:24]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N:31]2[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]2)=[O:22])[CH:17]=[CH:16][C:5]=1[C:6]([OH:8])=[O:7])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)C(NC(=O)Cc1ccc(C(=O)OCc2ccccc2)c(OCC)c1)c1ccccc1N1CCCCC1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(NC(=O)Cc1ccc(C(=O)O)c(OCC)c1)c1ccccc1N1CCCCC1

Procedure:
A solution of benzyl 2-ethoxy-4-[N-(α-ethoxycarbonyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate (0.140 g, 0.25 mmol) in ethanol (1.4 ml) is hydrogenated with 10% palladium/charcoal (0.03 g)for 4.5 hours at 50° C. under 5 bar of hydrogen. The mixture is filtered, evaporated down in vacuo and the evaporation residue is purified by column chromatography on silica gel (chloroform/methanol=10/1).
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[C:6]([Cl:9])[N:5]=[CH:4][N:3]=1.[CH3:10][C:11]([CH3:31])([CH3:30])[CH2:12][C:13]1[N:18]=[C:17]([CH2:19][OH:20])[CH:16]=[CH:15][C:14]=1[C:21]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=1[F:29].[H-].[Na+].Cl>C1COCC1>[Cl:9][C:6]1[C:7]([CH3:8])=[C:2]([O:20][CH2:19][C:17]2[CH:16]=[CH:15][C:14]([C:21]3[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=3[F:29])=[C:13]([CH2:12][C:11]([CH3:31])([CH3:30])[CH3:10])[N:18]=2)[N:3]=[CH:4][N:5]=1
Reactant: Cc1c(Cl)ncnc1Cl
Reactant: COc1ccc(F)c(-c2ccc(CO)nc2CC(C)(C)C)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2ccc(COc3ncnc(Cl)c3C)nc2CC(C)(C)C)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 80.6 %

Procedure:
To a solution of 4,6-dichloro-5-methylpyrimidine (160 mg) and (6-(2,2-dimethylpropyl)-5-(2-fluoro-5-methoxyphenyl)pyridin-2-yl)methanol (300 mg) in THF (8.0 mL) was added 60% sodium hydride (60 mg) at 0° C., and the mixture was stirred at 50° C. for 2 hr. The reaction mixture was neutralized with 1N hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (340 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[N:12]1([C:17]2[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=2)[CH:16]=[N:15][CH:14]=[N:13]1.[OH-].[Na+]>C(O)C.O>[N:12]1([C:17]2[CH:24]=[CH:23][C:20](/[CH:21]=[CH:10]/[C:9]([C:4]3[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=3)=[O:11])=[CH:19][CH:18]=2)[CH:16]=[N:15][CH:14]=[N:13]1
Reactant: O=Cc1ccc(-n2cncn2)cc1
Reactant: CC(=O)c1cc(Cl)cc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(/C=C/c1ccc(-n2cncn2)cc1)c1cc(Cl)cc(Cl)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 16.6 %

Procedure:
To a solution of 1-(3,5-dichlorophenyl)ethanone (0.5 g, 2.6 mmol) in ethanol (20 mL) was added 4-(1H-1,2,4-triazol-1-yl)benzaldehyde (0.46 g, 2.65 mmol) and the reaction was cooled to 0° C. Sodium hydroxide (0.22 g, 5.29 mmol) in water (10 mL) was then added and the reaction was allowed to stir for 2 h at 0° C. The reaction was extracted with EtOAc and the combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to afford the title compound (0.149 g, 17%):); ESIMS m/z 430.05 ([M+H]+) 344.08
Reaction SMILES: C([O:3][C:4]1[CH:5]=[CH:6][C:7]([CH3:18])=[C:8]([NH:10][C:11](=[O:17])[C:12](=O)[CH:13]([CH3:15])C)[CH:9]=1)C.[Cl-].[Al+3].[Cl-].[Cl-].Cl[C:24]1C=CC=C(Cl)C=1>>[OH:3][C:4]1[CH:5]=[CH:6][C:7]([CH3:18])=[C:8]2[C:9]=1[C:13]([CH3:15])=[C:12]([CH3:24])[C:11](=[O:17])[NH:10]2
Reactant: CCOc1ccc(C)c(NC(=O)C(=O)C(C)C)c1
Reactant: Clc1cccc(Cl)c1
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1c(C)c2c(O)ccc(C)c2[nH]c1=O
Reaction time: 1.5 h
Yield: 46.2 %

Procedure:
N-(5-ethoxy-2-methylphenyl)-2-oxo-3-methylbutanamide (8.8 g, 35.3 mmol) was dissolved in m-dichlorobenzene (100 ml). Aluminum chloride (20.6 g, 155 mmol) was added to the solution, and the mixture was placed in a bath of 100° C. and stirred for 1.5 hours. The reaction mixture was poured in ice--water, and the precipitate was collected by filtration. To the filtrate, a mixture of chloroform--methanol (5:1) was added. The organic phase was extracted, and dried. The solvent was distilled off under reduced pressure. The resultant residue was recrystallized from methanol--ether to obtain 3.3 g in total of the title compound as yellow powder (46.2%).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[OH:27][CH2:28][C:29]([NH:33][S:34]([C:37]1[S:41][C:40]([NH2:42])=[N:39][C:38]=1[CH3:43])(=[O:36])=[O:35])([CH2:31][OH:32])[CH3:30]>>[OH:32][CH2:31][C:29]([NH:33][S:34]([C:37]1[S:41][C:40]([NH:42][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([C:2]([F:25])([F:26])[F:1])=[CH:4][C:5]([C:15]4[CH:16]=[CH:17][C:18]([C:21]([F:22])([F:24])[F:23])=[CH:19][CH:20]=4)=[N:6][C:7]=23)=[O:13])=[N:39][C:38]=1[CH3:43])(=[O:36])=[O:35])([CH2:28][OH:27])[CH3:30]
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Cc1nc(N)sc1S(=O)(=O)NC(C)(CO)CO
Product: Cc1nc(NC(=O)c2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)sc1S(=O)(=O)NC(C)(CO)CO

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C. 1) and 2-amino-4-methyl-thiazole-5-sulfonic acid (2-hydroxy-1-hydroxymethyl-1-methyl-ethyl)-amide (example B.9) according to general procedure II. Yellow solid. MS (ISP) 637.0 [(M−H)−]; mp 250° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[S:35])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:25]=[C:24]3[C:20]([CH2:21][N:22]([C@@H:27]([CH:32]([CH3:34])[CH3:33])[C:28]([O:30]C)=[O:29])[C:23]3=[O:26])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1.[Li+].[OH-].Cl>C1COCC1.CO.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[S:35])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:25]=[C:24]3[C:20]([CH2:21][N:22]([C@@H:27]([CH:32]([CH3:33])[CH3:34])[C:28]([OH:30])=[O:29])[C:23]3=[O:26])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=S)Nc4ccccc4F)cc3)cc2C1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=S)Nc4ccccc4F)cc3)cc2C1=O
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
The compound of example 51 (0.224 g, 0.000456 mol) was taken in THF (4 mL) and MeOH (1 mL). To this reaction mixture, 1 N LiOH (0.095 g, 0.0022 mol) was added and the reaction mixture was stirred at room temperature for 2-3 h. After completion of the reaction, the solvent was evaporated and the residue obtained was dissolved in water and acidified with 1 N HCl to obtain the title compound, which was filtered and dried.
Reaction SMILES: CS(C)=O.[OH:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]([OH:14])=O)=[N:10][CH:11]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.O[NH:28][C:29](=[NH:33])[CH:30]([CH3:32])[CH3:31]>CC(=O)OCC>[CH:30]([C:29]1[N:33]=[C:12]([C:9]2[N:10]=[CH:11][C:6]([OH:5])=[CH:7][CH:8]=2)[O:14][N:28]=1)([CH3:32])[CH3:31]
Reactant: CC(C)C(=N)NO
Reactant: O=C(O)c1ccc(O)cn1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)c1noc(-c2ccc(O)cn2)n1
Temperature: 90 °C

Procedure:
To DMSO (25 mL) was added 5-hydroxy-pyridine-2-carboxylic acid (1.0 g) and CDI (1.3 g). After 15 minutes N-hydroxy-isobutyramidine (820 mg) was added. After 1 hour the mixture was heated to 90° C. for 1 hour. After the mixture reached room temperature, it was diluted with EA and washed three times with HCl (0.1 M). The organic phase was dried (Na2SO4) and concentrated to provide the title compound. MS ESI+: m/z=206 [M+H]+.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][C:7]([O:15][CH3:16])=[C:8]([O:13][CH3:14])[CH:9]=2)[CH2:4]1.[CH3:17][O:18][C:19]1[C:34]([O:35][CH3:36])=[CH:33][C:22]2[CH2:23][C:24](=[O:32])[N:25]([CH2:28][CH2:29][CH2:30]Cl)[CH2:26][CH2:27][C:21]=2[CH:20]=1>>[CH3:17][O:18][C:19]1[C:34]([O:35][CH3:36])=[CH:33][C:22]2[CH2:23][C:24](=[O:32])[N:25]([CH2:28][CH2:29][CH2:30][N:2]([CH3:1])[CH:3]3[CH2:12][CH2:11][C:10]4[C:5](=[CH:6][C:7]([O:15][CH3:16])=[C:8]([O:13][CH3:14])[CH:9]=4)[CH2:4]3)[CH2:26][CH2:27][C:21]=2[CH:20]=1
Reactant: CNC1CCc2cc(OC)c(OC)cc2C1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCCl)CC2
Product: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)C1CCc3cc(OC)c(OC)cc3C1)CC2

Procedure:
The title compound is prepared analogously to Example 1 by reacting 2-methylamino-6,7-dimethoxy-1,2,3,4-tetrahydronaphthalene with 1-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-chloro-propane. Mp: 236°-238° C.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([NH:16][C:17]([CH:19]3[CH2:22]C[CH2:20]3)=[O:18])[C@@H:13]([OH:23])[C@H:12]2[OH:24])=[C:4]([NH:25][CH2:26][CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:3]=1.Cl.N[C@H]1C[C@@H](N2C=NC3C2=NC(Cl)=NC=3NCC(C2C=CC=CC=2)C2C=CC=CC=2)[C@H](O)[C@@H]1O.ClC1N=C2C(N=CN2)=C(NCC(C2C=CC=CC=2)C2C=CC=CC=2)N=1.C(Cl)(=O)C(C)C>>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([NH:16][C:17](=[O:18])[CH:19]([CH3:22])[CH3:20])[C@@H:13]([OH:23])[C@H:12]2[OH:24])=[C:4]([NH:25][CH2:26][CH:27]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[N:3]=1
Reactant: O=C(N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O)C1CCC1
Agent: CC(C)C(=O)Cl
Agent: Cl
Agent: Clc1nc(NCC(c2ccccc2)c2ccccc2)c2nc[nH]c2n1
Product: CC(C)C(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O

Procedure:
The title compound is prepared by the same method as cyclobutanecarboxylic acid {(1S,2R,3S,4R)-4-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-amide from (1S,2R,3S,5R)-3-amino-5-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-cyclopentane-1,2-diol hydrochloride (an intermediate for preparing the compound of Example 22) and isobutyryl chloride to afford the title compound. LCMS (electrospray): m/z [MH+] 535.26. 1H nmr (MeOD, 400 MHz); 8.00(s, 1H), 7.40-7.30(m, 8H), 7.25-7.15(m, 2H), 4.75(m, 1H), 4.60(m, 1H), 4.50(m, 1H), 4.20(m, 2H), 3.95(m, 1H), 2.85(m, 1H), 2.70(m, 1H), 9.10(m, 1H), 1.20(m, 6H)
Reaction SMILES: C(N(C(C)C)CC)(C)C.CCN=C=NCCCN(C)C.[OH:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][CH:23]=1.[NH2:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35]>C1COCC1.O.C(=O)(O)[O-].[Na+]>[OH:21][C:22]1[CH:23]=[CH:24][C:25]([C:26]([NH:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[O:28])=[CH:29][CH:30]=1
Reactant: CCOC(=O)CCN
Reactant: O=C(O)c1ccc(O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CCNC(=O)c1ccc(O)cc1
Reaction time: 7 h
Yield: 79 %

Procedure:
Diisopropylethylamine (DIPEA, 25.3 mL, 145 mmol) is added dropwise to a solution of EDCI (13.8 g, 72.5 mmol), 4-hydroxybenzoic acid (10.0 g, 72.5 mmol) and ethyl 3-aminopropionate (11.1 g, 72.5 mmol) in THF (700 mL) at room temperature under nitrogen, after which the mixture is stirred for 7 h. The mixture is diluted with water (200 mL) and saturated aqueous sodium bicarbonate solution (100 mL) and extracted with ethyl acetate (3×200 mL). The combined organic extracts are washed with water (100 mL) and brine (100 mL), dried (MgSO4) and the solvents are removed under reduced pressure. The residue is purified by flash column chromatography on silica gel, eluting with hexanes/ethyl acetate (1:1 to 1:4), to afford ethyl 3-(4-hydroxybenzoylamino)propionate as a white crystalline solid (13.59 g, 79%): 1H NMR (CDCl3, 300 MHz) δ 1.27 (t, J=7.14 Hz, 3H), 2.64 (t, J=6.16 Hz, 2H), 3.71 (dt, J=6.09, 11.85 Hz, 2H), 6.86 (d, J=8.70 Hz, 2H), 6.89-6.93 (m 1H), 7.63 (d, J=8.65 Hz, 2H), 8.21-8.27 (m, 1H); APCI MS m/z 238 [C12H15NO4+H]+.
Reaction SMILES: C([O:3][C:4](=O)[NH:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:14])C.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>O=P(Cl)(Cl)Cl>[Cl:14][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:8]=1[CH2:7][CH2:6][NH:5][C:4]2=[O:3]
Reactant: CCOC(=O)NCCc1ccccc1Cl
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O=P(Cl)(Cl)Cl
Product: O=C1NCCc2c(Cl)cccc21
Yield: 8.9 %

Procedure:
Using an analogous procedure and workup as described in Example 1, step 4, [2-(2-chloro-phenyl)-ethyl]-carbamic acid ethyl ester (I-12c: 1.4 g, 6.167 mmol) in POCl3 (14 mL) was reacted with P2O5 (1.75 g, 12.334 mmol). The resulting mixture was heated to reflux for 1 hour to afford the crude product. Purification by column chromatography on silica gel (2% methanol in DCM) afforded 100 mg of the product (9% yield).
Reaction SMILES: C([O:5][C:6](=[O:37])[C@@H:7]1[CH2:11][C@@H:10]([N:12](C(OC(C)(C)C)=O)[C:13]([NH2:22])=[N:14]C(OC(C)(C)C)=O)[CH2:9][N:8]1C(OC(C)(C)C)=O)(C)(C)C.[ClH:38]>O1CCOCC1>[ClH:38].[ClH:38].[NH:12]([C@H:10]1[CH2:9][NH:8][C@H:7]([C:6]([OH:37])=[O:5])[CH2:11]1)[C:13]([NH2:22])=[NH:14]
Reactant: CC(C)(C)OC(=O)N=C(N)N(C(=O)OC(C)(C)C)[C@@H]1C[C@@H](C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Product: N=C(N)N[C@H]1CN[C@H](C(=O)O)C1

Procedure:
(4R)-1-(tert-Butyloxycarbonyl)-4-[N,N'-bis(tert-butyloxycarbonyl)guanidino]-L-proline tert-butyl ester (114 mg, 0.216 mmol) was treated with 4N HCl in dioxane (2 mL) for 48 hours at room temperature. The reaction mixture was evaporated under diminished pressure, coevaporated several times with diethyl ether and several times with methanol. The product was dried under high vacuum, and a quantitative yield of the title compound was obtained. Mass spectrum: m/z 173 (M+1); 400 MHz 1H NMR (CD3OD): δ2.49 (m, 1H); 2.58 (m, 1H); 3.40 (dd, 1H); 3.77 (dd, 1H); 4.42 (m, 1H); 4.66 (t, 1H).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:11][C:12]1[CH:13]=[C:14]([NH2:18])[CH:15]=[CH:16][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:11][C:12]1[CH:13]=[C:14]([NH:18][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: Nc1cccc(Cl)c1
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccnc1Nc1cccc(Cl)c1
Temperature: 140 °C
Yield: 22.2 %

Procedure:
A mixture of 2-chloro-3-nitropyridine (317 mg, 2.0 mmol), 3-chlorophenylamine (0.212 mL, 2.0 mmol) and potassium carbonate (829 mg, 6.0 mmol) in DMF (3 mL) was heated at 140° C. for 30 min using microwave irradiation. After cooling to RT, the reaction mixture was partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc (×3) and the combined organic fractions were washed with brine, dried (Na2SO4) and concentrated in vacuo. The resulting brown oil (370 mg) was purified by column chromatography (Si—PCC, gradient 0-100% DCM in cyclohexane) to afford the title compound as a red solid (111 mg, 22%). LCMS (Method B): RT 3.95 min [M+H]+ 250.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:26]=[CH:25][CH:24]=[CH:23][C:17]=1[C:18]([N:20]=[C:21]=[O:22])=[O:19]>>[Cl:15][C:16]1[CH:26]=[CH:25][CH:24]=[CH:23][C:17]=1[C:18]([NH:20][C:21]([NH:14][C:11]1[CH:10]=[CH:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:13][N:12]=1)=[O:22])=[O:19]
Reactant: Nc1ccc(-c2ccc(Cl)cc2)cn1
Reactant: O=C=NC(=O)c1ccccc1Cl
Product: O=C(NC(=O)c1ccccc1Cl)Nc1ccc(-c2ccc(Cl)cc2)cn1

Procedure:
5-(4-Chlorophenyl)-2-pyridylamine (0.6 gram) and 2-chlorobenzoyl isocyanate (0.7 gram) were reacted according to the teaching of Example 7. The identity of the product was confirmed by NMR, yield 920 mg, m.p. 228°-231° C.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11]([CH:15]2[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)([C:20]#[N:21])[CH:18]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=3)[NH:17][CH:16]2[C:36]([OH:38])=O)[CH:12]=[CH:13][CH:14]=1.[CH3:39][C:40]1([CH3:48])[O:44][C@@H:43]([CH2:45][CH2:46][NH2:47])[CH2:42][O:41]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>[CH3:39][C:40]1([CH3:48])[O:44][C@@H:43]([CH2:45][CH2:46][NH:47][C:36]([CH:16]2[CH:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[CH:10]=3)[C:19]([C:22]3[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=3)([C:20]#[N:21])[CH:18]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=3)[NH:17]2)=[O:38])[CH2:42][O:41]1
Reactant: N#CC1(c2ccc(Cl)cc2)C(c2cccc(Cl)c2)NC(C(=O)O)C1c1cccc(Cl)c1
Reactant: CC1(C)OC[C@H](CCN)O1
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
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)OC[C@H](CCNC(=O)C2NC(c3cccc(Cl)c3)C(C#N)(c3ccc(Cl)cc3)C2c2cccc(Cl)c2)O1

Procedure:
In a manner similar to the method described in Example 1e, rac-(2R,3R,4R,5S)-3,5-bis-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 42b (0.3 g, 0.5 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethylamine (0.3 g, 2 mmol), HATU (0.3 g, 0.75 mmol) and iPr2NEt (0.6 g, 4 mmol) in CH2Cl2 (30 mL) at room temperature for 20 h to give rac-(2R,3R,4R,5S)-3,5-bis-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethyl]-amide as a off white solid (0.25 g, 83%).