Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[C:12]([O:13][CH3:14])=[CH:11][C:10]([C:15]([F:18])([F:17])[F:16])=[CH:9][C:8]=2[O:19][CH3:20])[N:6]=1.[C:21]([O:25][C:26]([CH2:28][N:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[C:30]1[C:38](O)=[O:39])=[O:27])([CH3:24])([CH3:23])[CH3:22].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(N(CC)CC)C>C(Cl)Cl.O>[F:18][C:15]([F:16])([F:17])[C:10]1[CH:11]=[C:12]([O:13][CH3:14])[C:7]([C:5]2[N:6]=[C:2]([NH:1][C:38]([C:30]3[N:29]([CH2:28][C:26]([O:25][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:27])[C:37]4[C:32]([CH:31]=3)=[CH:33][CH:34]=[CH:35][CH:36]=4)=[O:39])[S:3][CH:4]=2)=[C:8]([O:19][CH3:20])[CH:9]=1
Reactant: CC(C)(C)OC(=O)Cn1c(C(=O)O)cc2ccccc21
Reactant: COc1cc(C(F)(F)F)cc(OC)c1-c1csc(N)n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COc1cc(C(F)(F)F)cc(OC)c1-c1csc(NC(=O)c2cc3ccccc3n2CC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 70.3 %

Procedure:
A mixture of 0.609 g of 2-amino-4-(4-trifluoromethyl-2,6-dimethoxyphenyl)thiazole, 0.606 g of N-(tert-butoxycarbonylmethyl)-2-indolecarboxylic acid, 1.062 g of BOP and 0.243 g of triethylamine in 30 ml of DCM is stirred at r.t. for 24 hours. 50 ml of water are then added, and the organic phase is separated after settling has taken place, dried over sodium sulphate and evaporated under vacuum. The residue is chromatographed on silica H, eluting with a DCM/AcOEt (100:5; v/v) mixture. 0.79 g of the expected product is obtained after crystallization in ether, m.p.=214°-216° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.ClC(OCC(C)C)=O.[CH3:28][O:29][C:30](=[O:57])[CH2:31][CH2:32][C@H:33]([C@@H:35]1[C@:52]2([CH3:53])[C@H:38]([C@H:39]3[C@H:49]([CH2:50][C@@H:51]2[OH:54])[C@:47]2([CH3:48])[C@@H:42]([CH2:43][C@@H:44]([NH2:55])[CH2:45][CH2:46]2)[CH2:41][C@H:40]3[OH:56])[CH2:37][CH2:36]1)[CH3:34]>C1COCC1.CCOCC>[CH3:28][O:29][C:30](=[O:57])[CH2:31][CH2:32][C@H:33]([C@@H:35]1[C@:52]2([CH3:53])[C@H:38]([C@H:39]3[C@H:49]([CH2:50][C@@H:51]2[OH:54])[C@:47]2([CH3:48])[C@@H:42]([CH2:43][C@@H:44]([NH:55][C:10](=[O:12])[CH2:9][NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:45][CH2:46]2)[CH2:41][C@H:40]3[OH:56])[CH2:37][CH2:36]1)[CH3:34]
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@@H](N)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@@H](NC(=O)CNC(=O)OC(C)(C)C)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Reaction time: 0.33 h
Yield: 62.4 %

Procedure:
To a solution of N-(t-butoxycarbonyl)glycine (marketed product) (14.7 g; 84.0 mmol) and Et3N (8.50 g; 11.6 ml; 84.0 mmol) in THF (400 ml), at 0° C. and under nitrogen, was added dropwise isobutyl chloroformate (11.5 g; 10.9 ml; 84.0 mmol). After 15 min a solution of (3β,5β,7α,12α)-3-amino-7,12-dihydroxy-cholan-24-oic acid methyl ester (prepared according to Example 5) (29.5 g; 70.0 mmol) in THF (100 ml) was added dropwise to the reaction mixture at 0° C. After 20 min the reaction mixture was allowed to rise to room temperature and stirred overnight. The suspension was filtered through a sintered funnel and the filtrate was evaporated under reduced pressure to give a residue that was dissolved in Et2O and washed with a saturated aqueous solution of NaHCO3 and H2O. The organic phase was separated, dried and then evaporated under reduced pressure. The solid residue was purified by flash chromatography to give the desired product as a white solid (25.3 g; 43.7 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]([CH3:17])[C:15](=[O:18])[N:14]([CH3:19])[C:13](=S)[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].CI.[CH3:23][C:24]1[CH:30]=[C:29]([CH3:31])[CH:28]=[C:27]([CH3:32])[C:25]=1[NH2:26]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]([CH3:17])[C:15](=[O:18])[N:14]([CH3:19])[C:13](=[N:26][C:25]3[C:27]([CH3:32])=[CH:28][C:29]([CH3:31])=[CH:30][C:24]=3[CH3:23])[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(-c2cc(=S)n(C)c(=O)n2C)cc1OC
Reactant: Cc1cc(C)c(N)c(C)c1
Solvent: CI
Solvent: C1CCOC1
Product: COc1ccc(-c2cc(=Nc3c(C)cc(C)cc3C)n(C)c(=O)n2C)cc1OC
Yield: 70.9 %

Procedure:
To a solution of 3,4-dihydro-6-(3,4-dimethoxyphenyl)-1,3-dimethyl-4-thioxo-2(1H)-pyrimidinone (1.51 g) in tetrahydrofuran (150 ml) was added methyl iodide (30 ml) and the mixture was refluxed for 90 minutes. The precipitate was added to 2,4,6-trimethylaniline (6 g) and the mixture was heated at 110°-120° C. for 3 hours. The reaction mixture was washed with a mixture of hexane and diisopropyl ether to remove excess 2,4,6-trimethylaniline. The resulting precipitate was collected by filtration and then dissolved in chloroform. The solution was washed with an aqueous solution of sodium bicarbonate, dried over magnesium sulfate and evaporated under reduced pressure to give crude product, which was purified by silica gel column chromatography to give 3,4-dihydro-6-(3,4-dimethoxyphenyl)-1,3-dimethyl-4-(2,4,6-trimethylphenylimino)-2(1H)-pyrimidinone (1.44 g); mp 68°-70° C. Thus obtained compound was recrystallized from a mixture of methanol and water (5:1) to give the desired compound as crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([F:24])[CH:19]=3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:17])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[F:25][C:26]1[C:31](B(O)O)=[CH:30][CH:29]=[CH:28][N:27]=1>>[F:24][C:20]1[CH:19]=[C:18]([C:8]2([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([C:31]4[C:26]([F:25])=[N:27][CH:28]=[CH:29][CH:30]=4)[CH:3]=3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:17])=[N:9]2)[CH:23]=[CH:22][N:21]=1
Reactant: NC1=NC(c2cccc(Br)c2)(c2ccnc(F)c2)c2ccccc21
Reactant: OB(O)c1cccnc1F
Product: NC1=NC(c2cccc(-c3cccnc3F)c2)(c2ccnc(F)c2)c2ccccc21
Yield: 19 %

Procedure:
The title compound was synthesized from 1-(3-bromophenyl)-1-(2-fluoropyridin-4-yl)-1H-isoindol-3-amine (Example 116) as described in Example 67 Scheme #10, D in 19% yield using 2-fluoropyridine-3-boronic acid. 1H NMR (DMSO-d6) δ 8.26-8.19 (m, 1 H), 8.15 (d, J=5.31 Hz, 1 H), 8.08-7.99 (m, 1 H), 7.95-7.79 (m, 2 H), 7.59-7.38 (m, 7 H), 7.37-7.30 (m, 1 H), 7.18-6.82 (m, 3 H); MS (ESI) m/z 399 [M+1]+.
Reaction SMILES: [CH3:1][C:2]([C:4]1[C:9]([O:10][CH3:11])=[CH:8][C:7]([O:12][CH3:13])=[CH:6][C:5]=1[OH:14])=[O:3].O1CCOCC1.[H-].[Na+].C(O)(=O)C.C([O:29][C:30](=O)[C:31]([CH3:35])([CH3:34])[C:32]#[N:33])C>>[CH3:34][C:31]([CH3:35])([C:30](=[O:29])[CH2:1][C:2](=[O:3])[C:4]1[C:9]([O:10][CH3:11])=[CH:8][C:7]([O:12][CH3:13])=[CH:6][C:5]=1[OH:14])[C:32]#[N:33]
Reactant: CCOC(=O)C(C)(C)C#N
Reactant: COc1cc(O)c(C(C)=O)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: COc1cc(O)c(C(=O)CC(=O)C(C)(C)C#N)c(OC)c1
Temperature: 0 °C

Procedure:
A mixture of 73.5 g of 2-hydroxy-4,6-dimethoxyacetophenone, 260 g of dimethylcyanoacetic acid ethyl ester and 375 ml of absolute dioxane is introduced into a suspension of 28.6 g of NaH in 7.3 g of dimethylcyanoacetic acid ethyl ester at 0°-10°, while stirring. The mixture is heated for 1 hour at 80°, cooled and poured into acetic acid and the resulting solution is stirred into ice water to give 2,2-dimethyl-3,5-dioxo-5-(2-hydroxy-4,6-dimethoxyphenyl)-pentanonitrile; m.p. 112°-113°.
Reaction SMILES: [CH:1]1[C:10]2[C:9]([NH2:11])=[N:8][C:7]3[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=3[NH:5][C:4]=2[S:3][CH:2]=1.[CH3:16][O:17][CH2:18][CH2:19][C@H:20]1[CH2:25]N[CH2:23][CH2:22][NH:21]1.CS(C)=O.C1(C)C=CC=CC=1>C(OCC)(=O)C>[CH3:16][O:17][CH2:18][CH2:19][C@@H:20]1[NH:21][CH2:22][CH2:23][N:11]([C:9]2[C:10]3[CH:1]=[CH:2][S:3][C:4]=3[NH:5][C:6]3[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=3[N:8]=2)[CH2:25]1
Reactant: NC1=Nc2ccccc2Nc2sccc21
Reactant: COCC[C@H]1CNCCN1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COCC[C@H]1CN(C2=Nc3ccccc3Nc3sccc32)CCN1
Temperature: 105 °C
Reaction time: 24 h
Yield: 19.8 %

Procedure:
Combine 4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylamine (1.26 g, 5.85 mmol), (S)-2-(2-methoxy-ethyl)-piperazine (2.53 g, 17.56 mmol), DMSO (4.0 ml), and toluene (16.0 ml). Stir and heat the mixture at 105° C. After 24 hours, cool the mixture to ambient temperature. Dilute the mixture with ethyl acetate and wash the organic layer with 0.1N NaOH and brine. Dry (sodium sulfate) and concentrate the organic layer to residue. Purify the residue on silica gel using a gradient of dichloromethane to dichloromethane/methanol (85:15) to give 395.8 mg (20%) of an brown foam: mass spectrum (ion spray): m/z=343.1 (M+1).
Reaction SMILES: C(Cl)C[Cl:3].C1C=CC2N(O)N=NC=2C=1.[OH:15][C@@H:16]([CH3:19])[CH2:17][NH2:18].C(OC([N:27]1[CH2:31][CH2:30][CH2:29][C@H:28]1[C:32](O)=[O:33])=O)(C)(C)C.Cl>O1CCOCC1>[ClH:3].[OH:15][C@@H:16]([CH3:19])[CH2:17][NH:18][C:32]([C@@H:28]1[CH2:29][CH2:30][CH2:31][NH:27]1)=[O:33]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: ClCCCl
Reactant: C[C@H](O)CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1COCCO1
Product: C[C@H](O)CNC(=O)[C@@H]1CCCN1

Procedure:
Compound I6 was prepared by EDC/HOBT-coupling of (S)-2-hydroxy-propylamine with pyrrolidine-1,2(S)-dicarboxylic acid 1-t-butyl ester (analogous to Step A of Example I4), followed by HCl-cleavage in dioxane (Step B of Example I5). The crude salt was used as such.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[C:20]([C:32]([NH:34][C:35]3[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=3)=[O:33])[CH:19]=2)(=O)=O)=CC=1.[CH3:41][C:42]([O:45][C:46]([NH:48][C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])=[O:47])([CH3:44])[CH3:43].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C)C=O.O>[C:26]1([CH2:25][O:24][C:21]2[CH:22]=[CH:23][C:18]([O:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][N:48]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[C:46]([O:45][C:42]([CH3:41])([CH3:43])[CH3:44])=[O:47])=[CH:19][C:20]=2[C:32]([NH:34][C:35]2[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=2)=[O:33])[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: Cc1ccc(S(=O)(=O)OCCOCCOc2ccc(OCc3ccccc3)c(C(=O)Nc3cccnc3)c2)cc1
Reactant: CC(C)(C)OC(=O)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N(CCOCCOc1ccc(OCc2ccccc2)c(C(=O)Nc2cccnc2)c1)C(=O)OC(C)(C)C
Temperature: 60 °C

Procedure:
2-{[2-({4-[(Phenylmethyl)oxy]-3-[(3-pyridinylamino)carbonyl]phenyl}oxy)ethyl]oxy}ethyl 4-methylbenzenesulfonate (may be prepared as described in Description 76; 500 mg, 0.89 mmol) was dissolved in N,N-dimethylformamide (10 ml). Di-tert-butyl iminodicarbonate (193 mg, 0.89 mmol) and Cs2CO3 (290 mg, 0.89 mmol) were added. The reaction mixture was heated at 60° C. for 3 h. After cooling to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with water, brine, dried over Na2SO4, and concentrated under reduced pressure to yield the title compound as an oil. 360 mg.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].Cl.[F:20][C:21]1[C:29]([F:30])=[CH:28][CH:27]=[C:26]2[C:22]=1[CH2:23][CH2:24][NH:25]2.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[F:20][C:21]1[C:29]([F:30])=[CH:28][CH:27]=[C:26]2[C:22]=1[CH2:23][CH2:24][N:25]2[C:15](=[O:17])[CH2:14][C:9]1[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[N:8]=1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: Fc1ccc2c(c1F)CCN2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)N1CCc2c1ccc(F)c2F
Yield: 55.8 %

Procedure:
The product is prepared according to the procedure described in example 5, but using 261 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 2 of example 1, 383 mg of 4,5-difluoro-2,3-dihydro-1H-indole hydrochloride, and 254 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 0.32 ml of pyridine and 4 ml of N,N-dimethylformamide. 210 mg of 2-[2-(4,5-difluoro-2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of a pale pink, powdery solid, the characteristics of which are the following:
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[O:14][C:13]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)=[N:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].Cl[C:35]1[N:40]=[C:39]([NH2:41])[N:38]=[C:37]([NH2:42])[CH:36]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CO>[F:23][C:2]([F:22])([F:1])[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[O:14][C:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:35]4[N:40]=[C:39]([NH2:41])[N:38]=[C:37]([NH2:42])[CH:36]=4)=[CH:17][CH:16]=3)=[N:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cc(Cl)nc(N)n1
Reactant: Oc1ccc(-c2nnc(Nc3cccc(C(F)(F)F)c3)o2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Product: Nc1cc(Oc2ccc(-c3nnc(Nc4cccc(C(F)(F)F)c4)o3)cc2)nc(N)n1
Temperature: 80 °C
Yield: 37.7 %

Procedure:
4-(5-{[3-(trifluoromethyl)-phenyl]amino}-1,3,4-oxadiazol-2-yl)phenol (160.6 mg, 0.5 mmol) was dissolved in 3 mL of anhydrous DMF in a 2-5 mL microwave vial (Personal Chemistry). Solid potassium bis(trimethylsilyl)amide (119.7 mg, 0.6 mmol) was added and the reaction mixture was stirred with heating at 80° C. for 10 min, then 6-chloro-2,4-diamino-pyrimidine (86.7 mg, 0.6 mmol) was added, followed by anhydrous K2CO3 (69.1 mg, 0.5 mmol). Then the vial was capped and microwaved at 200° C. for 20 min. Then the reaction mixture was diluted with ca. 1 mL of MeOH, filtered through 0.22 um syringe filter and purified by reverse-phase preparative HPLC in acetonitrile/water system with 0.01% TFA. Fractions, containing the product, were partitioned between ca. 40 mL of EtOAc and ca. 40 mL of saturated NaHCO3. EtOAc layer was washed with brine, dried over anhydrous Na2SO4 and filtered. Solvent was removed in vacuo to give the title product as a beige solid (81.0 mg). Yield 37.7%.
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:18]([O:20][CH3:21])=[O:19])=[CH:9][NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[C:24]1([S:30](Cl)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:1]1([C:7]2[C:8]([C:18]([O:20][CH3:21])=[O:19])=[CH:9][N:10]([S:30]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)(=[O:32])=[O:31])[C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1c[nH]c(-c2ccccc2)c1-c1ccccc1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Product: COC(=O)c1cn(S(=O)(=O)c2ccccc2)c(-c2ccccc2)c1-c1ccccc1
Yield: 79 %

Procedure:
Using methyl 4,5-diphenyl-1H-pyrrole-3-carboxylate (428 mg), sodium hydride (60% in oil, 74 mg) and benzenesulfonyl chloride (0.24 mL), a procedure as in Reference Example 4 was performed to give the title compound as white crystals (yield 506 mg, 79%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30](Cl)=[O:31])[C@H:13]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:15]=2)=[C:7]([O:33][CH2:34][CH3:35])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>>[ClH:22].[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30]([N:36]3[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]3)=[O:31])[C@H:13]([C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)[C@H:14]([C:16]3[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=3)[N:15]=2)=[C:7]([O:33][CH2:34][CH3:35])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C1CNCCN1
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCNCC1
Product: Cl

Procedure:
[(4S,5R)-2-(4-tert-Butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazol-1-yl]-piperazin-1-yl-methanone hydrochloride was prepared from (4S,5R)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 11) and piperazine in an analogous manner as described in example 25. LR-MS: 579.4 [(M+H)+]
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:33][C:34]([O:36]CC)=[O:35])[C:9]([C:11]1[CH:32]=[CH:31][C:14]2[N:15]([CH3:30])[C:16]([CH2:18][N:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27](=[NH:29])[NH2:28])=[CH:23][CH:22]=3)[CH3:20])=[N:17][C:13]=2[CH:12]=1)=[O:10].[OH-].[Na+]>>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:33][C:34]([OH:36])=[O:35])[C:9]([C:11]1[CH:32]=[CH:31][C:14]2[N:15]([CH3:30])[C:16]([CH2:18][N:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27](=[NH:28])[NH2:29])=[CH:23][CH:22]=3)[CH3:20])=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: CCOC(=O)CN(C(=O)c1ccc2c(c1)nc(CN(C)c1ccc(C(=N)N)cc1)n2C)c1ccccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CN(Cc1nc2cc(C(=O)N(CC(=O)O)c3ccccn3)ccc2n1C)c1ccc(C(=N)N)cc1

Procedure:
Prepared analogously to Example 26 from 1-methyl-2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(ethoxycarbonylmethyl)-amide-hydrochloride and sodium hydroxide solution.
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].C(=O)([O-])O.[K+].[CH2:15]([NH2:18])[CH2:16][CH3:17]>CC(C)=O.O>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([NH:18][CH2:15][CH2:16][CH3:17])[N:7]=1
Reactant: CCCN
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCCNc1nc(Cl)nc(Cl)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Cyanuric chloride (1) (36.9 g, 0.2 mole) was dissolved in acetone (600 ml) and cooled in an ice/acetone bath. Potassium hydrogen carbonate (25.03 g, 0.25 mole) was dissolved in water (150 ml) with propylamine (11.82 g, 0.2 mole) and added dropwise to the solution of (1) while maintaining the temperature below 0° C. The mixture was stirred for 1 hour at 0° C. and then stirred for 1 hour at room temperature. The acetone was evaporated off under reduced pressure and the residue (300 ml) was poured into water (11). The resulting white solid was filtered, washed with water and dried under vacuum.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10]CC)=[O:9].[CH2:17]([CH:20]([N:27]1[C:35]2[C:30](=[CH:31][C:32](/[C:36](/[CH3:41])=[CH:37]/[C:38](O)=[O:39])=[CH:33][CH:34]=2)[CH:29]=[CH:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:18][CH3:19]>>[CH2:17]([CH:20]([N:27]1[C:35]2[C:30](=[CH:31][C:32](/[C:36](/[CH3:41])=[CH:37]/[C:38]([NH:1][C:2]3[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=3[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:39])=[CH:33][CH:34]=2)[CH:29]=[CH:28]1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH2:18][CH3:19]
Reactant: CCCC(c1ccccc1)n1ccc2cc(/C(C)=C/C(=O)O)ccc21
Reactant: CCOC(=O)CCCOc1ccccc1N
Product: CCCC(c1ccccc1)n1ccc2cc(/C(C)=C/C(=O)Nc3ccccc3OCCCC(=O)O)ccc21

Procedure:
484 mg of compound 41 was obtained in a similar manner to those described in Examples 1 and 2 using 835 mg of ethyl 4-(2-aminophenoxy)butyrate and 626 mg of 3-[1-(α-propylbenzyl)indol-5-yl]isocrotonic acid obtained according to the procedures described in the Reference Examples 1-4.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH3:14])([CH3:13])[C:10](=[O:12])[CH3:11])=[CH:5][CH:4]=1.[CH3:15][O:16]C1C=CC(C(C2SCCS2)(C)C)=CC=1C=O>>[CH3:13][C:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[C:8]([CH:7]=1)[CH:15]=[O:16])([C:10](=[O:12])[CH3:11])[CH3:14]
Reactant: COc1ccc(C(C)(C)C(C)=O)cc1
Reactant: COc1ccc(C(C)(C)C2SCCS2)cc1C=O
Product: COc1ccc(C(C)(C)C(C)=O)cc1C=O

Procedure:
This compound was prepared from Compound 84 in the same manner of Compound 81.
Reaction SMILES: [NH2:1][C:2]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH2:5][CH2:6][CH2:7][CH3:8])[CH2:3][OH:4].[Na].Br[CH2:18][C:19]1[CH:20]=[C:21]([CH:34]=[C:35]([N:37]([CH3:42])[S:38]([CH3:41])(=[O:40])=[O:39])[CH:36]=1)[C:22]([NH:24][C@@H:25]([C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)[CH3:26])=[O:23]>CN(C=O)C.C1COCC1>[NH2:1][C:2]([CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)([CH2:5][CH2:6][CH2:7][CH3:8])[CH2:3][O:4][CH2:18][C:19]1[CH:20]=[C:21]([CH:34]=[C:35]([N:37]([CH3:42])[S:38]([CH3:41])(=[O:40])=[O:39])[CH:36]=1)[C:22]([NH:24][C@@H:25]([C:27]1[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=1)[CH3:26])=[O:23]
Reactant: CCCCC(N)(CO)Cc1ccccc1
Reactant: C[C@@H](NC(=O)c1cc(CBr)cc(N(C)S(C)(=O)=O)c1)c1ccc(F)cc1
Agent: [Na]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCCCC(N)(COCc1cc(C(=O)N[C@H](C)c2ccc(F)cc2)cc(N(C)S(C)(=O)=O)c1)Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2-amino-2-benzylhexane-1-ol intermediate II (0.100 mg, 0.48 mmol) in 1.1 mL DMF cooled to 0° C. was added sodium hexamethyldisylazide (0.48 mL, 0.48 mmol, 1 M in THF). The reaction mixture was stirred at 0° C. for 5 min and intermediate A 3-(bromomethyl)-N-[(1R)-1-(4-fluorophenyl)ethyl]-5-[methyl(methylsulfonyl)amino]benzamide (0.040 g, 0.090 mmol) in 1.8 mL DMF was added dropwise. The reaction mixture was stirred at 0° C. for 1.5 h, and quenched by adding water. The aqueous layer was washed with EtOAc (3×), and the combined organics were washed with brine, dried over Na2SO4, filtered and concentrated. Purification by silica gel chromatography (20 g silica, 0->8% 0.1% NH4OH in i-PrOH/hexanes) afforded 3-{[(2-amino-2-benzylhexyl)oxy]methyl}-N-[(1R)-1-(4-fluorophenyl)ethyl]-5-[methyl(methyl sulfonyl)amino]benzamide. 1H NMR (400 MHz, CDCl3) δ 7.73 (s, 1H), 7.69 (s, 1H), 7.53 (s, 1H), 7.37-7.34 (m, 2H), 7.29-7.20 (m, 3H), 7.17-7.15 (m, 2H), 7.04 (m, 2H), 6.56 (br s, 1H), 5.30 (m, 1H), 4.56 (s, 2H), 3.34 (s, 3H), 3.20 (m, 2H), 1.59 (d, J=6.9 Hz, 3H), 1.60-1.39 (br m, 6H), 0.90 (t, J=7.0 Hz, 3H).
Reaction SMILES: [N:1]12[C:7](=[O:8])[CH2:6][CH:5]1[CH2:4][C:3](=O)[CH:2]2[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].P(Cl)(Cl)[Cl:21]>CN(C=O)C.C1(C)C=CC=CC=1>[Cl:21][C:3]1[CH2:4][CH:5]2[N:1]([C:7](=[O:8])[CH2:6]2)[C:2]=1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11]
Reactant: O=C1CC2CC(=O)N2C1C(=O)OCc1ccccc1
Reactant: ClP(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)C1=C(Cl)CC2CC(=O)N12
Reaction time: 5 h

Procedure:
Benzyl 1-azabicyclo[3.2.0]heptane-3,7-dione-2-carboxylate (26 mg, 0.1 mmol) in anhydrous DMF (0.5 ml) containing PCl3 (27 mg, 0.2 mmol) is kept at 25° C. for 5 hrs. The mixture is diluted with toluene (5 ml), washed with H2O (5×1 ml) 5% HCl (2 ml), 5% NaHCO3 (2 ml) and brine, dried with MgSO4, and filtered. Evaporation of the solvent in vacuo provides crude benzyl 3-chloro-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][NH:15][CH2:16][CH:17]2[CH2:19][CH2:18]2)=[CH:9][C:8]=1[O:20][CH3:21].C(N(CC)CC)C.[CH3:32][O:33][C:34](=[O:37])[CH2:35]Br>C(#N)C>[CH3:32][O:33][C:34](=[O:37])[CH2:35][N:15]([CH2:14][CH2:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]2[CH:22]=[CH:23][CH:24]=[C:2]([F:1])[CH:3]=2)=[C:8]([O:20][CH3:21])[CH:9]=1)[CH2:16][CH:17]1[CH2:19][CH2:18]1
Reactant: COc1cc(CCNCC2CC2)ccc1OCc1cccc(F)c1
Reactant: COC(=O)CBr
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)CN(CCc1ccc(OCc2cccc(F)c2)c(OC)c1)CC1CC1
Reaction time: 8 h
Yield: 97.2 %

Procedure:
0.271 g (0.82 mmol) of [2-[4-(3-fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]-(cyclopropylmethyl)-amine, 0.140 ml (1 mmol) of triethylamine and 0.155 g (0.89 mmol) of bromo-acetic acid methyl ester were dissolved in 5 ml of acetonitrile and the reaction was carried out at 70° C. overnight. Solvent was removed under vacuum, water was added to the residue and the product was extracted with ethyl acetate. The crude product was purified by flash chromatography (hexane/ethyl acetate 100:0→80:20 gradient v:v) and 0.32 g (97% yield) of the title compound was isolated as a yellow oil.