Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23]Br)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[N:27]1([C:33]2[O:34][C:35]3[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=3[N:37]=2)[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C(N(CC)CC)C>O1CCCC1>[F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:30]2[CH2:31][CH2:32][N:27]([C:33]3[O:34][C:35]4[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=4[N:37]=3)[CH2:28][CH2:29]2)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: c1ccc2oc(N3CCNCC3)nc2c1
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NCC(F)(F)F)C1(CCCCN2CCN(c3nc4ccccc4o3)CC2)c2ccccc2-c2ccccc21

Procedure:
A solution of 0.3 g (0.7 mmol) of 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide, 0.2 g (0.98 mmol) of 2-(piperazin-1-yl)-benzoxazole and 1 ml of triethylamine in 10 ml of tetrahydrofuran is refluxed for 48 hours. The reaction mixture is then poured onto water, extracted twice with dichloromethane and the combined organic phases are dried over sodium sulphate. The product is purified by column chromatography on silica gel (eluant: cyclohexane/ethyl acetate=1:1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[CH2:12]([N:19]1[CH2:23][CH2:22][CH:21]([O:24][C:25](=[O:30])[CH2:26][C:27]([CH3:29])=O)[CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH3:31][O:32][C:33](=[O:38])/[CH:34]=[C:35](\[NH2:37])/[CH3:36]>C(O)(C)C.C(Cl)(Cl)Cl>[CH3:31][O:32][C:33]([C:34]1[CH:7]([C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:26]([C:25]([O:24][CH:21]2[CH2:22][CH2:23][N:19]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:20]2)=[O:30])=[C:27]([CH3:29])[NH:37][C:35]=1[CH3:36])=[O:38]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: COC(=O)/C=C(/C)N
Reactant: CC(=O)CC(=O)OC1CCN(Cc2ccccc2)C1
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC2CCN(Cc3ccccc3)C2)C1c1cccc([N+](=O)[O-])c1
Yield: 99.9 %

Procedure:
In 5 ml of isopropanol were dissolved 1.51 g (0.01 mole) of 3-nitrobenzaldehyde, 2.61 g (0.01 mole) of 1-benzyl-3-acetoacetoxypyrrolidine, and 1.15 g (0.01 mole) of 3-aminocrotonic acid methyl ester and the solution thus obtained was refluxed for 8 hours. Then, the solvent was distilled off under reduced pressure, the residue thus formed was dissolved in chloroform, the solution was washed, in succession, with diluted hydrochloric acid, water, a saturated aqueous sodium hydrogencarbonate solution, and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure to provide 4.91 g of 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-(1-benzylpyrrolidin-3-yl)ester 5-methyl ester as a caramel form.
Reaction SMILES: [C:1](Cl)(=[O:10])[C:2]1[NH:9][C:7](=[O:8])[NH:6][C:4](=[O:5])[CH:3]=1.[NH2:12][C@H:13]([C:17]([OH:19])=[O:18])[CH:14]([CH3:16])[CH3:15].C(=O)=O.CC(C)=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[O:8]=[C:7]1[NH:9][C:2]([C:1]([NH:12][CH:13]([CH:14]([CH3:16])[CH3:15])[C:17]([OH:19])=[O:18])=[O:10])=[CH:3][C:4](=[O:5])[NH:6]1
Reactant: CC(C)[C@H](N)C(=O)O
Reactant: O=C(Cl)c1cc(=O)[nH]c(=O)[nH]1
Agent: CN(C)c1ccncc1
Agent: O=C=O
Solvent: CC(C)=O
Solvent: ClCCl
Product: CC(C)C(NC(=O)c1cc(=O)[nH]c(=O)[nH]1)C(=O)O
Temperature: 25 °C

Procedure:
In a dry 3-necked, round bottomed flask, equipped with a magnetic stirrer, a thermometer, a nitrogen inlet tube and the dropping funnel containing the orotoyl chloride solution, 6.56 g (56 mmol) of Valine is suspended, with stirring, in 50 mL of dry DCM. To this suspension a catalytic amount (˜0.1 mmol) of DMAP is also added. The suspension is stirred in a dry ice and acetone bath to a temperature of about −15° C. When the target temperature is reached the drop wise addition of orotoyl chloride is commenced. Addition of orotoyl chloride continues, with constant cooling and stirring, until all of the orotoyl chloride is added, after which the reaction is allowed to warm to room temperature with constant agitation. The solution is then filtered to remove any remaining Valine and the volatile DCM is removed from the filtrate under reduced pressure, the remainder is then purified by flash chromatography (ethyl acetate/hexanes; 1/6), yielding 2-(2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxamido)-3-methylbutanoic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:38]=[CH:37][C:6]([CH2:7][O:8][CH2:9][CH2:10][CH2:11][C@@:12]2([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[O:17][C:16](=[O:18])[N:15]([C@H:19]([C:21]3[CH:26]=[CH:25][C:24]([CH2:27][C:28]([OH:30])=[O:29])=[CH:23][CH:22]=3)[CH3:20])[CH2:14][CH2:13]2)=[CH:5][CH:4]=1.[C:39]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:38]=[CH:37][C:6]([CH2:7][O:8][CH2:9][CH2:10][CH2:11][C@@:12]2([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[O:17][C:16](=[O:18])[N:15]([C@H:19]([C:21]3[CH:22]=[CH:23][C:24]([CH2:27][C:28]([O:30][CH3:39])=[O:29])=[CH:25][CH:26]=3)[CH3:20])[CH2:14][CH2:13]2)=[CH:5][CH:4]=1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(COCCC[C@]2(c3ccccc3)CCN([C@@H](C)c3ccc(CC(=O)O)cc3)C(=O)O2)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)Cc1ccc([C@H](C)N2CC[C@](CCCOCc3ccc(OC)cc3)(c3ccccc3)OC2=O)cc1
Reaction time: 8 h
Yield: 37 %

Procedure:
To a mixture of 2-(4-((S)-1-((R)-6-(3-(4-methoxybenzyloxy)propyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenyl)acetic acid (260 mg, 0.50 mmol) and K2CO3 in DMF (2 mL) was added CH3I (0.2 g, 1 mmol). The resulting mixture was stirred overnight. The solid was filtered, and the filtrate was concentrated to give the crude product, which was purification by TLC to afford methyl 2-(4-((S)-1-((R)-6-(3-(4-methoxybenzyloxy)propyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenyl)acetate (100 mg, 37%). 1H NMR (CDCl3): δ=1.42 (d, 3H), 1.68 (m, 1H), 1.88 (m, 2H), 2.12 (m, 1H), 2.23 (m, 2H), 2.78 (m, 1H), 3.29 (m, 2H), 3.44 (s, 2H), 3.64 (s, 3H), 3.75 (s, 3H), 4.28 (s, 2H), 5.56 (q, 1H), 6.73 (m, 4H), 6.92 (m, 2H), 7.14 (m, 2H), 7.25 (m, 5H).
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:28])([CH3:27])[CH2:19][NH:20][S:21]([CH:24]([CH3:26])[CH3:25])(=[O:23])=[O:22])=[CH:14][CH:13]=2)=[CH:8][C:7]=1[N+:29]([O-:31])=[O:30])C.[OH-].[Na+].Cl>C(O)C.O>[F:28][C:18]([C:15]1[CH:14]=[CH:13][C:12]([C:9]2[CH:10]=[CH:11][C:6]([CH2:5][C:4]([OH:32])=[O:3])=[C:7]([N+:29]([O-:31])=[O:30])[CH:8]=2)=[CH:17][CH:16]=1)([CH3:27])[CH2:19][NH:20][S:21]([CH:24]([CH3:25])[CH3:26])(=[O:22])=[O:23]
Reactant: CCOC(=O)Cc1ccc(-c2ccc(C(C)(F)CNS(=O)(=O)C(C)C)cc2)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)S(=O)(=O)NCC(C)(F)c1ccc(-c2ccc(CC(=O)O)c([N+](=O)[O-])c2)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of {4′-[1-fluoro-1-methyl-2-(propane-2-sulfonylamino)-ethyl]-3-nitro-biphenyl-4-yl}-acetic acid ethyl ester. (0.341 g, 0.731 mmol, prepared in example 47) in Ethanol (5.0 mL) is added a solution of 6.7% NaOH (15.0 mL) and the resulting mixture is stirred under N2 at ambient temperature for 72 h. The mixture is diluted with H2O (100 mL) and acidified with 37% HCl. Extraction with EtOAc followed by drying (MgSO4), filtration, and evaporation of the filtrate in vacuo gives the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[N:13]=[N:14][C:15]1[C:21]([O:22][CH2:23][CH:24]([CH2:29][CH3:30])[CH2:25][CH2:26][CH2:27][CH3:28])=[CH:20][C:18]([NH2:19])=[C:17]([O:31][CH2:32][CH:33]([CH2:38][CH3:39])[CH2:34][CH2:35][CH2:36][CH3:37])[CH:16]=1)([O-:3])=[O:2].N(OS(=O)(=O)O)=O.S(=O)(=O)(O)O.[C:52]1([CH3:65])[CH:57]=[CH:56][CH:55]=[C:54]([N:58]([CH2:62][CH2:63][OH:64])[CH2:59][CH2:60][OH:61])[CH:53]=1.S(=O)(=O)(O)[NH2:67]>CN1C(=O)CCC1>[N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1/[N:13]=[N:14]/[C:15]1[C:21]([O:22][CH2:23][CH:24]([CH2:29][CH3:30])[CH2:25][CH2:26][CH2:27][CH3:28])=[CH:20][C:18](/[N:19]=[N:67]/[C:57]2[CH:56]=[CH:55][C:54]([N:58]([CH2:62][CH2:63][OH:64])[CH2:59][CH2:60][OH:61])=[CH:53][C:52]=2[CH3:65])=[C:17]([O:31][CH2:32][CH:33]([CH2:38][CH3:39])[CH2:34][CH2:35][CH2:36][CH3:37])[CH:16]=1)([O-:3])=[O:2]
Reactant: CCCCC(CC)COc1cc(N=Nc2ccc([N+](=O)[O-])cc2[N+](=O)[O-])c(OCC(CC)CCCC)cc1N
Reactant: Cc1cccc(N(CCO)CCO)c1
Reactant: NS(=O)(=O)O
Agent: O=NOS(=O)(=O)O
Agent: O=S(=O)(O)O
Solvent: CN1CCCC1=O
Product: CCCCC(CC)COc1cc(/N=N/c2ccc([N+](=O)[O-])cc2[N+](=O)[O-])c(OCC(CC)CCCC)cc1/N=N/c1ccc(N(CCO)CCO)cc1C
Reaction time: 0.5 h

Procedure:
4-((2,4-Dinitrophenyl)diazenyl)-2,5-bis(2-ethylhexyloxy)aniline (0.54 g, 1 mmol) is dissolved in NMP (10 ml) and to this is added 40% (w/w) nitrosyl sulfuric acid in sulfuric acid (0.38 g, 1.2 mmol). After 30 minutes, the mixture is added to a solution of 2,2′-(m-tolylazanediyl)diethanol (0.20 g, 1 mmol) and sulfamic acid (0.5 g) in IMS (100 ml). A dark oily solid separates immediately. After stirring overnight, the aqueous supernatant is decanted off, the oily solid washed with further water, then dried at 40° C. The pure title compound is acquired as a blue-black solid after multiple purifications over silica gel, eluting with dichloromethane containing an increasing concentration of ethyl acetate (0.54 g, 72%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([N:14]1[CH2:19][CH2:18][NH:17][C:16](=[O:20])[CH2:15]1)=[O:13].F[B-](F)(F)F.[CH2:26]([O+](CC)CC)[CH3:27].O.C(=O)([O-])O.[Na+]>ClCCl>[Cl:1][C:2]1[C:7]([C:8]([F:11])([F:9])[F:10])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([N:14]1[CH2:15][C:16]([O:20][CH2:26][CH3:27])=[N:17][CH2:18][CH2:19]1)=[O:13]
Reactant: O=C1CN(C(=O)c2cccc(C(F)(F)F)c2Cl)CCN1
Reactant: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCOC1=NCCN(C(=O)c2cccc(C(F)(F)F)c2Cl)C1
Reaction time: 18 h

Procedure:
To a solution of 4-{[2-chloro-3-(trifluoromethyl)phenyl]carbonyl}-2-piperazinone (0.613 g, 2 mmol, e.g. as prepared in Intermediate 1) in Dichloromethane (5 ml) at room temperature was added triethyloxonium tetrafluoroborate (950 mg, 5.00 mmol). The reaction mixture was stirred for 18 hours. Dichloromethane (20 ml) and iced water (10 ml) were added and the pH was adjusted to pH 7 with solid sodium hydrogen carbonate. The organic phase was separated, washed with brine, dried and evaporated to give crude 1-{[2-chloro-3-(trifluoromethyl)phenyl]carbonyl}-5-(ethyloxy)-1,2,3,6-tetrahydropyrazine which was used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].Cl[CH2:13][C:14]([O:16][CH:17]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15].C(OCC)(=O)C>CN(C)C=O>[CH:17]([O:16][C:14]([CH2:13][N:5]1[CH:6]=[CH:7][C:2](=[O:1])[CH:3]=[CH:4]1)=[O:15])([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(CCl)OC(c1ccccc1)c1ccccc1
Reactant: Oc1ccncc1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(Cn1ccc(=O)cc1)OC(c1ccccc1)c1ccccc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 73 %

Procedure:
4 g (42.06 mmol) of 4-hydroxypyridine was dissolved in 80 ml of N,N-dimethylformamide, and 8.7 g (62.92 mmol) of pottasium carbonate and 16.45 g (63 mmol) of benzhydryl α-chloroacetate were added thereto. After stirring for 4 hours at 60° C., 200 ml of ethyl acetate was added to the reaction solution, and washed with water and a saturated sodium chloride aqueous solution followed by drying over anhydrous sodium sulfate and treating with active carbon. The solvent was distilled off under reduced pressure, and the crystal residue was washed with ether to obtain 9.8 g (yield: 73%) of 1-benzhydryloxycarbonylmethyl-4-pyridone.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:16]=[C:15]3[C:11]([C:12]([C:17]4[NH:18][C:19]5[CH2:24][CH2:23][NH:22][CH2:21][C:20]=5[N:25]=4)=[N:13][NH:14]3)=[CH:10][CH:9]=2)[C:5]([CH2:26][C:27]([F:30])([F:29])[F:28])=[CH:4][C:3]=1[OH:31].[N:32]1[C:41]2[C:36](=[CH:37][C:38]([CH:42]=O)=[CH:39][CH:40]=2)[CH:35]=[CH:34][CH:33]=1>>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:16]=[C:15]3[C:11]([C:12]([C:17]4[NH:18][C:19]5[CH2:24][CH2:23][N:22]([CH2:42][C:38]6[CH:37]=[C:36]7[C:41](=[CH:40][CH:39]=6)[N:32]=[CH:33][CH:34]=[CH:35]7)[CH2:21][C:20]=5[N:25]=4)=[N:13][NH:14]3)=[CH:10][CH:9]=2)[C:5]([CH2:26][C:27]([F:28])([F:29])[F:30])=[CH:4][C:3]=1[OH:31]
Reactant: O=Cc1ccc2ncccc2c1
Reactant: Oc1cc(CC(F)(F)F)c(-c2ccc3c(-c4nc5c([nH]4)CCNC5)n[nH]c3c2)cc1F
Product: Oc1cc(CC(F)(F)F)c(-c2ccc3c(-c4nc5c([nH]4)CCN(Cc4ccc6ncccc6c4)C5)n[nH]c3c2)cc1F

Procedure:
The title compound was prepared from 2-fluoro-4-[3-(4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-6-yl]-5-(2,2,2-trifluoro-ethyl)-phenol (100 mg, 0.21 mmol) and quinoline-6-carbaldehyde (72.9 mg, 0.46 mmol) using the method of Example 51. The crude material was purified initially over silica and finally by Prep TLC (Mobile Phase: 10% MeOH-DCM) to afford the title compound as an off white solid in 22.9% yield, 28 mg.
Reaction SMILES: C[CH:2]1[O:7][CH:6](C)[CH2:5][N:4]([CH2:9][CH:10](O)C)[CH2:3]1.[Cl:13]N>>[ClH:13].[Cl:13][CH2:10][CH2:9][N:4]1[CH2:5][CH2:6][O:7][CH2:2][CH2:3]1
Reactant: NCl
Reactant: CC(O)CN1CC(C)OC(C)C1
Product: Cl
Product: ClCCN1CCOCC1

Procedure:
An amount, 398.5 grams, of 2,6-dimethyl-N-(2-hydroxypropyl) morpholine (2.3 moles) was condensed with the free chloroamine obtained from 390.5 grams N-chloroethyl morpholine hydrochloride (2.3 moles) as described above to give 325.4 grams (55.7%) of the catalyst as a pale yellow oil, bp 122°-124° C. at 0.3 mm of Hg. The structure was confirmed by elemental analysis, calc. 62.9 C, 10.6 H, 9.8 N; found 62.2 C, 10.4 H, 9.8 N.
Reaction SMILES: [CH2:1]([N:10]1[C:19](=[O:20])[C:18]2[N:17]([CH3:21])[CH:16]=[N:15][C:14]=2[N:13]([CH3:22])[C:11]1=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]=[CH2:9].C[N+]1([O-])CC[O:27]CC1.[OH2:31].S(S([O-])=O)([O-])=O.[Na+].[Na+]>C(O)(C)(C)C.CC(C)=O>[OH:31][CH:8]([CH2:9][OH:27])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][N:10]1[C:19](=[O:20])[C:18]2[N:17]([CH3:21])[CH:16]=[N:15][C:14]=2[N:13]([CH3:22])[C:11]1=[O:12]
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=CCCCCCCCn1c(=O)c2c(ncn2C)n(C)c1=O
Reactant: O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CC(C)(C)O
Product: Cn1cnc2c1c(=O)n(CCCCCCCC(O)CO)c(=O)n2C
Reaction time: 0.25 h
Yield: 54 %

Procedure:
A solution of 1-(8-nonenyl)-3,7-dimethylxanthine (810 mg, 2.7 mmol), 4-methylmorpholine-N- oxide (340 mg, 2.9 mmol) and 2.5% oxmium tetroxide in t-butanol (3 drops) in acetone (20 mL) and water (20 mL) was stirred for 24 hours. Saturated aqueous sodium dithionite solution (5 mL) was added. After stirring for 15 minutes, the reaction was extracted with 25% ethanol-dichloromethane (4×50 mL). The combined organic portions were dried over sodium sulfate, and the solvents were evaporated under vacuum. The solid residue was recrystallized (ethanol-chloroform), yielding 490 mg (54%) 1-(8,9-dihydroxynonyl)-3,7-dimethylxanthine (inventive compound no. 1561).
Reaction SMILES: Br[C:2]1[C:3]([NH:9][CH:10]([CH2:13][CH3:14])[CH2:11][CH3:12])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH2:15]([Sn](CCCC)(CCCC)C#CC)[CH2:16][CH2:17]C>C1(C)C=CC=CC=1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:8][C:5]1[N:4]=[C:3]([NH:9][CH:10]([CH2:13][CH3:14])[CH2:11][CH3:12])[C:2]([C:15]#[C:16][CH3:17])=[CH:7][N:6]=1
Reactant: CC#C[Sn](CCCC)(CCCC)CCCC
Reactant: CCC(CC)Nc1nc(Cl)ncc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC#Cc1cnc(Cl)nc1NC(CC)CC
Temperature: 120 °C
Yield: 74.8 %

Procedure:
To a microwave vial is added a solution of (5-bromo-2-chloro-pyrimidin-4-yl)-(1-ethyl-propyl)-amine (0.5 g, 1.80 mmol) in anhydrous toluene (10 mL), tributyl(1-propynyl)-tin (1.1 mL, 3.6 mmol) and Pd(PPh3)4 (41.5 mg, 0.036 mmol). The reaction mixture is heated at 120° C. for 1 h by employing microwave. The reaction mixture is diluted with EtOAc, washed with NaHCO3 aqueous solution and water, dried over Na2SO4, and concentrated in vacuo. Purification with column chromatography (SiO2, EtOAC/hexane 1:5) gave 0.32 g of (2-chloro-5-prop-1-ynyl-pyrimidin-4-yl)-(1-ethyl-propyl)-amine
Reaction SMILES: Cl[CH2:2][C:3]([Cl:5])=O.[NH2:6][N:7]1[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])([OH:17])[C:15]2[C:10](=[CH:11][CH:12]=C(Cl)C=2)[N:9]=[CH:8]1.[Cl:26][CH2:27][C:28](O)=O>C1C=CC=CC=1>[Cl:26][CH2:27][C:28]1[N:9]([C:10]2[CH:11]=[CH:12][C:3]([Cl:5])=[CH:2][C:15]=2[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])=[O:17])[CH:8]=[N:7][N:6]=1
Reactant: O=C(O)CCl
Reactant: O=C(Cl)CCl
Reactant: NN1C=Nc2ccc(Cl)cc2C1(O)c1ccccc1Cl
Solvent: c1ccccc1
Product: O=C(c1ccccc1Cl)c1cc(Cl)ccc1-n1cnnc1CCl
Yield: 34 %

Procedure:
2-Amino-5,2'-dichlorobenzophenone is reacted with formic acid, whereby 5, 2'-dichloro-2-formylaminobenzophenone (pale yellow granules melting at 106° to 107° C) is obtained. The product is then reacted with hydrazine hydrate, whereby 3-amino-6-chloro-4-(2-chlorophenyl)-3,4-dihydro-4-hydroxyquinazoline (colorless granules melting at 198° C (effervescence)) is obtained. The product is reacted with chloroacetyl chloride, whereby a bis-(monochloroacetyl) derivative of 3-amino-6-chloro-4-(2-chlorophenyl)-3,4-dihydro-4-hydroxyquinazoline (colorless powdery crystals melting at 157° to 158° C) is obtained. Further, the product is treated with monochloroacetic acid in dry benzene under refluxing, whereby crystals of 2-(3-chloromethyl-s-triazol-4-yl)-5, 2'-dichlorobenzophenone are obtained. Recrystallization from chloroform-n-hexane gives colorless granules melting at 139° to 140° C. Overall yield: 34%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]2[C@H:10]([CH2:11]2)[C@H:9]1[CH2:14][NH2:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=1)[C:20](O)=[O:21]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]2[C@H:10]([CH2:11]2)[C@H:9]1[CH2:14][NH:15][C:20](=[O:21])[C:19]1[CH:23]=[CH:24][CH:25]=[C:17]([Cl:16])[CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@@H]2[C@H]1CN
Reactant: O=C(O)c1cccc(Cl)c1
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@@H]2[C@H]1CNC(=O)c1cccc(Cl)c1

Procedure:
prepared by reaction of (1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester with 3-Chloro-benzoic acid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH2:14])=[CH:4][CH:3]=1.[CH2:15]([CH2:25][C:26](=O)[CH3:27])[C:16]1[CH:24]=[CH:23][C:22]2[O:21][CH2:20][O:19][C:18]=2[CH:17]=1>>[O:21]1[C:22]2[CH:23]=[CH:24][C:16]([CH2:15][CH2:25][CH:26]([NH:14][C:9]3[C:10]([CH3:13])=[N:11][O:12][C:8]=3[C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=3)[CH3:27])=[CH:17][C:18]=2[O:19][CH2:20]1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1N
Reactant: CC(=O)CCc1ccc2c(c1)OCO2
Product: Cc1noc(-c2ccc(Br)cc2)c1NC(C)CCc1ccc2c(c1)OCO2

Procedure:
Prepared according to the procedure described in Example 24, Step 1, using 5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylamine and piperonyl acetone.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][N:4]=[C:3]1[C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:38])[C:15]([CH:35]=[C:36]=[O:37])(OCC2C=CC=CC=2)[NH:16][C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[O:18])=[CH:9][CH:8]=1.[OH-:39].[Na+]>CO>[CH3:1][N:2]1[CH2:6][CH2:5][N:4]=[C:3]1[C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:38])[CH:15]([CH2:35][C:36]([OH:37])=[O:39])[NH:16][C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[O:18])=[CH:9][CH:8]=1
Reactant: [OH-]
Reactant: CN1CCN=C1c1ccc(NC(=O)C(C=C=O)(NC(=O)Nc2ccc(Cl)cc2)OCc2ccccc2)cc1
Agent: [Na+]
Solvent: CO
Product: CN1CCN=C1c1ccc(NC(=O)C(CC(=O)O)NC(=O)Nc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (2S) N-[4-(1-methyl-4,5-dihydro-1H-imidazol-2-yl)phenyl]-2-benzyloxycarbonylmethyl-2-(4-chlorophenylaminocarbonylamino)-acetamide (from EXAMPLE 59, 60 mg, 0.11 mmol) in MeOH (3 mL) at room temperature, 1N aq. NaOH (0.50 mL) was added. After being stirred at room temperature overnight, the mixture was concentrated in vacuo. The residue (after being neutralized to acidic with TFA) was purified by HPLC to give the titled compound as a powder (26 mg). MS
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[C:13]([OH:21])(=O)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[N+:22]([C:25]1[CH:33]=[CH:32][C:28]([CH2:29][CH2:30][NH2:31])=[CH:27][CH:26]=1)([O-:24])=[O:23].C(N(CC)CC)C>C(OCC)(=O)C.C(Cl)Cl>[N+:22]([C:25]1[CH:26]=[CH:27][C:28]([CH2:29][CH2:30][NH:31][C:13](=[O:21])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:32][CH:33]=1)([O-:24])=[O:23]
Reactant: CCCCCCC(=O)O
Reactant: NCCc1ccc([N+](=O)[O-])cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCCCCC(=O)NCCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.3 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.86 g, 20.1 mmol) and heptanoic acid (2.38 mL, 16.8 mmol) were added sequentially to a solution of 4-nitrophenethylamine (3.40 g, 16.8 mmol), triethylamine (2.81 mL, 20.1 mmol) and methylene chloride (25 mL). After stirring 18 h at ambient temperature, the reaction mixture was diluted with ethyl acetate; washed sequentially with water, 1N aqueous hydrochloric acid, water, saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride; dried over anhydrous sodium sulfate; filtered and concentrated under reduced pressure to provide 3.80 g (81%) of heptanoic acid [2-(4-nitro-phenyl)-ethyl]-amide as an off-white solid.
Reaction SMILES: C[C:2]([S:7][C:8]1[S:12][C:11]([NH:13][C:14]([N:16]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[CH2:17][CH2:18]C2C=CC=CC=2)=[O:15])=[N:10][CH:9]=1)(C)[C:3]([OH:5])=[O:4].ClCC[S:35]([C:38]1[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=1)(=[O:37])=[O:36].C(OC(=O)CSC1SC(N)=NC=1)C>>[CH3:31][C@H:28]1[CH2:29][CH2:30][C@H:25]([N:16]([CH2:17][CH2:18][S:35]([C:38]2[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=2)(=[O:37])=[O:36])[C:14](=[O:15])[NH:13][C:11]2[S:12][C:8]([S:7][CH2:2][C:3]([OH:5])=[O:4])=[CH:9][N:10]=2)[CH2:26][CH2:27]1
Reactant: Cc1ccc(S(=O)(=O)CCCl)cc1
Reactant: CC(C)(Sc1cnc(NC(=O)N(CCc2ccccc2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O
Agent: CCOC(=O)CSc1cnc(N)s1
Product: Cc1ccc(S(=O)(=O)CCN(C(=O)Nc2ncc(SCC(=O)O)s2)[C@H]2CC[C@H](C)CC2)cc1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of 2-methyl-2-{2-[3-(trans-4-methyl-cyclohexyl)-3-phenethyl-ureido]-thiazol-5-ylsulfanyl}-propionic acid using 1-(2-chloro-ethanesulfonyl)-4-methyl-benzene and (2-aminothiazol-5-ylsulfanyl)acetic acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH3:9])=[N:6][CH:7]=1.C(O[CH:13]=[C:14]([S:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[O:26])=[O:25])[S:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:17])=[O:16])C>Cl.C1(C)C=CC=CC=1.N12CCCC1=NCCC2>[C:27]1([S:24]([C:14]([S:15]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)(=[O:17])=[O:16])=[CH:13][N:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=2)[CH3:9])(=[O:25])=[O:26])[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CNc1ccc(Cl)cn1
Reactant: CCOC=C(S(=O)(=O)c1ccccc1)S(=O)(=O)c1ccccc1
Agent: C1CN=C2CCCN2C1
Agent: Cl
Solvent: Cc1ccccc1
Product: CN(C=C(S(=O)(=O)c1ccccc1)S(=O)(=O)c1ccccc1)c1ccc(Cl)cn1

Procedure:
A mixture of 5-chloro-2-(methylamino)pyridine (0.41 g), 2-ethoxy-1,1-bis(phenylsulphonyl)ethene and concentrated hydrochloric acid (1 drop) in toluene (20 ml) was heated at reflux for 4 hours and then the mixture was treated with 1,5-diazabicyclo[4.3.0]-non-5-ene (3 drops) and heated at reflux for 18 hours. The reaction mixture was cooled and concentrated in vacuo to give an oil which was triturated with ethanol to give a brown solid which was recrystallised from toluene to give 1,1-bis(phenylsulphonyl)-2-[N-(5-chloropyrid-2-yl)-N-methylamino]ethene (0.2 g), mp. 205°-206° C.