Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([N:12]=[N+]=[N-])([CH3:11])[CH3:10])=[CH:5][CH:4]=1.[H][H]>CO.[Pt]=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH2:12])([CH3:10])[CH3:11])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(C)(C)N=[N+]=[N-])cc1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CO
Product: COc1ccc(C(C)(C)N)cc1
Yield: 94.8 %

Procedure:
1.58 g of platinum oxide were added to a solution of 21.0 g of 1-(4-methoxyphenyl)-1-methylethyl azide [prepared as described in step (a) above] in 100 ml of methanol. The reaction mixture was then stirred for 5 hours under a stream of hydrogen. At the end of this time, the mixture was filtered, diluted with methylene chloride, and washed with an aqueous solution of sodium hydrogencarbonate, with water and with a saturated aqueous solution of sodium chloride, in that order. It was then dried over anhydrous magnesium sulfate, and concentrated by evaporation under reduced pressure, to give 17.2 g (yield 95%) of the title compound.
Reaction SMILES: [OH:1][CH:2]([CH3:6])[C:3]([OH:5])=[O:4].CC(C)([O-])C.[K+].[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Cl)=[CH:17][CH:16]=1>>[OH:1][CH:2]([CH3:6])[C:3]([O:5][CH2:19][C:18]1[CH:21]=[CH:22][C:15]([O:14][CH3:13])=[CH:16][CH:17]=1)=[O:4]
Reactant: COc1ccc(CCl)cc1
Reactant: CC(O)C(=O)O
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: COc1ccc(COC(=O)C(C)O)cc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a stirred solution of DL-2 hydroxypropionic acid (9.0 g, 100 mmole) in 100 ml dry DMP was added potassium tert-butoxide (12.34 g, 110 mmole) and the mixture was stirred for one hour at 60° C. 4-methoxybenzyl chloride was (18.8 g 120 mmole) was added and the mixture was stirred for eight hours at 60° C. The mixture was evaporated under reduced pressure and 250 ml ethyl acatate was added The organic phase was washed four times with water. The organic phase was dried with sodium sulfate and concentrated in vacuo. Yield: 16.8 g
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[CH:6][C:5]=1[C:13]([OH:22])([C:18]([F:21])([F:20])[F:19])[C:14](OC)=[O:15])([O-])=O.Cl>C(OCC)(=O)C.C1COCC1.[Pd]>[NH2:10][C:8]1[CH:9]=[C:4]2[C:5]([C:13]([OH:22])([C:18]([F:21])([F:20])[F:19])[C:14](=[O:15])[NH:1]2)=[CH:6][CH:7]=1
Reactant: COC(=O)C(O)(c1ccc([N+](=O)[O-])cc1[N+](=O)[O-])C(F)(F)F
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Nc1ccc2c(c1)NC(=O)C2(O)C(F)(F)F
Reaction time: 8 h
Yield: 6.2 %

Procedure:
To a solution of methyl 2-(2,4-dinitrophenyl)-3,3,3-trifluoro-2-hydroxypropanoate (1.3 g, 4.01 mmol) in ethyl acetate (18 mL) was added pH3 HCl (5.2 mL) followed by 10% Pd/C (350 mg) in ethyl acetate (3 mL). The mixture was stirred overnight under an atmosphere of H2. The reaction mixture was filtered through a pad of Celite and the filtrate was concentrated in vacuo. The crude residue obtained was partitioned between, dichloromethane (25 mL) and aqueous saturated NaHCO3 (15 mL). The organic phase was separated and the aqueous phase was extracted dichloromethane (2×25 mL). The organic phases were combined, dried over Na2SO4, filtered, and concentrated. Purification by silica gel chromatography (50-100% ethyl acetate/hexanes) provided 6-amino-3-hydroxy-3-(trifluoromethyl)indolin-2-one (921 mg, 99%) To a solution of 6-amino-3-hydroxy-3-(trifluoromethyl)indolin-2-one (58 mg, 0.25 mmol) in THF (0.5 mL) at 0° C. was added BH3.THF complex (1 M in THF, 1 mL, 0.95 mmol) dropwise. The mixture was stirred for 5 min at 0° C. then for 3 h at room temperature. The reaction was quenched by adding very carefully 6M HCl (3.5 mL) until no more gas release was observed. The mixture was then stirred at 80° C. for 2 h. The solvent was removed under reduce pressure and the solid residue obtained was dissolved in DMF (3 mL), filtered and purified by reverse phase HPLC (10-99% CH3CN/H2O) to provide 3-(trifluoromethyl)-1H-indol-6-amine (30 mg, 54%, TFA salt).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C(C([NH:13][C:14]1[N:22]=[C:21]([N:23]2[CH2:27][CH2:26][C@@H:25]([NH:28][C:29]([NH:31][C@@H:32]3[CH2:36][CH2:35][NH:34][CH2:33]3)=[O:30])[CH2:24]2)[N:20]=[C:19]2[C:15]=1[N:16]=[CH:17][N:18]2[C@@H:37]1[CH2:41][C@H:40]([NH:42][C:43](=[O:46])[CH2:44][CH3:45])[C@@H:39]([OH:47])[C@H:38]1[OH:48])CC)C.FC(F)(F)C(O)=O.ClC1N=C2C(N=CN2[C@@H]2C[C@H](NC(=O)CC)[C@@H](O)[C@H]2O)=C(N[CH2:79][C:80]2[C:89]3[C:84](=[CH:85][CH:86]=[CH:87][CH:88]=3)[CH:83]=[CH:82][CH:81]=2)N=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[OH:47][C@H:39]1[C@@H:38]([OH:48])[C@H:37]([N:18]2[CH:17]=[N:16][C:15]3[C:19]2=[N:20][C:21]([N:23]2[CH2:27][CH2:26][C@@H:25]([NH:28][C:29]([NH:31][C@@H:32]4[CH2:36][CH2:35][NH:34][CH2:33]4)=[O:30])[CH2:24]2)=[N:22][C:14]=3[NH:13][CH2:79][C:80]2[C:89]3[C:84](=[CH:85][CH:86]=[CH:87][CH:88]=3)[CH:83]=[CH:82][CH:81]=2)[CH2:41][C@@H:40]1[NH:42][C:43](=[O:46])[CH2:44][CH3:45]
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCc4cccc5ccccc45)nc(Cl)nc32)[C@H](O)[C@@H]1O
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NC(CC)CC)nc(N4CC[C@@H](NC(=O)N[C@@H]5CCNC5)C4)nc32)[C@H](O)[C@@H]1O
Solvent: O=C(O)C(F)(F)F
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCc4cccc5ccccc45)nc(N4CC[C@@H](NC(=O)N[C@@H]5CCNC5)C4)nc32)[C@H](O)[C@@H]1O

Procedure:
This compound is prepared analogously to N-((1S,2R,3S,4R)-4-{6-(1-Ethyl-propylamino)-2-[(R)-3-((R)-3-pyrrolidin-3-ylureido)-pyrrolidin-1-yl]-purin-9-yl}-2,3-dihydroxy-cyclopentyl)-propionamide trifluoroacetate by replacing N-{(1S,2R,3S,4R)-4-[2-chloro-6-(1-ethyl-propylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-propionamide with N-((1S,2R,3S,4R)-4-{2-chloro-6-[(naphthalen-1-ylmethyl)-amino]-purin-9-yl}-2,3-dihydroxy-cyclopentyl)-propionamide trifluoroacetate.
Reaction SMILES: C1C=CC(P([N:15]=[N+:16]=[N-:17])(C2C=CC=CC=2)=O)=CC=1.O[CH:19]([C:32]1[CH:33]=[C:34]([Si:37]([CH2:42][CH3:43])([CH2:40][CH3:41])[CH2:38][CH3:39])[O:35][CH:36]=1)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[N:15]([CH:19]([C:32]1[CH:33]=[C:34]([Si:37]([CH2:42][CH3:43])([CH2:40][CH3:41])[CH2:38][CH3:39])[O:35][CH:36]=1)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[N+:16]=[N-:17]
Reactant: CCCCCCCCCCCCC(O)c1coc([Si](CC)(CC)CC)c1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCCCCCCCCC(N=[N+]=[N-])c1coc([Si](CC)(CC)CC)c1
Reaction time: 48 h

Procedure:
A solution of diphenylphosphonyl azide (143 mg, 0.52 mmol in THF (2 ml) was added over a period of 15 minutes to a solution of 4-(1-hydroxytridecyl)-2-triethylsilylfuran (200 mg, 0.52 mmol), triphenylphosphine (140 mg, 0.52 mmol) and diethyl azidocarboxylate (90 mg, 0.52 mmol) in THF (10 ml) at room temperature. After stirring for 2 days, the mixture was evaporated in the presence of a minimum amount of silica gel. The residue was purified by flash chromatography on silica using 5% ethyl ether/hexane to give the titled azide.
Reaction SMILES: [C:1]1([CH3:18])[CH:6]=[CH:5][C:4]([NH:7][S:8]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][N:12]=2)(=[O:10])=[O:9])=[CH:3][CH:2]=1.Br[CH2:20][C:21]([O:23]C(C)(C)C)=[O:22]>>[CH3:17][C:14]1[CH:15]=[CH:16][C:11]([S:8]([N:7]([CH2:20][C:21]([OH:23])=[O:22])[C:4]2[CH:5]=[CH:6][C:1]([CH3:18])=[CH:2][CH:3]=2)(=[O:10])=[O:9])=[N:12][CH:13]=1
Reactant: Cc1ccc(NS(=O)(=O)c2ccc(C)cn2)cc1
Reactant: CC(C)(C)OC(=O)CBr
Product: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ccc(C)cn2)cc1

Procedure:
prepared by reaction of 5-methyl-pyridine-2-sulfonic acid p-tolylamide with tert-butyl bromoacetate
Reaction SMILES: Br[C:2]1[N:3]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[C:4]2[C:9]([C:10]=1[C:11]#[N:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[NH:20]1[CH:24]=[CH:23][CH:22]=[CH:21]1.C(=O)([O-])[O-].[Cs+].[Cs+]>[Cu]I.CN(C=O)C>[OH:19][C:16]1[CH:17]=[CH:18][C:13]([N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:10]([C:11]#[N:12])=[C:2]2[N:20]2[CH:24]=[CH:23][CH:22]=[CH:21]2)=[CH:14][CH:15]=1
Reactant: c1cc[nH]c1
Reactant: N#Cc1c(Br)n(-c2ccc(O)cc2)c2ccccc12
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: N#Cc1c(-n2cccc2)n(-c2ccc(O)cc2)c2ccccc12
Temperature: 120 °C
Reaction time: 48 h

Procedure:
2-Bromo-1-(4-hydroxy-phenyl)-1H-indole-3-carbonitrile (Example 1), 1.4 eq pyrrole, 2 eq cesium carbonate and 20 mol % copper(I) iodide was mixed in a oven-dried vial, DMF was added and the mixture was flushed with nitrogen. The vial was sealed and stirred at 120° C. for 48 hours. The reaction-mixture was cooled to rt, diluted with EtOAc and filtered through silica. The crude mixture was evaporated to dryness and subjected to reversed phase preparative HPLC. Appropriate fractions were combined and evaporated, and identified by 1H-NMR and LC/MS. Purity was determined by analytical HPLC. ES/MS m/z: 300.2 (M+H), 298.3 (M−H); 1H NMR (acetone-d6, 500 MHz): 7.74 (m, 1H), 7.41-7.35 (m, 2H), 7.27 (m, 214), 7.23 (m, 1H), 6.98 (m, 214), 6.95 (t, 2H, J=2.2 Hz) and 6.23 (t, 2H, J=2.2 Hz).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:12]3[CH2:14][O:13]3)[CH:9]=2)[C:4](=[O:15])[O:3]1.[OH:16][CH2:17][C@H:18]1[NH:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19]1>CCO>[OH:16][CH2:17][C@H:18]1[N:23]([CH2:14][CH:12]([OH:13])[C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[C:4](=[O:15])[O:3][C@H:2]([CH3:1])[CH2:11]3)[CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CCN[C@H](CO)C1
Reactant: C[C@@H]1Cc2cc(C3CO3)ccc2C(=O)O1
Solvent: CCO
Product: C[C@@H]1Cc2cc(C(O)CN3CCN(C(=O)OC(C)(C)C)C[C@H]3CO)ccc2C(=O)O1
Temperature: 155 °C

Procedure:
A solution of (3R)-3-methyl-6-(oxiran-2-yl)-3,4-dihydro-1H-isochromen-1-one (325 mg, 1.59 mmol) and tert-butyl (3S)-3-(hydroxymethyl)piperazine-1-carboxylate (345 mg, 1.59 mmol dissolved in EtOH (7 mL) was heated in a sealed tube to 155° C. for 3 hours in the microwave. The reaction was cooled and concentrated to give crude product which was purified via MPLC (40-100% EtOAc/Hexane) to give the title compound as a mixture of diastereomers.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]4[CH:33]=[CH:32][C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[N:25]=4)=[CH:18][CH:17]=3)=[CH:10][N:11]2[CH3:14])=[CH:7][CH:6]=1)=[O:4].CN1C2C(=CC=C(C(O)=O)C=2)[C:37](CC2C=CC(OCC3C=CC4C(=CC=CC=4)N=3)=CC=2)=[CH:36]1>>[CH2:14]([N:11]1[C:12]2[C:8](=[CH:7][CH:6]=[C:5]([C:3]([OH:2])=[O:4])[CH:13]=2)[C:9]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=3)=[CH:18][CH:17]=2)=[CH:10]1)[CH2:36][CH3:37]
Reactant: Cn1cc(Cc2ccc(OCc3ccc4ccccc4n3)cc2)c2ccc(C(=O)O)cc21
Reactant: COC(=O)c1ccc2c(Cc3ccc(OCc4ccc5ccccc5n4)cc3)cn(C)c2c1
Product: CCCn1cc(Cc2ccc(OCc3ccc4ccccc4n3)cc2)c2ccc(C(=O)O)cc21

Procedure:
This compound was prepared from the methyl ester (Example 11, part ii) by the method described in Example 10, part iii, m.p. 80°-82° C.
Reaction SMILES: [C:1]1([N:11]2[C:15]([OH:16])=[CH:14][CH:13]=[N:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Br[C:18]([CH3:25])([CH3:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:24][C:18]([O:16][C:15]1[N:11]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[N:12]=[CH:13][CH:14]=1)([CH3:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Oc1ccnn1-c1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccnn1-c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 1-(naphthalen-1-yl)-1H-pyrazol-5-ol (250 mg, 1.2 mmol), ethyl bromoisobutyrate (0.2 mL, 1.3 mmol) and potassium carbonate (318 mg, 1.3 mmol) in DMF (3 mL) was stirred at room temperature for 16 hours. Water was then added to the reaction mixture, extracted with ethyl acetate, dried over sodium sulfate and concentrated. Purification by preparative thin layer chromatography (95% dichloromethane/5% methanol) afforded ethyl 2-methyl-2-(1-(naphthalen-1-yl)-1H-pyrazol-5-yloxy)propanoate as a solid.
Reaction SMILES: [NH:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].[CH:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(CN)O.Cl>O>[CH:8](=[C:7]1[NH:1][C:2](=[O:3])[NH:4][C:5]1=[O:6])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C1CNC(=O)N1
Reactant: O=Cc1ccccc1
Agent: Cl
Solvent: NCCO
Solvent: O
Product: O=C1NC(=O)C(=Cc2ccccc2)N1
Temperature: 90 °C
Reaction time: 4 h
Yield: 89.8 %

Procedure:
50 g (0.5 mole) of hydantoin, 55 g (52 ml, 0.52 mole) of benzaldehyde and 46 g (45 ml, 0.7 mole of ethanol amine are admixed in 500 ml of water at 70° C. The temperature is raised to 90° C. and the reaction mixture is stirred for 4 hours. The solution is cooled and acidified with concentrated hydrochloric acid (pH 3-4). The mixture is allowed to stand at 10° C. for an hour, the product is filtered off, washed with cold water and dried. Thus 84.5 g of the desired compound are obtained, yield 89%. Mp.: 220°-222° C.
Reaction SMILES: [C:1]([C:3]1[CH:22]=[CH:21][C:6]([C:7]([N:9]2[CH2:20][CH2:19][C:12]3([NH:16][C:15](=[O:17])[NH:14][C:13]3=[O:18])[CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1)#[N:2].Cl[CH2:24][CH2:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:7]([N:9]2[CH2:20][CH2:19][C:12]3([NH:16][C:15](=[O:17])[N:14]([CH2:24][CH2:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3=[O:18])[CH2:11][CH2:10]2)=[O:8])=[CH:21][CH:22]=1)#[N:2]
Reactant: N#Cc1ccc(C(=O)N2CCC3(CC2)NC(=O)NC3=O)cc1
Reactant: CC(C)(C)OC(=O)CCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CCCN1C(=O)NC2(CCN(C(=O)c3ccc(C#N)cc3)CC2)C1=O

Procedure:
A mixture of 2.4 g (8.0 mmol) of the compound from Step B, 1.8 g (10.1 mmol) tert.-butyl 4-chlorobutanoate (prepared according to Chem. Ber. 1965, 98, 2312), 2.8 g (20.3 mmol) dry potassium carbonate, and a catalytic amount potassium iodide in 50 ml dry DMF was heated at 100° C. for 6 h until the conversion was complete. It was poured into ice-cold water, and the crude solid title compound was collected by filtration. It was redissolved in hot ethyl acetate and dried over sodium sulfate, which was removed by filtration. The title hydantoin crystallized from the filtrate by addition of hexane.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][N:6]2[C:9]([C:12]3[CH:13]=[CH:14][C:15]([F:26])=[C:16]([C:18]4[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:17]=3)=[CH:10][N:11]=[C:5]2[N:4]=1.[Na].[NH:28]1[CH:32]=[CH:31][N:30]=[CH:29]1>>[F:26][C:15]1[CH:14]=[CH:13][C:12]([C:9]2[N:6]3[CH:7]=[CH:8][C:3]([CH2:2][N:28]4[CH:32]=[CH:31][N:30]=[CH:29]4)=[N:4][C:5]3=[N:11][CH:10]=2)=[CH:17][C:16]=1[C:18]1[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: N#Cc1ccccc1-c1cc(-c2cnc3nc(CBr)ccn23)ccc1F
Reactant: c1c[nH]cn1
Agent: [Na]
Product: N#Cc1ccccc1-c1cc(-c2cnc3nc(Cn4ccnc4)ccn23)ccc1F

Procedure:
5′-(7-Bromomethylimidazo[1,2-α]pyrimidin-3-yl)-2′-fluorobiphenyl-2-carbonitrile was reacted with the sodium salt of imidazole as described in Example 34 to give 2′-fluoro-5′-[7-(imidazol-1-ylmethyl)imidazo[1,2-α]pyrimidin-3-yl]biphenyl-2-carbonitrile: δH (360 MHz, CDCl3) 5.33 (2H, s), 6.62 (1H, d, J 7), 7.05 (1H, s), 7.15 (1H, s), 7.38-7.43 (1H, m), 7.52-7.73 (6H, m), 7.83 (1H, d, J 7), 7.92 (1H, s), 8.80 (1H, s); m/z (ES+) 395 (M++H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7](B(O)O)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].Br[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[O:22][C:23]([CH3:33])=[C:24]([CH2:26][CH2:27][N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)[N:25]=2)=[CH:17][CH:16]=1>>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[O:22][C:23]([CH3:33])=[C:24]([CH2:26][CH2:27][N:28]4[CH2:29][CH2:30][CH2:31][CH2:32]4)[N:25]=3)=[CH:17][CH:16]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCN1CCCC1
Product: Cc1oc(-c2ccc(-c3cccc(S(C)(=O)=O)c3)cc2)nc1CCN1CCCC1

Procedure:
The title compound is prepared in a manner substantially analogous to Example 35 starting from 3-Methylsulfonylbenzene boronic acid and 2-(4-Bromo-phenyl)-5-methyl-4-(2-pyrrolidin-1-yl-ethyl)-oxazole. MS (m/e): 411.1 (M+1)
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH2:8]/[C:7](=[CH:11]\N(C)C)/[C:6]1=O)([CH3:4])([CH3:3])[CH3:2].[N+]([O-])(O)=O.[N+]([O-])(O)=O.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([NH:38][C:39]([NH2:41])=[NH:40])[CH:29]=[CH:30][C:31]=1[N:32]1[CH:36]=[C:35]([CH3:37])[N:34]=[CH:33]1>>[C:1]([CH:5]1[C:6]2[N:41]=[C:39]([NH:38][C:28]3[CH:29]=[CH:30][C:31]([N:32]4[CH:36]=[C:35]([CH3:37])[N:34]=[CH:33]4)=[C:26]([O:25][CH3:24])[CH:27]=3)[N:40]=[CH:11][C:7]=2[CH2:8][CH2:9][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)/C=C1\CCCC(C(C)(C)C)C1=O
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Solvent: O=[N+]([O-])O
Product: COc1cc(Nc2ncc3c(n2)C(C(C)(C)C)CCC3)ccc1-n1cnc(C)c1

Procedure:
The title compound was prepared from crude 2-tert-butyl-6-[1-dimethylamino-meth-(E)-ylidene]-cyclohexanone (100 mg, 0.48 mmol) and N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-guanidine dinitrate (111 mg, 0.30 mmol) using in analogous manner the procedure described in example 45b). Obtained as a yellow solid (59 mg, 50%). MS ISP (m/e): 392.3 (100) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=9.43 (s, 1H), 8.22 (s, 1H), 7.76 (s, 1H), 7.64 (s, 1H), 7.43 (d, 1H), 7.19 (d, 1H), 7.02 (s, 1H), 3.78 (s, 3H), 2.51-2.65 (m, 2H), 2.14 (s, 3H), 1.91 (m, 2H), 1.73 (m, 1H), 1.40 (m, 1H), 1.03 (s, 9H).
Reaction SMILES: [OH:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@:3]1([CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2.C1CCC(N=C=NC2CCCCC2)CC1.C1C2C(COC([NH:62][C@H:63]([C:67](O)=[O:68])[CH:64]([CH3:66])[CH3:65])=O)C3C(=CC=CC=3)C=2C=CC=1>CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[NH2:62][C@H:63]([C:67]([O:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@:3]1([CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:68])[CH:64]([CH3:66])[CH3:65]
Reactant: CC(C)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: O=C(O)c1ccc(C[C@@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@H]2O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)[C@H](N)C(=O)O[C@@H]1c2ccccc2C[C@@]1(Cc1ccc(C(=O)O)cc1)C1=Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 36.3 %

Procedure:
To a solution of 4-(((1S,2S)-1-hydroxy-2,3-dihydro-1H,1′H-[2,2′-biinden]-2-yl)methyl)benzoic acid (230 mg, 0.60 mmol), DCC (148 mg, 0.72 mmol) and DMAP (7 mg, 0.06 mmol) in ethyl acetate (12 mL), was added N-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-valine (193 mg, 0.60 mmol) and then stirred at room temperature for 12 h. The solids were filtered, washed with ethyl acetate (25 ml) and the combined filtrate was washed with 1.5 N HCl (25 mL), water (25 mL), brine (10 mL), dried over anhydrous Na2SO4. The organic layer was evaporated under reduced pressure and the residue 1 (250 mg) was dissolved in dry THF (8 mL) and cooled to 0° C. Dimethylamine (8 mL, 20% in THF) was added drop wise at N2 atmosphere and the reaction mixture was slowly allowed to stir at room temperature for 1 h. The reaction mixture was evaporated under reduced pressure and the residue was purified by CombiFlash using 10% methanol in chloroform as an eluent to yield 105 mg (36%) of the title compound as an off white solid.
Reaction SMILES: [C:1]([C:4]1[CH:8]=[CH:7][S:6][CH:5]=1)(=O)[CH3:2].[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1>C1CCCCC1.[Ti](Cl)(Cl)(Cl)Cl>[O:12]1[CH2:13][CH2:14][N:9]([C:1]([C:4]2[CH:8]=[CH:7][S:6][CH:5]=2)=[CH2:2])[CH2:10][CH2:11]1
Reactant: CC(=O)c1ccsc1
Reactant: C1COCCN1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: C1CCCCC1
Product: C=C(c1ccsc1)N1CCOCC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 31.4 %

Procedure:
A solution of 57 g of titanium tetrachloride (TiCl4) in 100 ml of cyclohexane is added dropwise to a stirred solution of 75 g of 3-acetylthiophene and 160 g of morpholine in a liter of cyclohexane. When the addition is complete, the reaction mixture is further stirred at room temperature for 12 hours, then the precipitate is filtered off and the filtrate is concentrated by evaporation. The residue is distilled and has a boiling point of 98°/0.04 millibar. In this manner 36.5 g of 1-morpholino-1-(thiophen-3-yl)-ethylene are obtained in the form of a colourless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([N:12]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:13][C@H:14]([OH:23])[CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10][OH:11])=[CH:4][CH:3]=1.[C:31](O)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[CH2:24]([N:12]([C@H:9]([CH2:10][OH:11])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:31](=[O:38])[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:3][CH:4]=1)[CH2:13][C@H:14]([OH:23])[CH2:15][O:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: Nc1ccc(C[C@@H](CO)N(Cc2ccccc2)C[C@H](O)COc2ccccc2)cc1
Reactant: O=C(O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(C[C@@H](CO)N(Cc2ccccc2)C[C@H](O)COc2ccccc2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 98.2 %

Procedure:
To a mixture of (2S)-3-(4-aminophenyl)-2-[N-benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-1-propanol (77 mg) and benzoic acid (28 mg) in N,N-dimethylformamide (0.8 ml) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (57 mg), and the mixture was stirred at room temperature for 20 hours. The mixture was partitioned between hexane-ethyl acetate and water. The organic layer was separated, washed successively with water and brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated to give N-[4-[(2S)-2-[N-benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino)-3-hydroxypropyl]phenyl]-benzamide (95 mg) as a white amorphous powder.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[S:34](=[O:37])(=[O:36])[NH2:35])=[CH:24][CH:23]=2)[C:7](=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:18])[F:17])[N:9]=1)[CH2:2][CH2:3][CH3:4].[C:38](Cl)(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>>[C:38]([NH:35][S:34]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[C:25]1[CH:26]=[CH:27][C:22]([CH2:21][N:6]2[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:9][N:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:16]([F:19])([F:18])[F:17])[C:7]2=[O:20])=[CH:23][CH:24]=1)(=[O:37])=[O:36])(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCCCc1nn(-c2ccccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1
Product: CCCCc1nn(-c2ccccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)c2ccccc2)cc1
Yield: 75 %

Procedure:
The reaction of 5-n-butyl-2,4-dihydro-4-[(2'-sulfamoylbiphenyl-4-yl)methyl]-2-[2-(trifluoromethyl)phenyl]-3H-1,2,4-triazol-3-one (from Step C) with benzoyl chloride was carried out according to the method of Example 13, Step C. Flash chromatography of the crude product on silica gel (gradient elution with 0.5-5% MeOH in CH2Cl2) provided a 75% yield of the title compound as white crystals, mp 91°-93° C.; satisfactory purity by TLC 19:1 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 673 (M+K)+.