Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl.[CH:15]([C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[CH:20]2)=O.C(N(C(C)C)CC)(C)C.[B-].[Na+].P([O-])(O)(O)=O.[K+].[N:43]1[C:51]2[CH:50]=[CH:49][N:48]=[CH:47][C:46]=2[NH:45][C:44]=1[C:52]1[C:64]2[C:63]3[C:58](=[CH:59][CH:60]=[CH:61][CH:62]=3)[CH:57]([NH2:65])[C:56]=2[CH:55]=[CH:54][CH:53]=1>C(O)C>[N:43]1[C:51]2[CH:50]=[CH:49][N:48]=[CH:47][C:46]=2[NH:45][C:44]=1[C:52]1[C:64]2[C:63]3[C:58](=[CH:59][CH:60]=[CH:61][CH:62]=3)[CH:57]([NH:65][CH2:15][C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[NH:22][CH:21]=[CH:20]4)[C:56]=2[CH:55]=[CH:54][CH:53]=1
Reactant: O=Cc1ccc2[nH]ccc2c1
Reactant: NC1c2ccccc2-c2c(-c3nc4ccncc4[nH]3)cccc21
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Agent: O=P([O-])(O)O
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: c1ccc2c(c1)-c1c(-c3nc4ccncc4[nH]3)cccc1C2NCc1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 32.1 %

Procedure:
In a 5-ml three-necked flask, dissolve 74 mg of 4-(3H-imidazo[4,5-c]pyridin-2-yl)-fluorene-9(R,S)-amine, isolated as the dihydrochloride, in 0.5 ml of ethanol, add 45 mg of 5-formyl-indole and 70 μL of diisopropylethylamine and stir for 2 hours 30 minutes at room temperature. Then add 28 mg of sodium hydroborate and stir for 18 hours at room temperature. Pour the reaction mixture into 5 ml of a saturated aqueous solution of potassium dihydrogen phosphate, then extract 3 times with 10 ml of dichloromethane. After purification on silica gel, eluting with mixtures of dichloromethane and methanol (98-2, then 96-4 by volume), we obtain 34 mg of N-[4-(3H-imidazo[4,5-c]pyridin-2-yl)-9H-fluoren-9(R,S)-yl]-(1H-indol-5-yl-methyl)-amine, in the form of a white solid with the following characteristics:
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]2([N:17]3[CH2:18][CH2:19][CH2:20][CH2:21][CH:16]3[CH:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])[O:14]2)[CH2:10][CH2:9]1)C1C=CC=CC=1>[Pd]>[CH3:29][O:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[CH:15]1[CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][N:17]2[C:11]2([CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[O:14]1
Reactant: COc1ccccc1C1OC2(CCN(Cc3ccccc3)CC2)N2CCCCC12
Agent: [Pd]
Product: COc1ccccc1C1OC2(CCNCC2)N2CCCCC12

Procedure:
Utilizing the procedure described in Example 2 above, 8.9 g of hexahydro-1'-benzyl-1-(2-methoxyphenyl)spiro[3H-oxazolo[3,4-a]pyridine-3,4'-piperidine] is hydrogenated in the presence of a palladium on charcoal catalyst to obtain hexahydro-1-(2-methoxyphenyl)spiro[3H-oxazolo[3,4-a]pyridine-3,4'-piperidine] as an oil after evaporation of the organic layer. The oil, 5.8 g, is dissolved in 30 ml ether and added to a solution of 2.4 g oxalic acid dihydrate in 40 ml of ether. The precipitated solid is collected by filtration and recrystallized from methanol-ethyl acetate to obtain the oxalate salt; mp 185°-186° C.
Reaction SMILES: C(OC([NH:8][C:9]([CH3:19])([C:11]([O:13][CH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:12])[CH3:10])=O)(C)(C)C.[ClH:20].O1CCOCC1>C1COCC1>[ClH:20].[CH3:19][C:9]([C:11]([O:13][CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18]1)=[O:12])([CH3:10])[NH2:8]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)OC1CCCC1
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CC(C)(N)C(=O)OC1CCCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 82 %

Procedure:
Cyclopentyl N-(tert-butoxycarbonyl)-2-methylalaninate (0.254 g, 0.93 mmol) was dissolved in THF (5 ml) and treated with 4M HCl/dioxane (2 ml) and the reaction mixture was stirred at RT for 24 hours. The crude mixture was concentrated under reduced pressure and triturated with Et2O to give a white precipitate. This was further washed with Et2O to give the desired product as a white powder (0.16 g, 82% yield).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]=[CH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=O.[NH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][C:17]1=[O:25].N1CCCCC1>C(O)C>[O:25]=[C:17]1[NH:16][C:24]2[C:19](/[C:18]/1=[CH:1]\[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:20][CH:21]=[CH:22][CH:23]=2
Reactant: O=C1Cc2ccccc2N1
Reactant: CCOC(=O)C=Cc1ccccc1C=O
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOC(=O)CCc1ccccc1/C=C1/C(=O)Nc2ccccc21
Temperature: 90 °C
Reaction time: 8 h
Yield: 37.3 %

Procedure:
A mixture of 1 g of ethyl 3-(2-formylphenyl)propenate, 500 mg oxindole and 0.1 mL piperidine in 5 mL of ethanol was stirred at 90° C. overnight. The mixture was evaporated and purified on a silica gel column to give 450 mg of ethyl (E)-3-[(2-oxo-1,2-dihydroindol-3-ylidenemethyl)phenyl]propionate (M+1=322).
Reaction SMILES: [C:1]([C:9]([C:24]([OH:26])=[O:25])([OH:23])[C:10]([C:15](=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([OH:14])[C:11]([OH:13])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27]1([C@:33]23[NH:40][C@H:37]([CH2:38][CH2:39]2)[CH2:36][CH2:35][C@H:34]3[OH:41])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(O)(C)C>C(OCC)(=O)C>[C:15]([C:10]([C:11]([OH:13])=[O:12])([OH:14])[C:9]([C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([OH:23])[C:24]([OH:26])=[O:25])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[C:27]1([C@@:33]23[NH:40][C@@H:37]([CH2:38][CH2:39]2)[CH2:36][CH2:35][C@@H:34]3[OH:41])[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O[C@@H]1CC[C@H]2CC[C@]1(c1ccccc1)N2
Agent: O=C(O)C(O)(C(=O)c1ccccc1)C(O)(C(=O)O)C(=O)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: O[C@H]1CC[C@@H]2CC[C@@]1(c1ccccc1)N2
Temperature: 25 °C

Procedure:
A solution of (−)-dibenzoyl tartaric acid (4.85 g, 13.5 mmol) in ethyl acetate (100 ml) was added dropwise to a solution of (1R*,2R*,5R*)-1-phenyl-8-azabicyclo[3.2.1]octan-2-ol (Description 47; 11 g, 54.2 mmol) in hot ethyl acetate (250 ml). Iso-propyl alcohol (500 ml) was added and the mixture heated at reflux for 1 hour. The mixture was allowed to cool slowly to room temperature then filtered to yield the title compound (4.8 g, 46%, e.e. >99%).
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[C:5]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:6]3[C:11]([C:12]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:3]=1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.COCCOC>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:2]2[CH:15]=[CH:14][C:13]3[C:4](=[C:5]([C:22]4[CH:23]=[CH:24][C:25]5[C:26](=[CH:22][CH:5]=[CH:6][CH:7]=5)[CH:27]=4)[C:6]4[C:11]([C:12]=3[C:16]3[CH:17]=[CH:18][C:19]5[C:20](=[CH:15][CH:2]=[CH:3][CH:4]=5)[CH:21]=3)=[CH:10][C:9]([C:32]3[CH:33]=[CH:34][C:29]([Cl:28])=[CH:30][CH:31]=3)=[CH:8][CH:7]=4)[CH:3]=2)=[CH:31][CH:30]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: Brc1ccc2c(-c3ccccc3)c3ccccc3c(-c3ccccc3)c2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Clc1ccc(-c2ccc3c(-c4ccc5ccccc5c4)c4cc(-c5ccc(Cl)cc5)ccc4c(-c4ccc5ccccc5c4)c3c2)cc1
Yield: 173.3 %

Procedure:
5.0 g (8.5 mmol) of 2-bromo-9,10-diphenylanthracene, 2.9 g (18.7 mmol) of 4-chlorophenylboronic acid, and 0.20 g (0.17 mmol) of tetrakis(triphenylphosphine)palladium were dissolved into 50 mL of 1,2-dimethoxyethane. Then, 25 mL of a 2 M aqueous solution of sodium carbonate were added, and the whole was refluxed under heating for 8 hours in an argon atmosphere. The resultant was stood to cool. After the completion of the reaction, the resultant was filtered, and the resultant solid was washed with water, methanol, and toluene to obtain 4.8 g of 2,6-bis(4-chlorophenyl)-9,10-di(2-naphthyl)anthracene (86% yield).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](=[O:27])[C:5](=[N:10][NH:11][C:12]1[C:25]([F:26])=[CH:24][C:15]2[O:16][C:17]([F:23])([F:22])[C:18]([F:21])([F:20])[O:19][C:14]=2[CH:13]=1)[C:6]([O:8][CH3:9])=[O:7].[CH3:28]OC(OC)N(C)C>>[CH3:1][O:2][C:3]1[C:4](=[O:27])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[N:10][N:11]([C:12]2[C:25]([F:26])=[CH:24][C:15]3[O:16][C:17]([F:23])([F:22])[C:18]([F:21])([F:20])[O:19][C:14]=3[CH:13]=2)[CH:28]=1
Reactant: COCC(=O)C(=NNc1cc2c(cc1F)OC(F)(F)C(F)(F)O2)C(=O)OC
Reactant: COC(OC)N(C)C
Product: COC(=O)c1nn(-c2cc3c(cc2F)OC(F)(F)C(F)(F)O3)cc(OC)c1=O
Yield: 37 %

Procedure:
A mixture of methyl 4-methoxy-3-oxo-2-[(2,2,3,3,7-pentafluoro-2,3-dihydro-1,4-benzodioxin-6-yl)hydrazono]butanoate (6.84 g, 17.2 mmol) in N,N-dimethylformamide dimethyl acetal (68 mL) was heated to reflux for 2.5 h. The mixture was concentrated in vacuo, diluted with brine, extracted with EtOAc, dried over MgSO4, filtered, concentrated in vacuo and purified by column chromatography on silica gel (hexane/EtOAc=50/50 to 0/100 and EtOAc/MeOH=100/0 to 70/30) and on basic silica gel (hexane/EtOAc=80/20 to 0/100 and EtOAc/MeOH=100/0 to 70/30) to yield the title compound (2.58 g, 37% yield) as a pale yellow solid: 1H NMR (DMSO-d6, 300 MHz): δ ppm 3.79 (3H, s), 3.83 (3H, s), 8.01 (1H, d, J=10.2 Hz), 8.16 (1H, d, J=7.2 Hz), 8.58 (1H, s).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:20])[CH2:9][C:10]#[C:11][C:12]1[S:13][CH:14]=[C:15]([C:17]([OH:19])=O)[N:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.C[NH3+].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.[CH3:63][NH:64][C@H:65]1[C:74]2[C:69](=[CH:70][CH:71]=[CH:72][CH:73]=2)[CH2:68][CH2:67][CH2:66]1>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[N:8]([CH3:20])[CH2:9][C:10]#[C:11][C:12]1[S:13][CH:14]=[C:15]([C:17](=[O:19])[N:64]([CH3:63])[C@H:65]2[C:74]3[C:69](=[CH:70][CH:71]=[CH:72][CH:73]=3)[CH2:68][CH2:67][CH2:66]2)[N:16]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CN[C@@H]1CCCc2ccccc21
Reactant: CN(CC#Cc1nc(C(=O)O)cs1)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: C[NH3+]
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(CC#Cc1nc(C(=O)N(C)[C@@H]2CCCc3ccccc32)cs1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 61.3 %

Procedure:
To a solution of 2-[3-(tert-butoxycarbonyl-methyl-amino)-prop-1-ynyl]-thiazole-4-carboxylic acid (1.11 g, 3.75 mmol) in DMF (20 mL) was added diisopropylethylamine (1.93 mL, 11.3 mmol), followed by 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium (1.57 g, 4.13 mmol). After stirring 15 min at RT, (1R)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine (0.60 g, 3.75 mmol) was added to the reaction mixture. After stirring overnight at RT, solvent was evaporated and the resulting brown oil was dissolved in ethylacetate (30 mL), washed with saturated aqueous sodium bicarbonate solution (50 mL), 1M HCl solution (50 mL), and brine (50 mL). The organic layer was dried over sodium sulfate, filtered, and evaporated under reduced pressure. The crude mixture was purified by column chromatography on silica gel (ethylacetate/cyclohexane 2:8 to 3:7) to give methyl-{3-[4-((R)-methyl-1,2,3,4-tetrahydronaphthalen-1-yl-carbamoyl)-thiazol-2-yl]-prop-2-ynyl}-carbamic acid tert-butyl ester (1.01 g, 61%). 1H-NMR (400 MHz, CDCl3): δ=7.75 (s, 1H (conformers)), 7.03-6.92 (m, 4H), 5.58-5.46 (m, 1H (conformers)), 4.18-4.09 (br, 2H), 2.75 (s, 3H (conformers)), 2.61 (s, 3H), 2.11-1.63 (m, 6H), 1.33 (s, 9H (conformers)). MS: m/z=462 (M+23).
Reaction SMILES: N1C=CC=C[CH:2]=1.C([N:10]1[C:14]([NH2:15])=[N:13][C:12]([S:16]([NH:19][C:20]2[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:27])(=[O:18])=[O:17])=[N:11]1)(=O)C.[H-].[Na+].CI>CN(C)C=O>[NH2:15][C:14]1[NH:10][N:11]=[C:12]([S:16]([N:19]([C:20]2[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:27])[CH3:2])(=[O:18])=[O:17])[N:13]=1
Reactant: CC(=O)n1nc(S(=O)(=O)Nc2c(Cl)cccc2Cl)nc1N
Reactant: c1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN(c1c(Cl)cccc1Cl)S(=O)(=O)c1n[nH]c(N)n1
Reaction time: 0.5 h

Procedure:
9.80 g (22.8 mmol) of the pyridine salt of 1-acetyl-5-amino-N-(2,6-dichlorophenyl)-1,2,4-triazole-3-sulphonamide was dissolved in 300 ml dimethylformamide and 0.89 g (29.7 mmol) 80% sodium hydride added portionwise at room temperature. The mixture was stirred for a further 30 minutes and 1.7 ml (27.8 mmol) methyl iodide added. The mixture was allowed to stand overnight and concentrated. The residue was taken up in 2N aqueous sodium hydroxide and made slightly acidic by addition of 3N hydrochloric acid. The crystals were separated, washed with water and ether and recrystallised from acetonitrile.
Reaction SMILES: O=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([NH2:14])=[O:13])[CH:10]=2)[NH:5][C:4]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[N:3]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH3:48][C:49]1[C:57]([CH3:58])=[CH:56][C:52]2[NH:53][CH:54]=[N:55][C:51]=2[CH:50]=1>CN(C=O)C>[CH3:48][C:49]1[C:57]([CH3:58])=[CH:56][C:52]2[N:53]([C:2]3[C:11]4[C:6](=[CH:7][CH:8]=[C:9]([C:12]([NH2:14])=[O:13])[CH:10]=4)[N:5]=[C:4]([C:15]4[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=4)[N:3]=3)[CH:54]=[N:55][C:51]=2[CH:50]=1
Reactant: Cc1cc2nc[nH]c2cc1C
Reactant: NC(=O)c1ccc2[nH]c(-c3cccnc3)nc(=O)c2c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: Cc1cc2ncn(-c3nc(-c4cccnc4)nc4ccc(C(N)=O)cc34)c2cc1C
Yield: 17.7 %

Procedure:
To a suspension of 4-oxo-2-(pyridin-3-yl)-1,4-dihydroquinazoline-6-carboxamide (prepared as described in scheme 4) (100 mg, 0.376 mmol, 1.0 eq.) in dry DMF (20 mL) was added benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (216 mg, 0.488 mmol, 1.3 eq.) and diaza(1,3)bicyclo[5.4.0]undecene (114.5 mg, 0.752 mmol, 2.0 eq.) following a procedure outlined in J. Org. Chem., 2007, 72, 1019440210. To the clear solution was then added 5,6-dimethyl-1H-benzo[d]imidazole (165.2 mg, 1.13 mmol, 3.0 eq.) and the mixture was stirred overnight at room temperature. The resultant precipitate was then collected by filtration and washed with dichloromethane, water, and ether. The product was dried in vacuo to give 26.3 mg of the desired product: (xlviii-a) as an off-white solid (6.7%). LCMS m/z=395.1 (M+1) (Method C) (retention time=1.68 min). 1H NMR (300 MHz, DMSO) δ 9.69 (s, 1H), 8.90 (s, 1H), 8.82 (d, J=15.2 Hz, 2H), 8.66 (s, 1H), 8.54 (d, j=8.6 Hz, 1H), 8.42 (s, 1H), 8.30 (d, J=8.5 Hz, 1H), 7.79 (s, 1H), 7.68 (s, 3H), 2.39 (s, 3H), 2.36 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].C1C(=O)N([Br:18])C(=O)C1>C(Cl)Cl>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:18])=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9]
Reactant: CC(=O)c1ccccc1N
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CC(=O)c1cc(Br)ccc1N
Temperature: -10 °C

Procedure:
A flask charged with 1-(2-aminophenyl)ethanone (135 mg) and DCM (2.5 mL) was cooled to −10° C. and NBS (178 mg) was added in several portions over 30 min. The reaction mixture was diluted with 10 mL DCM, washed with sat. aqueous NaHCO3, dried over Na2SO4, filtered and concentrated under reduced pressure, affording the title compound. MS (ESI+): m/z 215.06 (MH+). 1H NMR (400 MHz, CDCl3): δ 7.79 (s, 1H), 7.31 (d, J=8.8 Hz, 1H), 6.54 (d, J=8.8 Hz, 1H), 6.30 (br, 2H), 2.55 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)=[O:21])=[CH:16][CH:15]=1.[CH:31]1([CH2:34]Br)[CH2:33][CH2:32]1>>[CH:31]1([CH2:34][N:22]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=2)[C:20]([C:17]2[CH:18]=[CH:19][C:14]([C:3]3[CH:4]=[C:5]([C:8]4[O:9][C:10]([CH3:13])=[N:11][N:12]=4)[CH:6]=[CH:7][C:2]=3[CH3:1])=[CH:15][CH:16]=2)=[O:21])[CH2:33][CH2:32]1
Reactant: BrCC1CC1
Reactant: Cc1ccc(CNC(=O)c2ccc(-c3cc(-c4nnc(C)o4)ccc3C)cc2)cc1
Product: Cc1ccc(CN(CC2CC2)C(=O)c2ccc(-c3cc(-c4nnc(C)o4)ccc3C)cc2)cc1

Procedure:
N-(Cyclopropylmethyl)-2′-methyl-N-(4-methylbenzyl)-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-N-(4-methylbenzyl)-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide and cyclopropylmethyl-bromide using method L. LCMS; retention time 3.85 min, MH+ 452.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].[NH2:7][CH2:8][CH2:9][OH:10]>>[OH:10][CH2:9][CH2:8][N:7]([CH2:3][CH2:2][C:1]([O:5][CH3:6])=[O:4])[CH2:3][CH2:2][C:1]([O:5][CH3:6])=[O:4]
Reactant: C=CC(=O)OC
Reactant: NCCO
Product: COC(=O)CCN(CCO)CCC(=O)OC
Reaction time: 20 h
Yield: 100.6 %

Procedure:
At 20 to 30° C., 15.5 g of methyl acrylate was added to 5.00 g of 2-aminoethanol. The resulting mixture was allowed to stand for 20 hours, followed by concentration under reduced pressure, whereby 19.2 g of N-(2-hydroxyethyl)bis[2-(methoxycarbonyl)ethyl]amine was obtained (at a quantitative yield)
Reaction SMILES: [C:1]([C:5]1[N:9]([CH3:10])[N:8]([CH2:11][CH:12]2[CH2:14][CH2:13]2)[C:7](=[NH:15])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[Br:18][C:19]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:20]=1[C:21](Cl)=[O:22]>O1CCCC1.O.C(OCC)(=O)C>[C:1]([C:5]1[N:9]([CH3:10])[N:8]([CH2:11][CH:12]2[CH2:13][CH2:14]2)/[C:7](=[N:15]/[C:21](=[O:22])[C:20]2[CH:24]=[C:25]([C:28]([F:29])([F:30])[F:31])[CH:26]=[CH:27][C:19]=2[Br:18])/[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1cc(C(F)(F)F)ccc1Br
Reactant: Cn1c(C(C)(C)C)cc(=N)n1CC1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Cn1c(C(C)(C)C)c/c(=N\C(=O)c2cc(C(F)(F)F)ccc2Br)n1CC1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.9 %

Procedure:
To a solution of Example 3E (3.52 g, 17 mmol) in tetrahydrofuran (20 mL) was added sodium hydroxide (2.72 g, 68 mmol) in water (5.00 mL), followed by addition of a solution of 2-bromo-5-(trifluoromethyl)benzoyl chloride (3.85 g, 17 mmol) in tetrahydrofuran (5 mL) dropwise at 0° C. The mixture was stirred at room temperature for 1 hour then diluted with water (20 mL) and ethyl acetate (30 mL). The layers were separated and the organic extract was washed with brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, eluted with a gradient of 15-100% hexane in solvent B, solvent B: 10:1:0.5 ethyl acetate:methanol:triethylamine) to afford the title compound (6.3 g, 93%). 1H NMR (300 MHz, DMSO-D6) δ ppm 0.41-0.52 (m, 4H) 1.13-1.27 (m, 1H) 1.40 (s, 9H) 3.94 (s, 3H) 4.20 (d, J=6.74 Hz, 2H) 6.83 (s, 1H) 7.54 (dd, J=8.53, 2.18 Hz, 1H) 7.77-7.82 (m, 2H); MS (ESI) m/z 458 [M+H]+.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[N:7]=[C:8]([CH2:13][N:14]2[CH2:19][CH2:18][N:17]([S:20]([C:23]3[S:27][C:26]4[CH:28]=[C:29]([Cl:32])[CH:30]=[CH:31][C:25]=4[CH:24]=3)(=[O:22])=[O:21])[CH2:16][C:15]2=[O:33])[S:9][C:10]=1[CH2:11][NH2:12])C>CCO>[Cl:32][C:29]1[CH:30]=[CH:31][C:25]2[CH:24]=[C:23]([S:20]([N:17]3[CH2:18][CH2:19][N:14]([CH2:13][C:8]4[S:9][C:10]5[CH2:11][NH:12][C:4](=[O:3])[CH2:5][C:6]=5[N:7]=4)[C:15](=[O:33])[CH2:16]3)(=[O:22])=[O:21])[S:27][C:26]=2[CH:28]=1
Reactant: CCOC(=O)Cc1nc(CN2CCN(S(=O)(=O)c3cc4ccc(Cl)cc4s3)CC2=O)sc1CN
Solvent: CCO
Product: O=C1Cc2nc(CN3CCN(S(=O)(=O)c4cc5ccc(Cl)cc5s4)CC3=O)sc2CN1

Procedure:
{5-Aminomethyl-2-[4-(6-chloro-benzo[b]thiophene-2-sulfonyl)-2-oxo-piperazin-1-ylmethyl]-thiazol-4-yl}-acetic acid ethyl ester (12 mg, 0.02 mmol) is heated in EtOH (3 mL) for 3 days at 70° C. The precipitate which is formed is filtered to provide 2-[4-(6-chloro-benzo[b]thiophene-2-sulfonyl)-2-oxo-piperazin-1-ylmethyl]-4,7-dihydro-5H-thiazolo[5,4-c]pyridin-6-one. 1H NMR (300 MHz, DMSO) δ8.31 (d, 1H), 8.08-8.02 (m, 2H), 7.55 (dd, 1H), 4.67 (s, 2H), 4.36 (s (broad), 2H), 3.84 (s, 2H), 3.60-3.54 (m, 4H), 3.38 (t, 2H); MS (LC/MS-ESI) 496 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:18]([C:25]1[S:29][C:28]([NH2:30])=[N:27][N:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.C(N(C(C)C)CC)(C)C>ClCCl.O.CN(C)C=O>[CH2:18]([C:25]1[S:29][C:28]([NH:30][C:13]([C:12]2[CH:11]=[CH:10][C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:17][CH:16]=2)=[O:15])=[N:27][N:26]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(=O)O)cc1
Reactant: Nc1nnc(Cc2ccccc2)s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc(C(=O)Nc2nnc(Cc3ccccc3)s2)cc1
Temperature: 60 °C
Reaction time: 42 h
Yield: 11.6 %

Procedure:
1 g of 4-tert-butoxycarbonylaminobenzoic acid (4.21 mmol, 1 eq.) is placed in 12 mL of a 5/1 mixture of dichloromethane and dimethylformamide with stirring. 0.81 g of 5-benzyl-1,3,4-thiadiazol-2-amine (4.21 mmol, 1 eq.), 0.97 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (5.05 mmol, 1.2 eq.), 0.97 g of hydroxybenzotriazole (6.32 mmol, 1.5 eq.) and 1.74 mL of diisopropylethylamine (10.52 mmol, 2.5 eq.) are successively added. After 42 hours at room temperature, the medium is heated at 60° C. for 6 hours. 0.40 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.1 mmol, 0.5 eq.) and 0.322 g of hydroxybenzotriazole (3.16 mmol, 0.5 eq.) are added. After 18 hours, the medium is diluted with dichloromethane and water. The organic phase is separated out by settling, washed with water, dried over magnesium sulfate, filtered and evaporated. The residue is chromatographed on silica gel with a gradient of ethyl acetate in heptane ranging from 0% to 50%. The organic phase is evaporated to give 0.2 g of tert-butyl [4-(5-benzyl[1.3.4]thiadiazol-2-ylcarbamoyl)phenyl]carbamate.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1)#[N:2].[CH3:11][C:12](=[O:17])[CH2:13][C:14](=[O:16])[CH3:15].C([O-])(=O)C.[NH4+]>CC(O)C>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[C:13]([C:12](=[O:17])[CH3:11])[C:14](=[O:16])[CH3:15])=[CH:5][CH:4]=1)#[N:2]
Reactant: CC(=O)CC(C)=O
Reactant: N#Cc1ccc(C=O)cc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(C)O
Product: CC(=O)C(=Cc1ccc(C#N)cc1)C(C)=O

Procedure:
4-Cyanobenzaldehyde (2.62 g) was condensed with 2,4-pentanedione (3.0 g) in 2-propanol (10 ml) in the presence of ammonium acetate. Mp 86°-88° C., yield 0.55 g (13 %).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].O=[C:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([OH:19])=O)=[CH:14][CH:15]=2)[C:10](=[O:20])[O:9]1.CO[C:23](OC)([CH3:25])[CH3:24].CC1(C)[C@]2(CS(O)(=O)=O)C(C[C@H]1CC2)=O>O1CCCC1.CN(C)C=O.[OH-].[Na+].CC(C)=O.O.C(OCC)(=O)C>[CH3:24][C:23]1([CH3:25])[O:20][CH2:10][C:11]2[CH:12]=[C:13]([CH2:17][OH:19])[CH:14]=[CH:15][C:16]=2[CH2:8][O:9]1
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Reactant: COC(C)(C)OC
Agent: CC1(C)[C@@H]2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Agent: [Al+3]
Agent: [H-]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(C)OCc2ccc(CO)cc2CO1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a suspension of 25.1 g (661 mM) of lithium aluminum hydride in 1300 ml of tetrahydrofuran was added 50.77 g (264.2 mM) of 1,3-dioxo-1,3-dihydroisobenzofuran-5-carboxylic acid (trimellitic anhydride) in small portions under ice-cooling and the mixture was stirred at room temperature for one day. To this reaction mixture was added ethyl acetate with ice-cooling to decompose the excess lithium aluminum hydride and water was added until a white precipitate had formed. The precipitate was filtered off with the aid of celite and the celite was washed with ethyl acetate and ethanol. The filtrate and washes were pooled and the solvent was distilled off under reduced pressure. The crude [2,4-bis(hydroxymethyl)-phenyl]methanol thus obtained was dissolved in 100 ml of N,N-dimethylformamide. Then, 100 ml of acetone, 70 ml of 2,2-dimethoxypropane, and 5 g of DL-10-camphorsulfonic acid were added and the mixture was stirred at room temperature overnight. This reaction mixture was diluted with aqueous solution of sodium hydroxide and extracted with 6 portions of ethyl acetate. The pooled organic solution was dried over MgSO4 and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/1 to 1/1) to provide the title compound.