Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][CH2:11][C:12]2[CH:13]=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:33])[C:30](O)=[O:31])=[CH:25][CH:24]=1.C(Cl)CCl>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([N:9]([CH2:10][CH2:11][C:12]2[CH:13]=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=2)[C:30](=[O:31])[C:29]([C:26]2[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=2)=[O:33])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(NCCc2ccc(C(F)(F)F)nc2)cc1C
Reactant: O=C(O)C(=O)c1ccc(F)cc1
Solvent: ClCCCl
Solvent: ClCCl
Product: Cc1ccc(N(CCc2ccc(C(F)(F)F)nc2)C(=O)C(=O)c2ccc(F)cc2)cc1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 70 %

Procedure:
To a solution of (3,4-dimethyl-phenyl)-[2-(6-trifluoromethyl-pyridin-3-yl)-ethyl]-amine (500 mg, 1.70 mmol, as described in example 1, step 3) in CH2Cl2 (15 mL) was added under a nitrogen atmosphere at 0° C. (4-fluoro-phenyl)-oxo-acetic acid (300 mg, 1.78 mmol, commercially available) and EDC (342 mg, 1.78 mmol). After stirring for 12 h a ambient temperature, the mixture was washed with aqueous Na2CO3 (saturated, 15 mL) and water (15 mL), the combined aqueous layers were extracted with CH2Cl2 (3×15 mL) and the combined organic layers dried over sodium sulfate. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=95:5 to 60:40) afforded the title compound (527 mg, 70%) as a light yellow oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]([CH:19]=O)=[C:9]([CH2:12][CH2:13][C:14]([O:16]CC)=[O:15])[C:10]=1[CH3:11])=[O:5])C.[CH3:21][O:22][C:23]1[CH:31]=[C:30]2[C:26]([CH2:27][C:28](=[O:32])[NH:29]2)=[CH:25][CH:24]=1.N1CCCCC1.[OH-].[K+]>C(O)C>[C:14]([CH2:13][CH2:12][C:9]1[C:10]([CH3:11])=[C:6]([C:4]([OH:3])=[O:5])[NH:7][C:8]=1[CH:19]=[C:27]1[C:26]2[C:30](=[CH:31][C:23]([O:22][CH3:21])=[CH:24][CH:25]=2)[NH:29][C:28]1=[O:32])([OH:16])=[O:15]
Reactant: CCOC(=O)CCc1c(C=O)[nH]c(C(=O)OCC)c1C
Reactant: COc1ccc2c(c1)NC(=O)C2
Agent: [K+]
Agent: [OH-]
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1ccc2c(c1)NC(=O)C2=Cc1[nH]c(C(=O)O)c(C)c1CCC(=O)O
Temperature: 95 °C
Yield: 96.6 %

Procedure:
5-Formyl-4-(2-ethoxycarbonylethyl)-3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (591 mg), 6-methoxy-2-oxindole (333 mg) and piperidine (0.1 mL) in ethanol (4 mL) were stirred at 90° C. for 2 hours. Potassium hydroxide (537 mg) was added to the mixture and it was then stirred at 95° C. for and additional hour. The reaction mixture was cooled and concentrated, dissolved in water, and acidified with 2 N hydrochloric acid to pH 2. The precipitate was filtered, washed with water, and dried in a vacuum oven overnight to give 730 mg (99%) of 4-(2-carboxyethyl)-3-methyl-5-(6-methoxy-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole-2-carboxylic acid.
Reaction SMILES: C([Li])CCC.CCCCCC.[CH3:12][C:13]1([CH3:34])[CH2:17][O:16][C:15]([C:18]2[CH:33]=[CH:32][C:21]([O:22][CH2:23][CH2:24][CH2:25][N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:20][CH:19]=2)=[N:14]1.[Br:35]Br.Cl>O1CCCC1>[Br:35][C:33]1[CH:32]=[C:21]([CH:20]=[CH:19][C:18]=1[C:15]1[O:16][CH2:17][C:13]([CH3:34])([CH3:12])[N:14]=1)[O:22][CH2:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: BrBr
Reactant: CC1(C)COC(c2ccc(OCCCN3CCCCC3)cc2)=N1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC1(C)COC(c2ccc(OCCCN3CCCCC3)cc2Br)=N1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A 2.1 M solution of n-butyllithium in hexane (580 μl, 2 eq, 1.28 mmol) is added dropwise to a solution of 1-{3-[4-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)phenoxy]propyl}piperidine 1 (200 mg, 0.64 mmol, 1 eq) in cold (0° C.) tetrahydrofuran (10 ml), and the resulting solution is stirred 4 hours at 0° C. Bromine (64 μL, 2 eq, 1.28 mmol) is then added and the mixture is left to stir at 22° C. overnight. The solution is then poured into 5 ml of 0.1 N aqueous hydrogen chloride and extracted with ether. The aqueous layer is then made basic (pH 10) with 5 N sodium hydroxide and extracted with dichloromethane. The chlorinated solution is then dried over magnesium sulfate, concentrated under reduced pressure. 1-{3-[3-bromo-4-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)phenoxy]propyl}piperidine 17 is separated from the remaining starting material by careful chromatography over silicagel (dichloromethane/methanol, gradient).
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([Br:13])=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[Br:14].C[N+]1([O-])CC[O:19]CC1>C(#N)C.[Cl-].[Na+].O>[Br:14][C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([Br:13])[C:3]=1[CH:2]=[O:19])[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Br)c(CBr)c(Br)c1
Reactant: C[N+]1([O-])CCOCC1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COC(=O)c1cc(Br)c(C=O)c(Br)c1
Temperature: 50 °C

Procedure:
Methyl 3,5-dibromo-4-(bromomethyl)benzoate (INTERMEDIATE 24) (3.9 g) was dissolved in acetonitrile (100 mL) and to this was added 4 Å molecular sieves and N-methylmorpholine N-oxide (1.18 g) and the reaction heated to 50° C. for 12 h. The reaction mixture was poured into brine and extracted into ethyl acetate, dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography eluting with 90% hexane:10% ethyl acetate to give the title compound. 1H NMR (500 MHz, CDCl3): δ 10.27 (s, 1H); 8.29 (s, 2H); 3.99 (s, 3H).
Reaction SMILES: C([O:5][C:6](=[O:23])[CH:7]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[OH:22])[NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])CCC>C(Cl)Cl.O>[C:12]([O:11][C:9]([NH:8][CH:7]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[OH:22])[C:6]([OH:23])=[O:5])=[O:10])([CH3:15])([CH3:13])[CH3:14]
Reactant: CCCCOC(=O)C(NC(=O)OC(C)(C)C)c1ccccc1O
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(C(=O)O)c1ccccc1O

Procedure:
Similarly, N-t-butoxycarbonyl-2-(2-hydroxyphenyl)glycine n-butyl ester was hydrolyzed to give N-t-butoxycarbonyl-2-(2-hydroxyphenyl)glycine, m.p. 125° (methylene chloride-water).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([CH2:31][C:32]2[S:33][C:34](Br)=[CH:35][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2].[CH:38]([C:40]1[CH:41]=[C:42](B(O)O)[CH:43]=[CH:44][CH:45]=1)=[O:39]>>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([CH2:31][C:32]2[S:33][C:34]([C:44]3[CH:43]=[CH:42][CH:41]=[C:40]([CH:38]=[O:39])[CH:45]=3)=[CH:35][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2]
Reactant: O=Cc1cccc(B(O)O)c1
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(Br)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(-c4cccc(C=O)c4)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5bromo-2-thienylmethyl)-4-chlorobenzene 71 obtained in Example 128-(4) and 3-formylphenylboronic acid were treated in a manner similar to Example 168-(1) to give 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(3-formylphenyl)-2-thienylmethyl)benzene as a colorless solid. APCI-Mass m/Z 660/662 (M+NH4).
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH:24]=[CH:25][C@H:26]4[CH2:31][CH2:30][C@H:29]([CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:28][CH2:27]4)=[CH:20][CH:19]=3)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[H][H]>C1(C)C=CC=CC=1.C(O)C.[Pd]>[CH2:1]([C@H:6]1[CH2:7][CH2:8][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C@H:26]4[CH2:31][CH2:30][C@H:29]([CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:28][CH2:27]4)=[CH:20][CH:19]=3)=[CH:14][CH:13]=2)[CH2:10][CH2:11]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCC[C@H]1CC[C@H](C=Cc2ccc(-c3ccc([C@H]4CC[C@H](CCCCC)CC4)cc3)cc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCCC[C@H]1CC[C@H](CCc2ccc(-c3ccc([C@H]4CC[C@H](CCCCC)CC4)cc3)cc2)CC1

Procedure:
2.20 g of 4-(trans-4-pentylcyclohexyl)-4'-[2-(trans-4-pentylcyclohexyl)vinyl]biphenyl were suspended in toluene/ethanol (3:2) in a sulphonation flask, treated with 200 mg of palladium/carbon (10%) and hydrogenated at normal pressure and 50° C. until the hydrogen uptake came to a standstill. Filtration of the mixture and concentration of the filtrate gave a white semi-crystalline residue which, after recrystallization from 100 ml of hexane, yielded 1.55 g of 4-(trans-4-pentylcyclohexyl)-4'-[2-(trans-4-pentylcyclohexyl)ethyl]biphenyl as colourless needles; transition (presumably S-S) 219.5° C., transition S-N 243.2° C., cl.p. (N-I) 256.1° C. This substance was found to be very strongly super-coolable; upon cooling to room temperature it still did not crystallize. Rf-value (hexane): 0.32.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[N:6][CH:7]=1.[CH3:15][N:16]([CH:18]=O)[CH3:17].COC(OC)N(C)C>CCOC(C)=O>[CH3:15][N:16]([CH3:18])/[CH:17]=[CH:1]/[C:2]1[N:3]=[CH:4][C:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[N:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: Cc1cnc(C(=O)OC(C)(C)C)cn1
Agent: COC(OC)N(C)C
Solvent: CCOC(C)=O
Product: CN(C)/C=C/c1cnc(C(=O)OC(C)(C)C)cn1
Temperature: 130 °C
Reaction time: 5 h

Procedure:
A mixture of t-butyl 5-methylpyrazine-2-carboxylate (1.35 g), DMF (25 mL) and N,N-dimethylformamide dimethylacetal (25 mL) was stirred at 130° C. for 5 h. The reaction solution was cooled to RT and diluted with EtOAc. The mixture was washed with a saturated NaCl solution three times. The organic layer was dried over anhydrous MgSO4, and the insoluble matter was separated by filtration. The filtrate was concentrated and the residue was purified by silica gel column chromatography to obtain the title compound (648 mg). 1H-NMR (CDCl3) δ (ppm): 1.63 (s, 9H), 3.00 (s, 6H), 5.16 (d, J=12.8 Hz, 1H), 7.72 (d, J=12.8 Hz, 1 H), 8.16 (d, J=1.2 Hz, 1H), 8.81 (d, J=1.6 Hz, 1H).
Reaction SMILES: [C:1]([N:5]1[CH2:31][CH2:30][CH2:29][C:8]2[C:9](Br)=[C:10]3[C:19]4[CH:18]=[C:17]([C:20]5[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=5)[C:16]([O:26][CH3:27])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:32])([CH3:4])([CH3:3])[CH3:2].[N:33]1[CH:38]=[CH:37][CH:36]=[C:35](B(O)O)[CH:34]=1.C([O-])([O-])=O.[K+].[K+]>C(COC)OC.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>[C:1]([N:5]1[CH2:31][CH2:30][CH2:29][C:8]2[C:9]([C:35]3[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=3)=[C:10]3[C:19]4[CH:18]=[C:17]([C:20]5[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=5)[C:16]([O:26][CH3:27])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:32])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1cccnc1
Reactant: COc1cc2c(cc1-c1cccnc1)-c1c(Br)c3c(n1CC2)C(=O)N(C(C)(C)C)CCC3
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: [K+]
Solvent: O
Solvent: COCCOC
Product: COc1cc2c(cc1-c1cccnc1)-c1c(-c3cccnc3)c3c(n1CC2)C(=O)N(C(C)(C)C)CCC3
Temperature: 90 °C
Yield: 69.1 %

Procedure:
A mixture of 45 mg of 13d, 20 mg of pyridine-3-boronic acid, 30 mg of K2CO3 and 10 mg of Pd(PPh3)4 in 2 ml of degassed dimethoxyethane was heated at 90° C., for 16 hr. The reaction mixture was cooled, diluted with water and the product was extracted with ethyl acetate. The extract was washed once with 2N KOH and once with water, dried and concentrated. The residue was purified by chromatography over silica gel, using a gradient of toluene/acetone as eluent. The isolated product was triturated with diethyl ether, to provide 31 mg of 13e as white, crystalline material; Mp 310-312° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]2[CH:10]([O:11]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[O:22])=[CH:17][CH:16]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]([OH:11])[CH:12]([N:26]2[CH2:25][CH2:24][N:23]([C:21](=[O:22])[C:18]3[CH:17]=[CH:16][C:15]([Cl:14])=[CH:20][CH:19]=3)[CH2:28][CH2:27]2)[CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CC2OC2C1
Reactant: O=C(c1ccc(Cl)cc1)N1CCNCC1
Product: CC(C)(C)OC(=O)N1CC(O)C(N2CCN(C(=O)c3ccc(Cl)cc3)CC2)C1
Temperature: 130 °C
Yield: 84.2 %

Procedure:
This is an example of Procedure A in Scheme 1 above. 6-Oxa-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (1.85 g 1 eq) and (4-Chloro-phenyl)-piperazin-1-yl-methanone (2.2 g 1 eq) were added into a sealed tube. The mixture was heated to 130° C. for 5 h. The resulting oil was purified by column chromatography (EtOAc:MeOH:Et3N 10:1:0.01) to give 3.38 g of desired product as a sticky oil (84% yield). 1H-NMR (300 MHz, DMSO): δ 1.43 (s, 9 H), 2.40-2.80 (m, 4 H), 3.15-3.85 (m, 9 H), 4.26-4.30 (m, 1 H), 7.35 (d, 2 H), 7.38 (d, 2 H) Retention Time (LC, method: Formic acid polar): 1.19 min. MS (M+H+): 410
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[CH:10]=[N:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)=[N:13][CH:14]=2)[NH2:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.F[C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][N:27]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH:1]1([CH:7]([NH:8][C:26]2[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][N:27]=2)[C:9]2[CH:14]=[N:13][C:12]([C:15]3[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=3)=[N:11][CH:10]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: NC(c1cnc(-c2ccc(C(F)(F)F)cc2)nc1)C1CCCCC1
Reactant: COC(=O)c1ccc(F)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(NC(c2cnc(-c3ccc(C(F)(F)F)cc3)nc2)C2CCCCC2)nc1
Temperature: 120 °C
Yield: 85.4 %

Procedure:
A mixture of crude (+/−)-1-cyclohexyl-1-{2-[4-(trifluoromethyl)phenyl]pyrimidin-5-yl}methanamine (405 mg, 1.21 mmol), methyl 6-fluoronicotinate (225 mg, 1.45 mmol), and potassium carbonate (501 mg, 3.62 mmol) in N,N-dimethylformamide (4.2 ml) was heated to 120° C. for 12 hours. The reaction mixture was diluted with water to precipitate a crude solid that was collected by filtration. The crude material was purified via ISCO MPLC (SiO2, 0-50% ethyl acetate in heptane) to yield the product (0.486 g, 86%) as a solid. 1H NMR (400 MHz, CDCl3, δ): 8.78 (s, 2H), 8.70 (d, J=1.6 Hz, 1H), 8.55 (d, J=8.2 Hz, 2H), 7.94 (dd, J=8.8, 2.0 Hz, 1H), 7.74 (d, J=8.2 Hz, 2H), 6.31 (d, J=8.8 Hz, 1H), 5.38 (d, J=7.0 Hz, 1H), 4.76 (t, J=6.9 Hz, 1H), 3.84 (s, 3H), 1.97 (d, J=12.5 Hz, 1H), 1.59-1.88 (m, 5H), 1.04-1.34 (m, 5H). MS (M+1): 471.2.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[OH:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1>>[F:15][C:14]([F:17])([F:16])[C:12]1[CH:11]=[C:10]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)[N:9]=[C:8]([C:4]2[CH:3]=[C:2]([C:33]3[CH:34]=[CH:35][C:30]([CH2:29][OH:28])=[CH:31][CH:32]=3)[CH:7]=[CH:6][CH:5]=2)[N:13]=1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(-c3cccc(Br)c3)n2)cc1
Reactant: OCc1ccc(B(O)O)cc1
Product: OCc1ccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)c2)cc1

Procedure:
The title compound was prepared from 2-(3-bromo-phenyl)-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (example E.3) (0.22 g, 0.5 mmol) and commercially available 4-hydroxymethyl-phenyl-boronic acid (0.09 g, 0.6 mmol) according to the general procedure VI. Obtained as a white solid (0.199 g, 54%). MS (ISP) 475.1 [(M+H)+]; mp 171° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[O:11][CH2:10][CH:9]([CH2:13][NH2:14])[O:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl[CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:29]=[C:28]2[C:23]([CH:24]=[CH:25][C:26](=[O:30])[O:27]2)=[CH:22][CH:21]=1.C(N(C(C)C)CC)(C)C.[I-].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3]1[C:12]2[O:11][CH2:10][CH:9]([CH2:13][NH:14][CH2:16][CH2:17][CH2:18][O:19][C:20]3[CH:21]=[CH:22][C:23]4[CH:24]=[CH:25][C:26](=[O:30])[O:27][C:28]=4[CH:29]=3)[O:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: O=c1ccc2ccc(OCCCCl)cc2o1
Reactant: COc1cccc2c1OCC(CN)O2
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc2c1OCC(CNCCCOc1ccc3ccc(=O)oc3c1)O2
Yield: 24.4 %

Procedure:
2,3-Dihydro-5-methoxy-1,4-benzodioxin-2-methanamine (1.29 g, 6.61 mmole), 7-(3-chloropropoxy)coumarin (1.59 g, 6.7 mmole), diisopropylethylamine (2.5 ml, 14.35 mmole) and sodium iodide (4.96 g, 33.1 mmole) were combined in 75 ml of DMF and heated at 80°-100° C. for 3 days under a nitrogen atmosphere. The solvent was then removed and replaced with dichloromethane. The mixture was washed with an equal volume of saturated aqueous sodium bicarbonate, with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered, and concentrated in vacuum. The residue was column chromatographed on silica gel using 30% ethyl acetate/dichloromethane as eluant. The product-containing fractions (Rf=0.25 on silica gel tlc with 2.5% methanol/dichloromethane) were combined and concentrated in vacuum and the residue (0.68 g) redissolved in dichloromethane and boiled on a hot plate, the dichloromethane gradually being replaced with isopropanol. 2N HCl/isopropanol (4 ml) was added and the title compound was collected by filtration and dried in vacuum at 80° C. The procedure yielded 0.64 g of white solid, monohydrochloride, m.p. 202°-204° C.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.CN(C1CCCCC1)C.Cl.[CH3:25][CH:26]([NH2:30])[CH:27]([CH3:29])[CH3:28].[Cl:31][C:32]1[CH:33]=[CH:34][C:35]2[S:40](=[O:42])(=[O:41])[NH:39][C:38](=O)[NH:37][C:36]=2[CH:44]=1>O>[Cl:31][C:32]1[CH:33]=[CH:34][C:35]2[S:40](=[O:42])(=[O:41])[N:39]=[C:38]([NH:30][CH:26]([CH3:25])[CH:27]([CH3:29])[CH3:28])[NH:37][C:36]=2[CH:44]=1
Reactant: CC(C)C(C)N
Reactant: O=C1Nc2cc(Cl)ccc2S(=O)(=O)N1
Agent: Cl
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O
Solvent: CN(C)C1CCCCC1
Product: CC(C)C(C)NC1=NS(=O)(=O)c2ccc(Cl)cc2N1
Temperature: 195 °C
Reaction time: 0.25 h
Yield: 37.4 %

Procedure:
Phosphorus pentoxide (7.55 g, 53.2 mmol), N,N-dimethylcyclohexylamine (17 ml, 113 mmol) and 1,2-dimethylpropylamine hydrochloride (12.4 g, 100.4 mmol) were carefully mixed and heated with mechanical stirring on an oil bath at 190-200° C. for about 15 min. To the homogeneous mass was added 6-chloro-3,4-dihydro-3-oxo-1,2,4-benzothiadiazine 1,1-dioxide (5.84 g, 25.1 mmol) and the mixture was stirred at 235° C. for 2 h. After cooling to about 100° C., water (200 ml) was added and the dark mixture was hydrolysed by stirring over night at room temperature. The precipitate was isolated by filtration and recrystallised from ethanol with decolorising charcoal to give 2,83 g (37%) of the pure title compound; m.p. (DSC) 264.7° C.; 1H-NMR (DMSO-d6): δ 0.90 (dd, 6H, CH(CH3)2), 1.09 (d, 3H, NCHCH3), 1.76 (m, 1H, CH(CH3)2), 3.70 (m, 1H, NHCH), 7.15 (br., 1H, NH), 7.28 (m, 2H, ArH), 7.68 (d, 1H, ArH), 10.3 (br.s, 1H, NH); (C12H16N3Cl1O2S1) calc. C, 47.76; H, 5.34; N 13.92; found C, 47.66; H, 5.47; N, 13.91.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:21][CH:20]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:29][C:30]1[C:31]([F:43])=[C:32]([CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=1)[C:33](O)=[O:34]>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][N:17]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:21][CH:20]=2)[C:33](=[O:34])[C:32]2[CH:36]=[C:37]([C:39]([F:40])([F:41])[F:42])[CH:38]=[C:30]([Cl:29])[C:31]=2[F:43])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)c1ccc(CNCCc2cccc(OCc3ccccc3)c2)cc1
Reactant: O=C(O)c1cc(C(F)(F)F)cc(Cl)c1F
Product: CC(C)(C)c1ccc(CN(CCc2cccc(OCc3ccccc3)c2)C(=O)c2cc(C(F)(F)F)cc(Cl)c2F)cc1

Procedure:
The title compound was prepared in analogy to Example 1, using [2-(3-benzyloxy-phenyl)-ethyl]-(4-tert-butyl-benzyl)-amine (S9-C43) and 3-chloro-2-fluoro-5-(trifluoromethyl)benzoic acid. MS: 597.3 [ISP (M+H)+].
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10](=[O:38])[C@H:11]([N:14]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]2[O:35][CH2:36][O:37][C:31]=2[CH:30]=1)[S:15]([C:18]1[C:23]([CH3:24])=[CH:22][C:21]([O:25][CH3:26])=[CH:20][C:19]=1[CH3:27])(=[O:17])=[O:16])[CH2:12][OH:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:39](OC(=O)C)(=[O:41])[CH3:40]>N1C=CC=CC=1>[CH2:1]([O:8][NH:9][C:10](=[O:38])[C@H:11]([N:14]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]2[O:35][CH2:36][O:37][C:31]=2[CH:30]=1)[S:15]([C:18]1[C:23]([CH3:24])=[CH:22][C:21]([O:25][CH3:26])=[CH:20][C:19]=1[CH3:27])(=[O:17])=[O:16])[CH2:12][O:13][C:39](=[O:41])[CH3:40])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(C)c(S(=O)(=O)N(Cc2ccc3c(c2)OCO3)[C@H](CO)C(=O)NOCc2ccccc2)c(C)c1
Solvent: c1ccncc1
Product: COc1cc(C)c(S(=O)(=O)N(Cc2ccc3c(c2)OCO3)[C@H](COC(C)=O)C(=O)NOCc2ccccc2)c(C)c1
Temperature: 25 °C

Procedure:
To a solution of N-benzyloxy-2(R)-[(3,4-methylenedioxybenzyl)-(4-methoxy-2,6-dimethylbenzenesulfonyl)amino]-3-hydroxypropionamide (450 mg, 0.82 mmol) in pyridine (2 mL) at 0° C. was added acetic anhydride (0.09 mL, 0.98 mmol). The reaction mixture was allowed to warm to room temperature over 12 h and then partitioned between 2 N aqueous hydrochloric acid and methylene chloride (100 mL). The methylene chloride layer was separated, dried over magnesium sulfate, and concentrated. Purification of the residue by preparative TLC (30% ethyl acetate-hexanes) gave N-benzyloxy-2(R)-[(3,4-methylenedioxy-benzyl)-(4-methoxy-2,6-dimethylbenzenesulfonyl)amino]-3-acetoxypropionamide.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[CH:8]=[C:9](N)[CH:10]=1)=[O:4].N(OCCC(C)C)=O.[I:27]CI>N1CCCCC1.CC#N>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[CH:8]=[C:9]([I:27])[CH:10]=1)=[O:4]
Reactant: ICI
Reactant: COC(=O)c1cc(N)cc(-c2ccc(C)cc2)c1
Agent: CC(C)CCON=O
Solvent: CC#N
Solvent: C1CCNCC1
Product: COC(=O)c1cc(I)cc(-c2ccc(C)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
A mixture of 5-amino-4′-methyl-biphenyl-3-carboxylic acid methyl ester (10.9 g, 45.2 mmol), iso-amyl nitrite (36.5 ml, 271.4 mmol) and diiodomethane (23 ml, 271.4 mmol) was stirred at room temperature for 1 hour. The mixture was then heated to 65° C. and kept at this temperature for 8 hours. The reaction mixture to room temperature and then added to a stirred solution of piperidine/CH3CN (V:V=90 ml: 90 ml). A vigorous exothermic reaction ensued. The excess volatile reagents were removed by rotary evaporation. The residue was diluted with ethyl acetate, washed with 10% hydrochloric acid, water, brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography, eluting with n-hexane, followed by n-hexane/ethyl acetate (20:1), giving 5-Iodo-4′-methyl-biphenyl-3-carboxylic acid methyl ester as white yellow solid (10.5 g, 66%).